SNPMiner Trials by Shray Alag


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Report for Mutation L858R

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 298 clinical trials

Clinical Trials


1 A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Single-agent Tarceva® (Erlotinib) Following Complete Tumor Resection With or Without Adjuvant Chemotherapy in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma Who Have EGFR-positive Tumors

This is a study to evaluate the effectiveness of erlotinib compared with a placebo sugar pill following complete surgical removal of the tumor with or without chemotherapy after surgery in Stage IB-IIIA NSCLC patients.

NCT00373425 Non-small Cell Lung Cancer Drug: Erlotinib Drug: Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Disease-free Survival in Participants With EGFR Mutation - Positive Tumors. --- L858R ---

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Overall Survival in Participants With EGFR Mutation - Positive Tumors. --- L858R ---

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Number of Participants With Adverse Events (AEs). --- L858R ---

Primary Outcomes

Description: DFS is the time from the date of randomization until the first day non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

Measure: Disease Free Survival (DFS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: DFS is the time from the date of randomization until the first day that non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

Measure: Disease Free Survival (DFS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cutoff date of 11 June 2014 (maximum time on follow-up was 78 months).

Secondary Outcomes

Description: Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

Measure: Overall Survival (OS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

Measure: Overall Survival (OS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Description: Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Disease-free Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Disease-free Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Description: Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Overall Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months)

Description: Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Overall Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months)

Description: An AE was defined as any untoward medical occurrence in a study participant and did not necessarily have a causal relationship with study treatment. An AE was considered serious if it resulted in death, a life-threatening situation, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant, other important medical events, or is on the Astellas Always Serious List. A drug-related AE was any AE with at least a possible relationship to study treatment as assessed by the investigator. Severity was graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0, where Grade 1=Mild AE; Grade=2 Moderate AE; Grade 3=Severe AE; Grade 4=Life-threatening or disabling; Grade 5=Death related to AE. AEs leading to death include deaths that occurred more than 30 days after the last dose of study drug.

Measure: Number of Participants With Adverse Events (AEs)

Time: From the date of first dose of study drug until 30 days after the last dose. The median time on treatment was 11.9 months for erlotinib and 21.9 months for placebo. Data are based off the 11 June 2014 data cut-off date.

2 A Phase 1, Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Daily Oral Administration of AV-412 in Patients With Refractory or Relapsed Solid Tumor Malignancies

AV-412 is a new oral therapy developed to inhibit the growth of solid tumors in patients who have not responded to standard therapy or surgical interventions, or who have experienced relapse. This study will test the safety of AV-412 and determine the maximum tolerated dose for the treatment of solid tumors.

NCT00381654 Tumor Drug: AV-412
MeSH:Neoplasms
HPO:Neoplasm

Criteria for Inclusion: 1. ≥ 18 year old males or females 2. Documented measurable or evaluable solid tumor malignancy that is relapsed, refractory, locally advanced, or metastatic 3. Patients entered to MTD Cohort B must have: - Histologically or cytologically confirmed NSCLC - No prior therapy with erlotinib, gefitinib, or any other EGFR-kinase inhibitor - Previously documented exon 19 deletion and/or exon 21 L858R mutations - Measurable disease according to RECIST 4. Disease that is currently refractory to, or not amenable to, standard therapy 5. Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor 6. Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months 7. --- L858R ---

Inability to comply with protocol requirements Criteria for Inclusion: 1. ≥ 18 year old males or females 2. Documented measurable or evaluable solid tumor malignancy that is relapsed, refractory, locally advanced, or metastatic 3. Patients entered to MTD Cohort B must have: - Histologically or cytologically confirmed NSCLC - No prior therapy with erlotinib, gefitinib, or any other EGFR-kinase inhibitor - Previously documented exon 19 deletion and/or exon 21 L858R mutations - Measurable disease according to RECIST 4. Disease that is currently refractory to, or not amenable to, standard therapy 5. Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor 6. Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months 7. --- L858R ---

Primary Outcomes

Measure: To evaluate the safety, tolerability, and dose-limiting toxicities (DLT), and determine the maximum tolerated dose (MTD) of AV-412 when administered once daily by the oral route for 4 weeks (4 weeks equals one dosing cycle)

Time: one year

Secondary Outcomes

Measure: To characterize the pharmacokinetic (PK) profile of AV-412 in all patients. Extensive PK collection and assay to be performed in expanded MTD Cohorts

Time: 18 months

Measure: Evaluate potential pharmacodynamic (PD) markers of AV-412 action, in expanded MTD Cohorts ONLY

Time: two years

Measure: Preliminary evaluation of the antineoplastic activity of AV-412 (assessed by evidence and duration of disease stabilization or objective response, and time to disease progression)

Time: two years

3 Sequential Phase I/II Trial of Oral Vorinostat in Combination With Erlotinib in Non-small-cell Lung Cancer Patients With Mutations at Epidermal Growth Factor Receptor With Disease Progression After Erlotinib Treatment

This is an open label, non-randomized, sequential, phase I/II trial in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) with EGFR mutations after progression to Erlotinib. The study will have two parts. The first part (phase I) will be a dose finding (MTD) study to be implemented at three hospitals. The second part of the study (phase II) will asses the safety and efficacy of the combination. In this second part (phase II) patients will be treated with oral Erlotinib 150 mg P.O daily plus oral Vorinostat administered according to the results of the phase I. The study endpoints to be evaluated will include safety and response rate (RR) as primary endpoints and clinical benefit rate (CBR), time to progression, time to response, response duration and progression free survival as secondary endpoints. All the patients (phase I and II) will be treated until progression disease, unacceptable toxicity or withdrawal of the consent, and will be treated at the discretion of the principal investigator.

NCT00503971 Non-small Cell Lung Cancer Drug: Vorinostat plus Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21 (Exon 19 mutations characterized by in-frame deletions (747-750), and Exon 21 mutations resulting in L858R substitutions). --- L858R ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Time: First cycle

Secondary Outcomes

Measure: Efficacy: Objective response rate; Time to progression; Time to response Response duration;Progression free survival;Clinical Benefict Rate

Time: Along the study

Measure: Exploratory Endpoints: Molecular analysis (EGFR mutations; thioredoxin; Hsp70; methylation of 14-3-3 sigma and CHFR, EGFR mutation at serum (in blood samples from patients)

Time: baseline, after cycle 3 and at the end of treatment

4 A Phase II Trial of Adjuvant Erlotinib in Patients With Resected, Early Stage Non-Small Cell Lung Cancer (NSCLC) With Confirmed Mutations in the Epidermal Growth Factor Receptor (EGFR)

In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

NCT00567359 Non-small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The median amount of time measured from the time of registration until the time of disease recurrence or death.. Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R --- --- T790M --- --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung - Erlotinib is a pill taken daily and participants may continue to receive erlotinib for up to two years, as long as the cancer does not return and they do not experience any unacceptable side effects. --- L858R ---

Primary Outcomes

Description: The number of participants alive and free from disease recurrence 2 years after enrollment. Participants were monitored for disease recurrence with the use of surveillance radiographs. When possible and medically appropriate, tissue biopsies were obtained to prove recurrence.

Measure: 2-year Disease-free Survival

Time: 2 years

Secondary Outcomes

Description: Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 3.0) from the start of treatment until 30 days after the end of treatment. Serious adverse events were defined as adverse events that were grade 3 or greater and deemed to be possibly, probably or definitely related to the study treatment.

Measure: Number of Participants With Treat Related Serious Adverse Events

Time: From the start of treatment until 30 days after the end of treatment, up 13 months total

Description: The median amount of time from the time of registration until death due to any cause

Measure: Median Overall Survival

Time: From the time of registration until death, up to approximately 9 years

Description: The median amount of time measured from the time of registration until the time of disease recurrence or death.

Measure: Median Disease Free Survival

Time: From registration to disease recurrence or death, up to approximately 9 years

5 A Phase II Study of Erlotinib and Chemotherapy for Patients With Stage IB-IIIA NSCLC With EGFR Mutations (ECON)

The purpose of this study is to try to improve the odds that your cancer may be cured. Pemetrexed and cisplatin are traditional chemotherapy drugs that have been shown to help some patients with non-small cell lung cancer. Many different types of cancer cells, including your type of lung cancer, have a protein on their surface called the epidermal growth factor receptor (EGFR). Stimulation of these receptors can result in growth of cancer cells and progression of cancer. In addition, your cancer has an EGFR mutation (a specific abnormality in the genetic code for EGFR). Erlotinib (TarcevaTM) is a newer drug which has shown benefit for patients with lung cancers that contain an EGFR mutation. Erlotinib works by blocking this receptor and depriving the cancer cells of this message to grow and multiply. In this research study, we plan to combine erlotinib with traditional chemotherapy drugs to see if the combination works better than chemotherapy alone. The main purpose of this research is to find out the good and bad effects that the combination of these 3 drugs (pemetrexed, cisplatin and erlotinib) has when given to patients with early stage non-small cell lung cancer before surgery. A secondary purpose is to find out the good and bad effects that occur when erlotinib is given to patients after surgery for 2 years.

NCT00577707 Non Small Cell Lung Cancer Lung Cancer Drug: erlotinib Drug: Pemetrexed Drug: Cisplatin Procedure: Resection
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R ---

- Other serious illness or medical condition including unstable cardiac disease requiring treatment, history of significant neurologic or psychiatric disorders (including psychotic disorders, dementia, or seizures), or active uncontrolled infection - Women who are pregnant or breast-feeding - Psychiatric illness or social situation that would limit compliance with study requirements Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R ---

Primary Outcomes

Description: Complete Response (CR): Disappearance of all clinical evidence of tumor. Partial Response (PR): A 50% or greater decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Minor Response (MR): A > 25% and < 50% decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Stable Disease (SD): A less than 25% decrease. This includes a decrease of less than 25% in the sum of the products of the measured lesions, and any increase of less than 25% in the sum of the products of the measured lesions. There may be no appearance of new disease sites for this category. Progressive Disease (PD): A ≥25% increase in one or more lesions, or appearance of new lesions.

Measure: Number of Patients With Pathologic Complete Response Rate

Time: Patients will undergo a CT scan of chest every 3 months for year 1 and every 4 months for year 2. In years 3 and 4, a chest CT or chest x-ray every 6 months.

Secondary Outcomes

Measure: Number of Participants With Response After 21 Days of Single Agent Erlotinib for Stage IB-IIIA NSCLC With a Known EGFR Mutation

Time: calculate the response rate after 21 days of single agent erlotinib

Measure: Number of Patients With a Response Rate, 3-year Overall Survival and Median Survival of Patients With a Known EGFR Mutation Receiving Neoadjuvant Chemotherapy and Erlotinib (and Adjuvant Erlotinib).

Time: 3 years

6 Detection of Epithelial Growth Factor Receptor (EGFR) Mutation in Malignant Pleural Effusion of Lung Cancer Patients and Cancer Cell Lines Establishment

1. Detection EGFR mutation of cancer cells from malignant pleural effusion. 2. Established the cancer cell lines with without EGFR mutation from malignant pleural effusion.

NCT00752076 NSCLC Other: cancer cell lines establishment
MeSH:Pleural Effusion, Malignant Pleural Effusion
HPO:Pleural effusion

In-frame deletions in exon 19 centered on codons 756 to 750 make up 45~50% of mutations, and another 35~45% consist of the missense mutation leucine to arginine at codon 858 (L858R) in exon 21 (8, 9, 10). --- L858R ---

It is interesting that exon 19 deletion have increased response and survival with TKIs compared with L858R cases (10, 13, 14). --- L858R ---

This is in contrast to the natural history of patients, where those with exon 19 deletions appear to have shorter survival than those with L858R (8). --- L858R ---

Primary Outcomes

Measure: EGFR mutation in malignant pleural effusion of lung cancer patients cancer cell lines establishment

Time: 1 year

7 A Study to Assess the Efficacy of Erlotinib for Leptomeningeal Carcinomatosis in EGFR Mutation Positive Non-small Cell Lung Cancer

To assess the efficacy and safety of erlotinib for non-small cell lung cancer patients with leptomeningeal carcinomatosis

NCT00830245 Leptomeningeal Carcinomatosis Non-small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Carcinoma Meningeal Carcinomatosis
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Age >18 2. Histologically or pathologically proven non-small cell lung cancer (NSCLC) 3. Leptomeningeal carcinomatosis confirmed by CSF cytology 4. A patients with EGFR mutation (including exon 19 deletion, L858R) 5. ECOG performance status 0-3 6. Expected life time more than at least 4 weeks 7. --- L858R ---

A patient who refused to sign the informed consent Inclusion Criteria: 1. Age >18 2. Histologically or pathologically proven non-small cell lung cancer (NSCLC) 3. Leptomeningeal carcinomatosis confirmed by CSF cytology 4. A patients with EGFR mutation (including exon 19 deletion, L858R) 5. ECOG performance status 0-3 6. Expected life time more than at least 4 weeks 7. --- L858R ---

Primary Outcomes

Measure: Overall survival

Time: 1 year

Secondary Outcomes

Measure: Cytology negative conversion rate

Time: 1 month, 2 months, 3 months, 4 months

Measure: Neurologic symptom improvement

Time: 1 month, 2 months, 3 months, 4 months

Measure: Response rate (extra-cranial disease)

Time: 2 months, 4 months

Measure: Response rate (brain)

Time: 2 months, 4 months

Measure: Quality of life

Time: 1 month, 2 months, 3 months, 4 months

Measure: Toxicities

Time: 1 month, 2 months, 3 months, 4 months

Measure: Prognostic factors

Time: N-A

8 A Randomized, Open-label, Multi-center Phase III Study of Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage IIIB/IV Non-Small Cell Lung Cancer Patients With EGFR Exon 19 or 21 Mutation (Optimal)

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as erlotinib have proved effective in second or third line therapy for advanced non-small cell lung cancer(NSCLC).It is well tolerated without the side effects usually associated with chemotherapy. The mutations in EGFR exons 19 or 21 have been reported to be associated with efficacy of EGFR TKIs.Based on the encouraging preliminary results from the Spanish lung cancer group' prospective study reported that the efficacy of Tarceva as first line treatment for metastatic NSCLC patients with EGFR mutation would delay disease progression,prolong overall survival and be well tolerated, medium Progression-free survival(PFS) was around 12 months and OS reach 24 months,our study is designed to compare PFS between the patients with mutant EGFR treated by gemcitabine/carboplatin and those by erlotinib in the first-line setting. We assumed 11 months of PFS on Tarceva arm versus 6 months on chemotherapy arm with a=0.025(alpha-spend for an interim analysis), 80% power and 12 months enrolment period, 12 months FU duration to calculate the sample size. The sample size is 69 pairs. Considering about 10% drop-out rate, the final sample size is 152 patients.So, chemo-naive staged IIIb/IV patients with EGFR mutations in exon 19 or 21 will be enrolled into this open-label, randomized,multicenter phase III study.

NCT00874419 Non-small Cell Lung Cancer Drug: erlotinib Drug: gemcitabine/carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. EGFR exon19 deletions or exon 21 L858R mutation by the DNA direct PCR sequencing using fresh tumor sample or paraffin embed tumor sample. --- L858R ---

Primary Outcomes

Measure: Progression free survival

Time: 12 months

Secondary Outcomes

Measure: OS

Time: 24 months

Measure: ORR

Time: 24 months

Measure: Time to Progression

Time: 24 months

Measure: lung cancer symptoms and health-related quality of life (HRQoL)

Time: 24 months

Measure: explore the biological markers (tumor tissue)

Time: 24 months

9 Tailored Second Line Treatment by EGFR Mutation in Patients With Advanced Lung Adenocarcinoma

Currently the investigators have two different classes of second-line treatment options in recurrent non-small Cell Lung Cancer (NSCLC). In chemotherapy, docetaxel and pemetrexed produced similar treatment efficacy outcomes, while pemetrexed had a better tolerability. In recent analysis of pemetrexed clinical studies, a strong treatment-by-histology interaction in overall survival and progression free survival that indicated better efficacy for non-squamous patients treated with pemetrexed. These data supports that pemetrexed could be a preferable chemotherapy drug especially in adenocarcinoma NSCLC patients.

NCT00903292 Non-Small Cell Lung Cancer Drug: erlotinib (Tarceva) Drug: pemetrexed (Alimta)
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Since typical EGFR gene mutations (i.e., the deletion of typically five amino acids at codons 746-750 (ELREA) in exon 19 and a leucine-to-arginine mutation at codon 858 (L858R)) are a good predictor for tumor response to tyrosine kinase inhibitor, this present study is to tailor the patient's treatment according to his/her EGFR gene mutation status. --- L858R ---

Primary Outcomes

Measure: The primary analysis will be the overall best response rate, including a 95% confidence interval (Leemis and Trivedi 1996).

Time: 02/2009 - 04/2010

10 Phase II Randomized Assessing Pelvic Irradiation Combined With Cisplatin Alone or Cisplatin Plus Cetuximab in Patients With Carcinoma of the Cervix Stage IB2, II and III

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether radiation therapy given together with cisplatin is more effective with or without cetuximab in treating patients with cervical cancer. PURPOSE: This randomized phase II trial is studying giving radiation therapy together with cisplatin to see how well it works compared with radiation therapy and cisplatin given together with cetuximab in treating patients with stage IB, stage II, or stage IIIB cervical cancer.

NCT00957411 Cervical Cancer Biological: cetuximab Drug: cisplatin
MeSH:Uterine Cervical Neoplasms
HPO:Cervical polyp Cervix cancer

- Study the correlation between treatment response and analysis of EGFR mutations (exons 18-21 of the tyrosine kinase domain including the two hot spots L858R and E746-A750). --- L858R ---

Primary Outcomes

Measure: Recurrence-free survival at 2 years

Secondary Outcomes

Measure: Response as assessed by MRI after radiochemotherapy and before surgery according to RECIST criteria

Measure: Toxicity according to NCI CTCAE v3.0

11 Phase II Study of Erlotinib With or Without Hydroxychloroquine in Patients With Previously Untreated Advanced NSCLC and EGFR Mutations

The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.

NCT00977470 Non-small Cell Lung Cancer Drug: Erlotinib Drug: Hydroxychloroquine
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Specifically, patients harboring the most common mutations, deletions in exon 19 or the L858R mutation in exon 21 are eligible. --- L858R ---

Primary Outcomes

Description: A measure of progression-free survival in patients with advanced non small-cell lung cancer (NSCLC) and EGFR mutations treated with erlotinib as compared with patients treated with erlotinib plus hydroxychloroquine (HCQ). Disease progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, as seen on CT scan, or the appearance of one or more new lesions on CT scan.

Measure: Median Progression Free Survival

Time: From start of treatment until report of disease progression, assessed up to 10 years.

Description: This trial can detect a difference in proportions alive without progression at 9 months from 50% in the erlotinib arm to 77% in the erlotinib plus hydroxychloroquine (HCQ) arm, using an alpha of 0.15 and power of 85%, using the two-sided Likelihood Ratio test. Progression is defined as at least a 20% increase in the size of existing lesions or the appearance of one or more new lesions.

Measure: Nine-month Progression-free Survival Rate

Time: Nine months

Secondary Outcomes

Description: To evaluate the safety of treatment with erlotinib with and without hydroxychloroquine (HCQ). All participants receiving study treatment were evaluated for safety. Parameters included laboratory tests, hematological abnormalities, physical exam findings and spontaneous reports of adverse events reported by participants. Toxicities were evaluated and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = fatal.

Measure: Treatment Related Toxicity, > 10% Frequency, Any Grade

Time: 2 years

Description: Response is assessed via spiral CT scan, done at baseline and after every 2 cycles of study treatment. Standard RECIST (Response Evaluation Criteria in Solid Tumors) was used. Complete Response (CR) = disappearance of all target lesions; Partial Response (PR) = at least a 30% decrease in the size of target lesions, as compared to baseline; Progressive Disease (PD) = at least at 20% increase in the size of target lesions, or the appearance of one or more new lesions; Stable Disease (SD) = neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Response rate = CR + PR. Disease control rate = CR + PR + SD

Measure: Objective Tumor Response Rate Following Treatment With Erlotinib and With Erlotinib/HCQ.

Time: 2 years

Measure: Overall Survival of Patients Treated With Erlotinib and With Erlotinib/HCQ

Time: Until death

Other Outcomes

Description: Serial circulating tumor cell (CTC) analyses will be performed on peripheral blood and correlated with disease response.

Measure: Circulating Tumor Cell Quantification

Time: Until disease progression (median of 10.8 months)

Description: Correlation of molecular and genetic tumor characteristics with disease response. Genomic DNA will be extracted from tumor tissue and direct sequencing analysis will be performed to identify additional mutations.

Measure: EGFR Mutational Status

Time: 2 years

Description: [18F]-FMISO-PET/CT was performed on a 64-slice PET/CT scanner and tracer uptake was assessed using SUV (standardized uptake value), normalizing the radioactivity measured in tissue by the injected dose and the body weight of the patient. Mean and maximum SUV and threshold volume of FMISO uptake were measured to quantify the extent of hypoxia in the primary tumor. Imaging was performed before and after initiation of therapy with erlotinib.

Measure: Percent of Participants in Which FMISO-PET ([18F]-Fluoromisonidazole-positron Emission Tomography) is Able to Detect and Quantify Changes in Tumor Hypoxia After Erlotinib.

Time: 12 weeks

12 A Phase Ib Open-label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Cetuximab (Erbitux®) in Patients With Non-small Cell Lung Cancer With Progression Following Prior Erlotinib (Tarceva®) or Gefitinib (Iressa®)

The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.

NCT01090011 Carcinoma, Non-Small-Cell Lung Drug: Cetuximab Drug: Cetuximab Drug: BIBW 2992 Drug: BIBW 2992
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.. Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R ---

Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnancy or breast-feeding Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R ---

Primary Outcomes

Description: A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: CTCAE Grade 2 or higher decrease in cardiac left ventricular function CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days CTCAE Grade ≥3 rash despite standard medical management CTCAE Grade ≥3 fatigue lasting for more than 7 days CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.

Measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).

Time: from day 1 treatment until progression or undue toxicity, up to 28 days

Secondary Outcomes

Description: Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0

Measure: Highest CTCAE Grade

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Dose Reduction

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with adverse events leading to treatment discontinuation

Measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Death

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with drug-related serious adverse events

Measure: Frequency (%) of Patients With Related Serious Adverse Events

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy

Measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).

Measure: Concentration of Afatinib in Plasma for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.

Measure: Peak-trough Fluctuation (PTF)

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)

Measure: t1/2,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days

Measure: MRTpo,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)

Measure: CL/F,ss,15

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days

Measure: Vz/F,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.

Measure: Predose Plasma Concentrations of Afatinib for the Combination Arm

Time: Up to 57 days

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.

Measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.

Measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).

Measure: Duration of Objective Response (According to RECIST v1.1)

Time: up to 116 weeks

Description: Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.

Measure: Duration of Disease Control (According to RECIST v1.1)

Time: up to 116 weeks

Description: Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.

Measure: Progression-Free Survival (PFS) Time

Time: up to 116 weeks

13 Development of Circulating Tumour Cell Molecular Diagnostics Using a Novel Microfluidic Device

1. To compare EGFR mutations between primary non-small cell lung cancer (NSCLC) tumours and corresponding CTCs isolated by a label-free microfluidic device-based system 2. To characterize the association between clinical response in NSCLC patients treated with gefitinib and serial changes in CTC EGFR mutations detected by a label-free microfluidic device-based system The investigators recently developed a label-free, microfluidic device for capturing circulating tumour cells (CTCs) and acquired a Fluidigm Biomark digital PCR instrument for reliable low-level DNA quantification. The overall aim of this study is to test the feasibility of using these state-of-the-art devices to reliably detect clinically relevant EGFR mutations in CTCs.

NCT01193829 Patients With Non-small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

DNA will be extracted from the retrieved CTCs and tumour samples, and analyzed exon 19 deletion, L858R and T790M mutations by digital PCR on the Fluidigm Biomark according to methods described previously.23 --- L858R ---


14 A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors

Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.

NCT01259089 Adenocarcinoma of the Lung Non-small Cell Lung Cancer Drug: erlotinib hydrochloride Drug: Hsp90 inhibitor AUY922 Other: laboratory biomarker analysis Procedure: needle biopsy Genetic: mutation analysis Other: pharmacological study
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarci Adenocarcinoma of Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.. Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- T790M --- --- L858R ---

Gilbert's syndrome) Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- L858R ---

Primary Outcomes

Description: To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.

Measure: Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)

Time: During the first 4 weeks of treatment for each patient.

Description: Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions

Measure: Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922

Time: At 8 weeks from treatment initiation

Secondary Outcomes

Description: To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years

Description: Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Incidence of Reported Adverse Events in Phase I

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years

Description: Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Progression-free Survival (Phase II)

Time: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment

Description: Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.

Measure: Overall Survival (Phase II)

Time: From the time of first treatment with AUY922 to death, followed up to 2 years post treatment

Description: Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.

Measure: Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)

Time: From the time of first treatment with AUY922 to death, followed for up to 2 years

15 Phase II, Open-Label Study of Erlotinib (Tarceva®) Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Present Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor

This single arm, open-label study will evaluate the efficacy and safety of erlotinib (Tarceva) in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

NCT01260181 Non-Squamous Non-Small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.. Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator. --- L858R ---

Primary Outcomes

Description: Objective response (OR) was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of complete response (CR) and partial response (PR) four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response (Complete Response [CR]/Partial Response [PR]) Based on Computer Tomography (CT) or Magnetic Resonance Imaging (MRI) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

Secondary Outcomes

Description: Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Patients who had not died or progressed at the time of the final analysis were censored at the date of last contact.

Measure: Progression Free Survival (PFS) Based on CT or MRI According to RECIST v 1.1

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

Description: Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.

Measure: Overall Survival

Time: Baseline up to 5 years

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Measure: Percentage of Participants With Adverse Events

Time: Baseline up to 5 years

Description: Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.

Measure: Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Mutation in Study Population

Time: Screening (21 days prior to Day 1)

Description: The response duration was defined as the time of initial response (complete response (CR) /partial response (PR) whichever is first recorded) until documented disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression was defined as At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

Measure: Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

16 A Randomized Phase III Study of TaxoteRe Plus Cisplatin Versus AlImta Plus Cisplatin in 1st Line Non-squamous Cell Type Lung Cancer

This study is: - A multicenter, prospective, randomized, phase 3 trial. - To prove non-inferiority of Taxotere/Cisplatin compared to Pemetrexed/Cisplatin as a front line treatment of patients with non-squamous cell lung cancer. - 276 patients will be recruited.

NCT01282151 Carcinoma, Non Small Cell Lung Drug: Taxotere Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Inclusion Criteria: - Age >= 18 years old - ECOG performance status 0-2 - Non-squamous cell type non-small cell lung cancer (NSCLC) - Stage IV, Stage IIIB cannot be treated with curative intent or Relapsed after surgery or radiation therapy - No prior chemotherapy except adjuvant chemotherapy and concurrent chemoradiation treatment. --- L858R ---

Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Carcinoma, Non Small Cell Lung Carcinoma, Non-Small-Cell Lung Docetaxel is being used in 60mg/m2 3 weekly dosage in Japan and several east Asian institutions. --- L858R ---

Primary Outcomes

Description: months after beginning of first cycle chemotherapy

Measure: Progression Free Survival

Time: one year

Secondary Outcomes

Description: months from the beginning of first cycle chemotherapy

Measure: Overall Survival (months from the beginning of first cycle chemotherapy)

Time: three years

Description: Toxicity using CTCAE version 4.0

Measure: Safety Profile

Time: four months

Description: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Measure: Response rate

Time: 6-7th week

17 A Phase 1, Open-Label, Multiple-Ascending-Dose Study of DS-2248, an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Subjects With Advanced Solid Tumors

This phase 1 clinical trial is intended to understand the safety and tolerability of a new anticancer drug in subjects with advanced solid tumors. The patients who qualify for the study will receive a once daily dose of the drug taken by mouth and will undergo several tests to measure the drug in the blood and to understand the safety, tolerability and any effect of the drug on the tumor. The antitumor effect of the drug is not known in human.

NCT01288430 Solid Tumors Non-small Cell Lung Carcinoma Drug: DS-2248
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

- Either of the following: A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) -OR- Prior objective clinical benefit from EGFR-TKI, as evidenced by complete response (CR), partial response (PR), or stable disease (SD) ≥6 months as defined by RECIST or World Health Organization criteria. --- L858R ---

Primary Outcomes

Description: Objective response rate = the sum of complete response [CR] and partial response [PR] rates

Measure: Objective response rate

Time: Baseline to not more than 6 months

Secondary Outcomes

Description: Tumor response will be evaluated every 2 cycles using Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, if measurable tumors are available. Computed tomography (CT) and/or magnetic resonance imaging (MRI) should be used for tumor assessment unless another modality of disease assessment is necessary for the lesions.

Measure: Progression-free survival

Time: Baseline to not more than 6 months

Description: The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-2248 using non-compartmental analyses.

Measure: Study Part 1 - Determine the plasma pharmacokinetics of DS-2248

Time: Cycle 1 (Days 1, 2, 8, 15); Cycles 2, 3, (Days 1, 8, 15)

Description: The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-2248 using non-compartmental analyses.

Measure: Study Part 2 - Determine the plasma pharmacokinetics of DS-2248

Time: Day 1 for Cycle 3 and subsequent cycles

Description: Disease control rate (DCR) = the sum of complete response rate, partial response rate, and stable disease (SD) rate for a minimum of 12 weeks

Measure: Disease control rate

Time: Baseline to not more than 6 months

Measure: Response duration

Time: Baseline to not more than 6 months

Measure: Duration of stable disease

Time: Baseline to not more than 6 months

18 An Open-Label Multicenter Study of Erlotinib (Tarceva®) as First Line Therapy Until and Beyond RECIST Progression in NSCLC Patients Who Harbour EGFR Mutations

This open-label, single arm study will evaluate the safety and efficacy of Tarceva (erlotinib) as first-line therapy in participants with stage IV or recurrent non-small cell lung cancer who harbour epidermal growth factor receptor (EGFR) mutations. All participants will receive Tarceva 150 mg daily orally until disease progression or unacceptable toxicity occurs. At the investigator's discretion, participants may receive Tarceva beyond disease progression.

NCT01310036 Non-Squamous Non-Small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.. Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.. Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.. Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1). --- L858R ---

PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.. Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

Primary Outcomes

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Secondary Outcomes

Description: PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.

Measure: Progression-free Survival Per Investigator (PFS2)

Time: Approximately 68 months

Description: ORR was defined as the occurrence of either a confirmed complete (CR) or a partial response (PR, as a best overall response), as determined by RECIST, v. 1.1 criteria. CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: DCR was defined as CR + PR + Stable disease (SD). CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Description: OS was defined as the time from baseline to the date of death from any cause.

Measure: Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug.

Measure: Number of Participants With Adverse Events

Time: Approximately 68 months

Description: This outcome measure was not assessed.

Measure: Correlation Between EGFR Mutations in Plasma and Clinical Outcome (ORR/PFS/OS)

Time: Approximately 68 months

19 A Phase II Trial of Gefitinib Monotherapy in Pretreated Patients With Advanced Non-small Cell Lung Cancer Not Harboring Active EGFR Mutations

The investigators will examine efficacy and toxicity of gefitinib in Korean patients with EGFR wild tumors diagnosed with direct sequence test.

NCT01312337 Nonsmall Cell Lung Cancer Drug: salvage iressa
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Nonsmall Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Nonsmall Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L858R ---

Primary Outcomes

Measure: To determine disease control rate at 8 weeks will be 35% or higher in the the study group

Time: 6 months after the enrollment of the last patients

Secondary Outcomes

Measure: The number of patients who live longer than 6 months after enrollment

Time: 6 months after the enrollment of the last patients

20 e- Ab Sensor-based Real-time Detection of Mutant EGFR in Clinical Specimens From Patients of Non-small Cell Lung Cancer

The purpose of this study is to develop a real-time diagnostic technique with e- Ab sensor for specific EGFR mutation detection in clinical specimens of NSCLC patients, the investigators conduct a prospective clinical study. In comparison with results from direct sequencing of EGFR, the investigators evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). The potential factors which may interfere with the results would be investigated. With such technique, the investigators can obtain EGFR mutation information of NSCLC patients in cost-saving and time-saving way and can offer more individualized treatment for the investigators patients.

NCT01359436 Non-small Cell Lung Cancer (NSCLC) Device: Electrosensing antibody probing system (e- Ab sensing)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

In comparison with results from direct sequencing of EGFR, the investigators evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

However, only some EGFR mutations are associated with sensitivity to tyrosine kinase inhibitor treatment, especially deletion in exon 19 and L858R mutation in exon 21.4-5 Two recent phase III randomized clinical trials evaluated gefitinib treatment and chemotherapy in patients of advanced NSCLC with sensitive EGFR mutaions.6-7 --- L858R ---

8 For detection for specific EGFR mutations, mutation-specific monoclonal antibodies were developed to detect E746-A750 deletion in exon 19 and L858R in exon 21. --- L858R ---

In the study by Akhiko Kawahara et al, IHC assay of NSCLC tumor specimens with anti-delE746-A750 antibody showed a sensitivity of 79%, which was 83% by IHC assay with anti-L858R antibody.10 --- L858R ---

IHC assay with anti-L858R antibody also showed high specificity but low sensitivity (97% and 36%, respectively). --- L858R ---

For anti-L858R antibody, the sensitivity was 76%-95% and the positive predicted value was 99%-100%. --- L858R ---

Electrosensing antibody probing system (e- Ab sensor), which was developed for the rapid and sensitive detection of hapten, proteins, or viral antigen in medical samples, will be used for analyzing the interaction kinetics between mutation specific anti-EGFR and its antigen (EGFR with E746-A750 deletion or L858R mutation) present in the specimens of patients with lung cancer. --- L858R ---

In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

Primary Outcomes

Description: In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750)

Measure: The performance of e- Ab sensor

Time: 1 day

21 A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Study of ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer With Wild-type Epidermal Growth Factor Receptor

The primary objective of this study is to determine if the combination regimen of ARQ 197 with erlotinib will improve overall survival (OS) compared to erlotinib monotherapy in subjects with locally advanced or metastatic non-squamous NSCLC with wild-type EGFR who have received 1 or 2 prior systemic anti-cancer therapies in the Intent-to-Treat (ITT) population.

NCT01377376 Non-small-cell Lung Cancer Drug: ARQ 197 and Erlotinib Drug: Placebo and Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria 1. Male or female at least 20 years of age with life expectancy ≥ 3 months 2. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC with wild-type (excluding major activating mutation (exon 19 deletion and/or exon 21 L858R mutation)) EGFR gene status confirmed by a highly sensitive PCR assay 3. Evaluable disease according to RECIST, Version 1.1 4. Received one or two prior lines of systemic anti-cancer therapy for advanced or metastatic disease, one of which must be a platinum-based therapy 5. ECOG performance status of 0 or 1 6. --- L858R ---

Any other significant co-morbid condition that, in opinion of the investigator/sub-investigator, would impair study participation or cooperation Inclusion Criteria 1. Male or female at least 20 years of age with life expectancy ≥ 3 months 2. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC with wild-type (excluding major activating mutation (exon 19 deletion and/or exon 21 L858R mutation)) EGFR gene status confirmed by a highly sensitive PCR assay 3. Evaluable disease according to RECIST, Version 1.1 4. Received one or two prior lines of systemic anti-cancer therapy for advanced or metastatic disease, one of which must be a platinum-based therapy 5. ECOG performance status of 0 or 1 6. --- L858R ---

Primary Outcomes

Measure: Overall survival

Secondary Outcomes

Measure: Progression free survival

Description: Each assessment will be determined based on RECIST criteria version 1.1 by investigator

Measure: Objective response rate

Measure: Number of patients with adverse events

22 Molecular Analysis of Thoracic Malignancies

A research study to learn about the biologic features of cancer development, growth, and spread. We are studying components of blood, tumor tissue, normal tissue, and other fluids, such as urine, cerebrospinal fluid, abdominal or chest fluid in patients with cancer. Our analyses of blood, tissue, and/or fluids may lead to improved diagnosis and treatment of cancer by the identification of markers that predict clinical outcome, markers that predict response to specific therapies, and the identification of targets for new therapies.

NCT01385722 Thymus Cancer Thymoma Thymic Carcinoma Lung Cancer Carcinoma, Non-Small-Cell Lung Mesothelioma
MeSH:Carcinoma Mesothelioma Carcinoma, Non-Small-Cell Lung Thymoma Thymus Neoplasms
HPO:Carcinoma Neoplasm of the thymus Non-small cell lung carcinoma Thymoma

Over 90% of EGFR tyrosine kinase domain mutations associated with sensitivity to EGFR Tyrosine kinase inhibitor (TKI) therapy fall into two categories, in-frame deletions in exon 19, and the L858R point mutation in exon 21. --- L858R ---

Primary Outcomes

Measure: Collect detailed clinical information on patients with thoracic malignancies via the electronic medical record and a detailed patient questionnaire

Time: 20 years

23 A Phase II Trial of Radiation Therapy Combined With Iressa in Patients With Locally Advanced Non-small Cell Lung Cancer With Harboring Active EGFR Mutations

The purpose of this study is to access the effect and safety of radiotherapy combined whth Iressa for patients with locally advanced non-small cell lung cancer with harboring active EGFR mutations.

NCT01391260 Non-small Cell Lung Cancer Other: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically confirmed diagnosis of non-squamous NSCLC; Stage ⅢA-ⅢB(not suitable for surgery) or stage Ⅳ(only single-site single transfer ); - Untreated patients, or who completed ≤ 2 cycles of first-line chemotherapy (chemotherapy regimen: paclitaxel, docetaxel + cisplatin) within the previous month; - Patients with tumor EGFR mutation positive (exon 19 deletion mutation or exon 21 L858R substitution mutation); - Patients must be informed of the investigational nature of the study and must sign an informed consent form; - Presence of at least one measurable/evaluable according to RECIST criteria. --- L858R ---

Primary Outcomes

Measure: Response rate (RR)

Time: 1 year

Secondary Outcomes

Measure: Progression free survival (PFS)

Time: 2 years

Measure: Overall survival (OS)

Time: 2 years

Measure: Quality of life (MD-Anderson questionnaire)

Time: 1 year

24 A Randomized, Open-label Trial of Gefitinib Versus Combination of Vinorelbine Plus Platinum as Adjuvant Treatment in Pathological Stage II-IIIA(N1-N2) Non-small Cell Lung Cancer With EGFR Mutation

Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been characterized in a subset of patients with advanced NSCLC.The EGFR mutation rate was 30% in Chinese Non-small Cell Lung Cancer(NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This randomized phase III trial is studying gefitinib to see how well it works compared to cisplatin-based chemotherapy in treating patients who have undergone surgery for stage II-IIIA(N1-N2) NSCLC with EGFR activating mutation in Asian population.

NCT01405079 Non-small Cell Lung Cancer Drug: Gefitinib Drug: Vinorelbine+Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Target population is completely resected pathological stage II-IIIA(N1-N2) NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation. --- L858R ---

Primary Outcomes

Description: To evaluate the disease free survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for pathological stage II-IIIA(N1-N2) NSCLC with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Secondary Outcomes

Description: To evaluate the overall survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for stage II-IIIA(N1-N2) NSCLC with EGFR mutation.

Measure: Overall survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: To compare the randomized treatment arms in terms of 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate.

Measure: 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: The Total Score and TOI of FACT-L to Measure Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

25 Trial of Afatinib (BIBW 2992) in Suspected or Confirmed Mutant EGFR Lung Cancer Patients Unfit for Chemotherapy

The purpose of this study is to examine the efficacy and safety of using afatinib (BIBW 2992) to treat non-small cell lung cancer patients considered unfit for chemotherapy and have either suspected or confirmed Epidermal Growth Factor Receptor (EGFR) mutation.

NCT01415011 Carcinoma, Non-Small-Cell Lung Drug: Afatinib (BIBW 2992)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

L858R, exon 19 deletions, exon 20 insertions, T790M, list is not exhaustive), and WHO PS 0-3 Or No tissue suitable for EGFR genotyping, failed genotype, or EGFR genotyping unavailable, and NSCLC Adenocarcinoma sub-type, and Eligible smoking history: Never smoker (<100 cigarettes in lifetime), or Former smoker (stopped >1year ago and ≤10 pack-years) and WHO PS 0-2 - Unsuitable for or patient declining chemotherapy due to significant co-morbidity - Measurable disease according to RECIST version 1.1 - Adequate haematopoietic, hepatic and renal function defined as follows: Absolute neutrophil count (ANC) ≤1.5 x 109/L and platelet count ≤100 x 109/L - Bilirubin ≤1.5 x ULN, ALT (SGPT) ≤3 x ULN (or ≤ 5 x ULN in cases of liver metastases) - Serum creatinine clearance ≥45 ml/min - Palliative radiotherapy allowed unless to a solitary target lesion - Age 18 or over (no upper age limit) - Written informed consent that is consistent with ICH-GCP guidelines Exclusion Criteria: - Previous treatment with afatinib (BIBW 2992), or any EGFR-directed inhibitor - Any concurrent anticancer systemic therapy - Prior chemotherapy for relapsed and/or metastatic NSCLC - Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and registration - Suitable for radical radiotherapy - Palliative radiotherapy within 2 weeks prior to registration - Palliative radiotherapy to a solitary target lesion - Surgery (other than biopsy) within 4 weeks prior to registration - Inability to take oral medication, requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption, any medical co- morbidity affecting gastrointestinal absorption - Patients with current or pre-existing interstitial lung disease - Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient's participation in the trial - Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE version 4.0 Grade ≥3 diarrhoea of any etiology at baseline - Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants and/or leptomeningeal disease). --- L858R ---

Primary Outcomes

Description: Progression free survival will be determined by measurement of tumour size using RECIST version 1.1 at progression or date of patient death.

Measure: Progression free survival

Time: At 6 months

Secondary Outcomes

Measure: Overall response

Time: CT scan of chest & abdomen 4 weeks after registartion, then every 8 calender weeks until disease progression. CT scans every 12 weeks if patient is still on BIBW 2992 after 1 year of treatment.

Measure: Overall survival

Time: This will be measured in days, from the first day of treatment to the day of death.

Measure: Change in performance status

Time: At 1 month

Description: For each type of adverse event, the maximum toxicity grade will be obtained for each patient using CTCAE version 4.0 to closely monitor tolerability to BIBW 2992. Focus will be on those with a grade 3 or 4 BIBW 2992 related toxicities. The proportion of patients with any grade 3 or 4 event will also be examined.

Measure: Safety

Time: To be assessed at every timepoint i.e. baseline, fortnightly for the first 2 cycles and then monthly for 12 months and 2 monthly thereafter

Measure: Progression free survival in patients aged 70 and over

Time: At progression or patient death

Measure: Treatment compliance

Time: Compliance will be examined based on the time between starting treatment and stopping it completely

26 Phase I/II Clinical Trial Combining TUSC2-nanoparticles and Erlotinib in Stage IV Lung Cancer

The goal of phase 1 of this clinical research study is to find the highest dose of DOTAP:Chol-TUSC2 that can be safely given in combination with Tarceva (erlotinib hydrochloride) to patients with NSCLC. The goal of phase 2 of this clinical research study is to learn if the combination of DOTAP:Chol-TUSC2 and erlotinib hydrochloride can help to control NSCLC. The safety of this drug combination will also be studied in both phases. DOTAP:Chol-TUSC2 (previously FUS1) is a drug that helps transfer a gene called TUSC2 into cancer cells. Researchers think that cells without this gene may be involved in the development of lung cancer tumors. They want to find out if replacing the gene in these cells may keep the tissue from forming cancer cells. Erlotinib hydrochloride is designed to block a protein on tumor cells that may control tumor growth and survival. This may stop tumors from growing.

NCT01455389 Lung Cancer Drug: DOTAP:Chol-TUSC2 Drug: Erlotinib Drug: Dexamethasone Drug: Diphenhydramine
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Subjects must have specimens adequate for analysis of EGFR mutations (and other clinically relevant biomarkers) 4. All subjects with an activating EGFR mutation (exon 19 deletion or exon 21 L858R mutation) are eligible IF they have progressed following treatment with a first, second, or third generation EGFR inhibitor. --- L858R ---

Primary Outcomes

Description: MTD defined as dose level at which less than 2 participants experience dose-limiting toxicity (DLT). Toxicity graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 4. DLT will be grade > 3 toxicity occurring during the first cycle of therapy (i.e., within the first 3 weeks).

Measure: Maximum Tolerated Dose (MTD) Level for Drug Treatment Combination

Time: First 21 day cycle

Secondary Outcomes

Description: Responses determined by RECIST criteria. Responses will include only complete response (CR) + partial response (PR). Participants considered as non-responders when tumor progression by RECIST is observed. Measurable disease is defined as tumor masses with identifiable diameters measurable in two dimensions by computed tomography. Best overall response is best response designation recorded from the start of treatment until disease progression. Complete and partial responses have to be confirmed by two evaluations of the disease taken at least four weeks apart.

Measure: Response Rate

Time: After two, 21 day cycles

27 LUX-Lung 7: A Randomised, Open-label Phase IIb Trial of Afatinib Versus Gefitinib as First-line Treatment of Patients With EGFR Mutation Positive Advanced Adenocarcinoma of the Lung

This is a randomised, open-label, phase IIb trial of afatinib to compare to gefitinib in first-line treatment setting with patients who are having epidermal growth factor receptor mutation positive advanced adenocarcinoma of the lung.

NCT01466660 Lung Neoplasms Drug: Afatinib Drug: gefitinib
MeSH:Adenocarcinoma Lung Neoplasms Adenocarcinoma of Lung
HPO:Neoplasm of the lung

2. Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues. --- L858R ---

Primary Outcomes

Description: Progression-free survival (PFS) defined as the time from date of randomisation to date of disease progression, or date of death if a patient died earlier. Participants with no event (Disease progression (PD) or death) were censored. PD was primarily evaluated for the primary analysis by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started, together with an absolute increase in the SoD of target lesions of at least 5 millimetre (mm) or the appearance of one or more new lesions. For the final analysis (analysis cut-off date 12 April 2019) status and date of PD were determined by investigator assessment.

Measure: Progression-free Survival

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Description: Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason.

Measure: Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016)

Time: From first drug administration until last drug administration, up to 1482 days

Description: Overall survival (OS) which was defined as the time from the date of randomisation to the date of death. Participants for whom there is no evidence of death at the time of the analysis will be censored at the date that they were last known to be alive.

Measure: Overall Survival

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days.

Secondary Outcomes

Description: Objective response rate (ORR) which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

Measure: Objective Response Rate

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Description: Number of participants with objective response (best overall response of complete response or partial response) to study treatment over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

Measure: Time to Objective Response

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Description: Duration of objective response defined as the time of first objective response (best overall response of complete response or partial response) to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

Measure: Duration of Objective Response

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Description: Percentage of participants with disease control which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Responses of SD were only considered if they occur ≥42 days from date of randomisation. For the final analysis (analysis cut-off date 12 April 2019) disease control was determined by investigator assessment.

Measure: Disease Control

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Description: Duration of disease control defined as the time from randomisation to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) the status and date of disease progression were determined by investigator assessment.

Measure: Duration of Disease Control

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Description: Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size.

Measure: Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016)

Time: From first drug administration until last drug administration, up to 1482 days

Description: Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks.

Measure: Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015)

Time: Every 8 weeks, up to 56 weeks

28 Phase II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Preclinical data in lung cancer cell lines showed that EGFR mutation can potentially be a positive predictor for sensitivity to BKM120. Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). Therefore, combining BKM120 with erlotinib could potentially down-modulate PI3K-Akt activity resulting in a synergistic effect on cell growth inhibition and enhancing the response to erlotinib.

NCT01487265 Non Small Cell Lung Cancer Drug: BKM120 and Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

These include, but are not limited to mutations in L858R (Exon 21); Exon 19 deletion; G719S, G719A, G719C mutations (Exon 19);or L861Q (laboratory report required at enrollment). --- L858R ---

Primary Outcomes

Description: Percentage of patients who are alive and progression-free at 3 months (APF3) from first treatment.

Measure: Progression Free Survival at 3 Months

Time: 3 months

Secondary Outcomes

Description: Defined as the time from first treatment until death from any cause.

Measure: Overall Survival

Time: every 3 months after study treatment, projected 24 months

Description: Defined as the time from complete or partial response (CR or PR) until objective tumor progression. Tumor measurements will be obtained using CT scans of chest, abdomen and pelvis and assessed per RECIST v 1.1. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Duration of Response

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Defined as the percentage of complete and partial responses (CR + PR) among all patients. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Objective Response Rate

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Adverse events will be graded using CTCAE v4.3. and will be collected until 30 days after the discontinuation of study treatment for each participant. A non-serious adverse event is any untoward medical occurrence. A serious adverse event (SAE) is an event that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; requires intervention to prevent permanent impairment or damage. Specific AE and SAE terms are provided in the Adverse event module.

Measure: Number of Participants With Serious and Non-serious Adverse Events as a Measure of Safety.

Time: Every 2 weeks for 8 weeks, then every 8 weeks thereafter, estimated 24 months

29 A Phase 2A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Immune Response, Safety and Efficacy of HS-110 in Combination With Erlotinib vs. Erlotinib as a Single Agent in Patients With Advanced, Non-EGFR Mutated Non-Small Cell Lung Cancer (NSCLC)

This study will enroll patients with locally advanced or metastatic non-EGFR mutated Non-Small Cell Lung Cancer (NSCLC) lung cancer after failure of at least one but no more than two prior approved treatment regimens. Patients will be randomized to receive one of two doses of vaccine or placebo to be dosed twice weekly for 18 weeks (36 doses total) and patients will also receive erlotinib 150mg taken orally once daily for the duration of the trial. The study will examine the immune effects, safety and efficacy of two different doses of HS110 vaccine in combination with erlotinib versus erlotinib alone.

NCT01504542 Non-small Cell Lung Cancer Biological: HS110 vaccine Biological: Placebo Biological: HS110 vaccine
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This multicenter, randomized, double-blind, placebo-controlled study will enroll patients with advanced NSCLC (squamous cell or non-squamous cell) without EGFR mutations (either L858R or 746-750 deletions) who have had progression or recurrence of their disease following at least one but no more than two prior regimens (adjuvant therapy excluded) of approved therapy that did not include immunomodulating or anti-EGFR targeted therapy for their disease. --- L858R ---

Primary Outcomes

Description: Immune response will be evalulated by ELISPOT assays and change will be assessed from baseline.

Measure: Immunologic Response (defined as production of IFNƴ from CD8+ T cells as evaluated by ELISPOT assay)

Time: Week 18

Secondary Outcomes

Description: Incidence and severity of adverse events, changes in laboratory measures, physical exams and evaluation of autoimmune phenomena.

Measure: Safety of the combination of HS110 vaccine and erlotinib

Time: Up to 1 year

Description: Patients will have a CT scan performed at baseline, Week 12 and Week 22 or at the end of study visit in the case of early termination from study. Investigators will assess the disease response using irRC for overall response, CR, PR, SD or PD.

Measure: Tumor assessment by immunologic response criteria (irRC)

Time: Baseline, Week 12 and Week 22

Description: Analysis via a semiautomated, epithelial cell adhesion molecule-based immunomagnetic technique.

Measure: Exploratory Immunologic endpoint - evaluation of circulating tumor cells

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

Description: Analysis of cell surfance molecules by flow cytometry

Measure: Exploratory immunologic endpoint - immune function

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

Description: Examination of protein expression utilizing western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA) or mass spectrometry

Measure: Exploratory immunologic endpoint - proteomic profile

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

30 Multicenter, Randomized, Phase Ib/IIb Study to Evaluate the Efficacy and Tolerability of Gefitinib in Combination With Olaparib (AZD2281) Versus Gefitinib Alone, in Patients With EGFR Mutation Positive Advanced Non-small-cell Lung Cancer

This is a study of gefitinib plus olaparib gefitinib in combination with olaparib (AZD2281) versus gefitinib alone, in patients with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced non-small-cell lung cancer.

NCT01513174 Non Small Cell Lung Cancer Drug: Gefitinib Drug: Gefitinib plus olaparib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Tumor tissue available (according to the criterion of the specimen-processing laboratory) for EGFR mutation assessment: to be included in the study patients should present at least one EGFR mutation (exon 19 deletion or L858R with or without T790M). --- L858R ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose) defined as the highest dose level at which < 2 out of 6 patients experience a DLT

Time: 5 weeks

Secondary Outcomes

Measure: Progression-free survival

Time: An expected average of 2 years

Measure: Overall response rate

Time: An expected average of 2 years

Measure: Overall survival

Time: An expected average of 2 years

Measure: Peak Plasma Concentration

Time: Predose, half an hour, 1, 2, 4, 6 and 12 hours post-dose

31 A Phase I Dose-Escalation Study of Erlotinib in Combination With Pralatrexate in Subjects With Advanced Cancer

The goal of this clinical research study is to find the highest tolerable dose of the combination of erlotinib and pralatrexate that can be given to patients with advanced cancer. The safety of the drug combination will also be studied. Pralatrexate is designed to block the body's ability to make folic acid, a protein that may help cancer tissue to develop and spread. Erlotinib hydrochloride is designed to block proteins that are thought to cause cancer cells to grow. Erlotinib may help slow the growth of tumors.

NCT01532011 Advanced Cancers Solid Tumors Drug: Erlotinib Drug: Pralatrexate
MeSH:Neoplasms
HPO:Neoplasm

For the MTD expansion cohort, patients will be eligible if they meet one of the following criteria: I. Have an epidermal growth factor receptor (EGFR)-sensitive mutation (as G719C in exon 18, E746-A750 in exon 90, L858R in exon 21) and have been previously treated with EGFR inhibitor therapy but have subsequently developed resistance, OR II. --- G719C --- --- L858R ---

Primary Outcomes

Description: MTD defined by dose limiting toxicities (DLTs) that occur in the first cycle. DLT defined as any Grade 3 or 4 non-hematologic toxicity as defined in the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. Grade 4 hematologic toxicity lasting 2 weeks or longer despite supportive care. Grade 4 nausea or vomiting > 5 days despite maximum anti-nausea regimens, and any other Grade 3 non-hematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in NCI-CTCAE as attributable to therapy.

Measure: Maximum Tolerated Dose (MTD) of Erlotinib with Pralatrexate

Time: 8 weeks

Secondary Outcomes

Description: Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured in Hounsfield units (HU), by more than or equal to 15% (28).

Measure: Tumor Response

Time: 8 weeks

32 A Randomized Phase II Trial of Erlotinib Alone or in Combination With Bevacizumab in Patients With Non-Small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating patients with NSCLC.

NCT01532089 EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Lung Non-Squamous Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Biological: Bevacizumab Drug: Erlotinib Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

(CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).. Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R). --- L858R ---

Evaluated using time-dependent receiver operating characteristic curve and area under curve.. Inclusion Criteria: - Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. --- L858R ---

Genzyme, Response Genetics, etc); the laboratory report from the commercial laboratories report the specific mutations detected, and the method of detecting the exon 19 and exon 21 L858R point mutations must be available - Stage IV disease according to the 7th Edition of the American Joint Committee on Cancer staging system - Measurable disease - Life expectancy of >= 12 months - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 - Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 14 days prior to randomization - Platelet count >= 100,000/mm^3 obtained =< 14 days prior to randomization - Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to randomization - Total bilirubin =< 1.5 x upper limit of normal (ULN) obtained =< 14 days prior to randomization - Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or bone metastases obtained =< 14 days prior to randomization - Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x ULN obtained =< 14 days prior to randomization - Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0 obtained =< 14 days prior to randomization - Note: patients discovered to have >= 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate =< 1 g of protein in 24 hours - Negative pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only - Provide informed written consent - Willing to return to Academic and Community Cancer Research United (ACCRU) enrolling institution for follow-up - Willing to provide tissue and blood samples for correlative research purposes Exclusion Criteria: - Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component - Prior chemotherapy or treatment for metastatic non-small cell lung cancer - Any of the following: - Pregnant women - Nursing women - Men or women of childbearing potential who are unwilling to employ adequate contraception - Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens - Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive, per medical doctor (MD) discretion - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations, or any other medical condition that would limit compliance with study requirements - Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm - Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: non melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment (i.e. --- L858R ---

aortic aneurysm surgical repair or recent peripheral arterial thrombosis) =< 6 months prior to randomization - Radiotherapy to any site for any reason =< 14 days prior to randomization - Receiving any medications or substances that are strong or moderate inhibitors of CYP3A4; use of the following strong or moderate inhibitors are prohibited =< 7 days prior to randomization: - Strong inhibitors of CYP3A4: indinavir (Crixivan), nelfinavir (Viracept), atazanavir (Reyataz), ritonavir (Norvir), clarithromycin (Biaxin, Biaxin XL), itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), saquinavir (Fortovase, Invirase), telithromycin (Ketek) - Moderate inhibitors of CYP3A4: aprepitant (Emend), erythromycin (Erythrocin, E.E.S, Ery-Tab, Eryc, EryPed, PCE, fluconazole (Diflucan), grapefruit juice, verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM), diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Taztia XT, Tiazac) - Receiving any medications or substances that are strong or moderate inducers of CYP3A4; use of the following inducers are prohibited =< 7 days prior to randomization: efavirenz (Sustiva), nevirapine (Viramune), carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR), modafinil (Provigil), phenobarbital (Luminal), phenytoin (Dilantin, Phenytek), pioglitazone (Actos), rifabutin (Mycobutin), rifampin (Rifadin), St. John?s wort Inclusion Criteria: - Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. --- L858R ---

To investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R point mutations. --- L858R ---

Primary Outcomes

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Progression Free Survival (PFS)

Time: Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years

Secondary Outcomes

Description: Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Overall Survival

Time: Time from randomization to death of any causes, assessed up to 6 years

Description: The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).

Measure: Response Rate (Complete or Partial) to Each Treatment, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guidelines (Version 1.1)

Time: Up to 6 years

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator by mutation type.

Measure: Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R)

Time: From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years

Description: The number of patients experiencing toxicity defined as grade 3 or higher adverse events (using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) considered at least possibly related to treatment is reported below.

Measure: Number of Patients Experiencing Toxicity

Time: Up to 42 days after treatment discontinuation

Other Outcomes

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Plasma Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Tumor Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods

Time: Baseline

Description: Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: EGFR T790M Mutations

Time: Up to 6 years

Description: Evaluated using time-dependent receiver operating characteristic curve and area under curve.

Measure: Predictive Value of Plasma VEGF-A Levels on Progression Free Survival in Patients Treated With Erlotinib Hydrochloride Alone or in Combination With Bevacizumab

Time: Baseline

33 Randomized, Double-Blind, Multicenter, Phase 2 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Metastatic or Advanced Non-Small Cell Lung Cancer (NSCLC)

A Randomized, Double-Blind, Multicenter, Phase 2 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Metastatic or Advanced Non-Small-Cell Lung Cancer (NSCLC).

NCT01560104 Non-Small -Cell Lung Cancer Drug: Veliparib Drug: Carboplatin Drug: paclitaxel Drug: placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Subjects with peripheral neuropathy ≥ grade 2. - Subjects with a known epidermal growth factor receptor (EGFR) mutation of exon 19 deletion or L858R mutation in exon 21. (Subjects with wild type epidermal growth factor receptor (EGFR), unknown status or other type of epidermal growth factor receptor (EGFR) mutation will be considered eligible). --- L858R ---

Primary Outcomes

Measure: Progression Free Survival (PFS)

Time: Radiographic evaluation starting from the third day of study treatment and on average every 6 weeks until documented progression or date of death from any cause, whichever came first, until patient is registered as off study.

Secondary Outcomes

Description: Continuously from date of randomization until date of death from any cause or until patient is registered as off study, whichever came first.

Measure: Overall Survival (OS)

Time: Monthly after patient is registered off study up to 36 months or until date of death from any cause, whichever came first.

Measure: Objective Response Rate (ORR)

Time: Radiographic evaluation starting from the third day of study treatment and on average every 6 weeks until documented progression or date of death from any cause, whichever came first, until patient is registered as off study.

Measure: Chemotherapy Induced Peripheral Neuropathy (CIPN)

Time: From date of screening, first day of study treatment and then every cycle (about every 3 weeks) until date of death from any cause or patient is registered as off study, whichever came first.

34 An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

NCT01562028 Lung Cancer Drug: Erlotinib Drug: Bevacizumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

BELIEF (Bevacizumab and ErLotinib In EGFR Mut+ NSCLC) Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. --- L858R ---

- Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R) Exclusion Criteria: - Patients with increased risk of bleeding - Patients with clinically significant cardiovascular diseases - Patients with a history of thrombosis or thromboembolism in the 6 months prior to treatment - Patients with gastrointestinal problems - Patients with neurologic problems - Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. --- L858R ---

Primary Outcomes

Description: Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first. Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Progression Free Survival

Time: From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.

Secondary Outcomes

Description: Time from the date of enrollment until death from any cause.

Measure: Overall Survival

Time: From the date of enrollment until death, assessed up to 48 months.

Description: Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death.

Measure: Time to Treatment Failure

Time: From the date of enrollment until discontinuation of treatment, assessed up to 48 months.

Description: Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Objective Response

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Disease Control

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Duration of Response

Time: Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).

Description: Adverse events graded according to NCI CTCAE V4.

Measure: Adverse Events

Time: Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).

35 Randomized, Open Label, Positive Controlled, Multicenter Trial to Evaluate Icotinib as First-line and Maintenance Treatment in EGFR Mutated Patients With Lung Adenocarcinoma

This study is designed to compare the efficacy and safety of first-line icotinib treatment and first-line chemotherapy followed by maintenance treatment with icotinib.

NCT01665417 EGFR Positive Non-small Cell Lung Cancer Adenocarcinoma Drug: Experimental Drug: Chemotherapy Drug: Chemotherapy
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Adverse events assessed by CTCAE4.0.. Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT); Patients must have previously untreated locally advanced or metastatic NSCLC; Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R). --- L858R ---

Exclusion Criteria: - Prior chemotherapy Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR Patients must not be receiving any other investigational agents Any evidence of interstitial lung disease Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT); Patients must have previously untreated locally advanced or metastatic NSCLC; Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R). --- L858R ---

Primary Outcomes

Description: PFS was defined as the time from the date of first dose of study medication to the date of first documentation of tumor progression or death due to any cause, whichever occurred first.

Measure: Progression-free survival

Time: 8 months

Secondary Outcomes

Description: OS was assessed via calculation of the time to death due to any cause from the date of randomization. A patient was censored at the last date they were known to be alive.

Measure: Overall survival

Time: 24 months

Description: TTP was defined as the time from the date of first dose of study medication to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP (in weeks) was calculated as (first event date minus first dose date +1)/7. Kaplan-Meier method was used.

Measure: Time to Tumor Progression

Time: 8 months

Description: Number of Subjects With Overall Confirmed Objective Disease Response According to the Response Evaluation Criteria in Solid Tumors(RECIST)1.1.

Measure: Objective response rate

Time: 3 months

Description: Adverse events assessed by CTCAE4.0.

Measure: Number of participants with adverse events

Time: 24 months

36 Phase IIIb, Open-Label Study of Erlotinib (Tarceva®) Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Present Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor

This open-label, multi-center study will evaluate the progression-free survival and safety of erlotinib in participants with locally advanced or metastatic non-small cell lung cancer with activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Participants will receive daily oral doses of erlotinib until disease progression or unacceptable toxicity.

NCT01667562 Non-Small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.. Percentage of Participants With Adverse Events. --- L858R ---

Primary Outcomes

Description: Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Patients who had not died or progressed at the time of the final analysis were censored at the date of last contact.

Measure: Progression-Free Survival as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v 1.1)

Time: Baseline until disease progression, or death, whichever occurs first (approximately up to 4 years and 9 months)

Secondary Outcomes

Description: Objective response (OR) was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of complete response (CR) and partial response (PR) four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Proportion of Participants With Objective Response as Assessed by RECIST v 1.1

Time: Baseline until disease progression, or death, whichever occurs first (approximately up to 4 years and 9 months)

Description: Disease control was defined as objective response or stable disease (SD) for at least 6 weeks. OR was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of CR and PR four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Proportion of Participants With Disease Control as Assessed by RECIST v 1.1

Time: Baseline until disease progression, or death, whichever occurs first (approximately up to 4 years and 9 months)

Description: Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.

Measure: Proportion of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations

Time: Screening up to approximately 7 days

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Measure: Percentage of Participants With Adverse Events

Time: Baseline up to approximately 4 years and 9 months

Description: The domains in the Quality of life score using the Functional Assessment of Cancer Therapy Lung (FACT-L) include physical, social/family, emotional, and functional well-being, and a lung cancer subscale include symptoms, cognitive function and regret of smoking. Minimum and maximum value of the scale is 0 and 4, respectively. Higher score indicate better health state.

Measure: Change From Baseline to End of Study in Quality of Life Score Using The Functional Assessment of Cancer Therapy Lung (FACT-L)

Time: Baseline and end of study (approximately 4 years and 9 months)

37 A Prospective, Open-labelled, Randomized, Multicenter Phase II Study to Evaluate Efficacy and Safety of Erlotinib vs NP Chemotherapy as Adjuvant Therapy in Post Radical Operation NSCLC Patients With EGFR19 or 21 Exon Mutation

This study is to compare 2-year Disease Free Survival Rate (DFSR) in post radical operation IIIA Non-Small Cell Lung Cancer (NSCLC) patients with Epidermal Growth Factor Receptor (EGFR) 19 or 21 exon mutation treated Erlotinib vs NP chemotherapy as adjuvant therapy.

NCT01683175 Non-small Cell Lung Cancer Stage III Drug: Erlotinib Drug: cis-platinum Drug: Vinorelbine
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - IIIA NSCLC patients according to TMN-staging of Lung Staging Standard version 7 2009, confirmed by histopathology or cytology after radical operation, and having EGFR exon 19 deletion mutation or exon 21 L858R single base substitution; - Accept study adjuvant therapy within 6 weeks post radical operation; - ECOP PS 0-1; Life expectancy ≥12 weeks; - Hematology: absolute neutrophil count (ANC) ≥1.5×10^9/L; platelet count ≥100×10^9/L; hemoglobin concentration ≥ 9.0 g/dL (permit to maintain hematologic criteria by blood transfusion); - Liver Function: TBil ≤1.5xULN; ALT and AST ≤2.5xULN; - Renal Function: Cr ≤1.25xULN, and Ccr ≥60ml/min; - Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days before study treatment; - Signed inform consent form by patient or his/her legal representative; - Comply with study protocol and procedure, and be able to take oral medication; Aged ≥18 years and ≦75 years; - Eligible patients of reproductive potential (both sexes) must agree to use a reliable method of birth control before enrollment, during the study period and for at least 30 days after their last dose of study therapy; Exclusion Criteria: - Having treated by Her-Target therapy, i.e. erlotinib, gefitinib, cetuximab, trastuzumab; - Having treated by any systemic anti-tumor therapy of NSCLC, including cytotoxic therapy, target medication treatment (i.e. --- L858R ---

Primary Outcomes

Description: 2-year disease free survival rate is defined as the estimation percentage of disease free survival patients with study treatment at 2-year.

Measure: 2-year disease free survival rate (DFSR)

Time: 2 years

Secondary Outcomes

Description: Disease free survival is defined as the time from randomization to disease recurrence or death which comes first.

Measure: disease free survival

Time: 5 years

Description: Overall survival is defined as the time from randomization to death.

Measure: overall survival (OS)

Time: 5 years

Description: The score of Functional Assessment of Cancer Therapy - Lung (FACT-L) subscale and Lung Cancer Symptom Scale (LCSS)

Measure: Quality of Life

Time: 5 years

Description: frequency of Adverse Event

Measure: Adverse Event (AE)

Time: 5 years

Description: Frequency of Serious Adverse Event (SAE)

Measure: Serious Adverse Event (SAE)

Time: 5 years

38 Pilot Study to Identify the Mechanism of De Novo Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) in NSCLC With EGFR Mutation.

This study is based on the following hypothesis "De novo resistance to EGFR-TKI in EGFR mutation positive patients is related with mutations in EGFR downstream genes". Investigators will prospectively collect genomic DNA and clinical data regarding treatment outcomes to EGFR-TKI in NSCLC patients with activating EGFR mutations. Investigators will sequence candidate mutations of EGFR downstream genes and analyze c-met gene amplification and protein expression in PTEN, HGF, and IGFR. To identify genetic mutations, amplification, and protein over expression as predictive markers of treatment outcomes, investigators analyzed the association of treatment outcomes with the presence of genetic alteration or protein over expression. Investigators will attempt to identify biomarkers that are able to predict de novo resistance to EGFR-TKI in EGFR mutated NSCLC.

NCT01697163 NSCLC

Inclusion Criteria: 1. Pathologically proven unresectable NSCLC 2. 20 years of age or older 3. Planned treatment with Iressa® 4. Patients with activating EGFR mutation (del 19, L858R) 5. Available detailed smoking history 6. Available tissue samples (archival tissue) for mutational or molecular analysis (representative paraffin block or unstained sections from tumor diagnostic specimen are mandatory) 7. Available blood sample 8. --- L858R ---

Primary Outcomes

Description: The primary objective is to compare hazard rates of PFS in patients treated with Iressa between with and without any molecular aberrancy in EGFR-downstream genes/proteins.

Measure: hazard rates of PFS

Time: 1year

Other Outcomes

Description: Overall survival (OS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Disease control rate (DCR) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Progression-free survival (PFS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification)

Measure: OS

Time: 2years

39 A Randomized Phase II Trial of Erlotinib, Cabozantinib, or Erlotinib Plus Cabozantinib as 2nd or 3rd Line Therapy in Patients With EGFR Wild-Type NSCLC

This randomized phase II trial studies how well giving erlotinib hydrochloride and cabozantinib-s-malate alone or in combination works as second or third line therapy in treating patient with stage IV non-small cell lung cancer. Erlotinib hydrochloride and cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving erlotinib hydrochloride together with cabozantinib-s-malate is more effective than erlotinib hydrochloride or cabozantinib-s-malate alone in treating non-small cell lung cancer.

NCT01708954 Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Drug: Cabozantinib S-malate Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Criteria: - Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined as follows: - EGFR mutation testing of tumor has been performed and did not demonstrate an EGFR tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for EGFR exon 19 deletion and exon 21 L858R mutations must have been included; OR - EGFR mutation testing has been attempted and is inconclusive (for example, due to lack of sufficient deoxyribonucleic acid [DNA] yield); OR - EGFR mutation status is unknown but tumor is positive for at least one alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation, human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene (RET) rearrangement/fusion, or one not listed following approval by the study chair prior to registration Inclusion Criteria: - INCLUSION CRITERIA STEP 1: - Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC) - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer TNM classification system - Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation of all sites of disease must be obtained within 4 weeks prior to registration - Prior to registration, the investigator/site must confirm that sufficient pathology material representative of patient's cancer is available for submission for MET immunohistochemical (IHC) testing - Patients must have received one or two lines of prior chemotherapy (first line platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one line of therapy); prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the time frames specified in the protocol - Patients must have discontinued treatment with any other type of investigational agent >= 4 weeks prior to registration - Patients must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs) - Patients with no known brain metastasis at baseline must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases; patients with brain metastases at baseline must have baseline brain imagining within 4 weeks prior to study registration and meet all of the specific criteria for brain mets listed in the protocol - Radiation related toxicities must have resolved to =< grade 1 prior to registration - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 - Patients must have an anticipated life expectancy greater than 3 months - Acceptable bone marrow, renal and hepatic function within 2 weeks prior to registration as defined in the protocol - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - INCLUSION CRITERIA STEP 2: - Patients must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2 - Patients must have radiographic progressive disease per RECIST v1.1 criteria after >= 2 courses of therapy on Arm A or Arm B - Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1 - Patients must have an ECOG performance status between 0-2 - Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 <= grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs Exclusion Criteria: - EXCLUSION CRITERIA STEP 1: - Patients without sufficient pathology material representative of the patient's cancer (tumor block or 10 unstained slides) - Prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor therapy, Met tyrosine kinase inhibitor therapy, or Met monoclonal antibody (MetMAb); prior antibody therapy such as bevacizumab or cetuximab is allowed with a washout period depending on dosing interval and investigational nature - Prior radiation therapy to the thoracic cavity, abdomen, or pelvis within 3 months prior to registration, to bone or brain metastasis within 14 days prior to registration, or to any other site within 28 days prior to registration - History of the following: Clinically-significant gastrointestinal (GI) bleeding within 6 months prior to registration; Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to registration; Any other signs indicative of pulmonary hemorrhage within 3 months prior to registration - Radiographic or other evidence of the following within 28 days prior to registration: • Tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor; Cavitating pulmonary lesion(s); Tumor in contact with, invading or encasing any major blood vessels - Psychiatric illness/social situations that would limit compliance with study requirements - History of major thrombotic events (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months prior to registration - Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). --- L858R ---

(low dose aspirin [=< 81 mg/day] and prophylactic LMWH are permitted) - Concomitant treatment of strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort) - Cardiovascular disorders including: Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening; - Concurrent uncontrolled hypertension; Any history of congenital long QT syndrome; Any of the following within 6 months prior to registration: - Unstable angina pectoris - Clinically-significant cardiac arrhythmias - Stroke (including transient ischemic attack [TIA], or other ischemic event) - Myocardial infarction - GI disorders particularly those associated with a high risk of perforation or fistula formation specified in the protocol - Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to registration - Uncontrolled, significant, intercurrent or recent illness - Prior malignancy within 2 years prior to registration which required systemic treatment or is currently active - Pregnant or breast-feeding - Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral therapy - Known chronic active hepatitis B - EXCLUSION CRITERIA (STEP 2): - Intervening anticancer treatment or major surgical procedure(s) between Step 1 and Step 2, except palliative radiation to the bone finishing >= 2 weeks prior to registration to Step 2 - Central nervous system (CNS) progression; patients with stable CNS disease are allowed - Intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of erlotinib and cabozantinib Criteria: - Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined as follows: - EGFR mutation testing of tumor has been performed and did not demonstrate an EGFR tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for EGFR exon 19 deletion and exon 21 L858R mutations must have been included; OR - EGFR mutation testing has been attempted and is inconclusive (for example, due to lack of sufficient deoxyribonucleic acid [DNA] yield); OR - EGFR mutation status is unknown but tumor is positive for at least one alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation, human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene (RET) rearrangement/fusion, or one not listed following approval by the study chair prior to registration Inclusion Criteria: - INCLUSION CRITERIA STEP 1: - Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC) - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer TNM classification system - Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation of all sites of disease must be obtained within 4 weeks prior to registration - Prior to registration, the investigator/site must confirm that sufficient pathology material representative of patient's cancer is available for submission for MET immunohistochemical (IHC) testing - Patients must have received one or two lines of prior chemotherapy (first line platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one line of therapy); prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the time frames specified in the protocol - Patients must have discontinued treatment with any other type of investigational agent >= 4 weeks prior to registration - Patients must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs) - Patients with no known brain metastasis at baseline must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases; patients with brain metastases at baseline must have baseline brain imagining within 4 weeks prior to study registration and meet all of the specific criteria for brain mets listed in the protocol - Radiation related toxicities must have resolved to =< grade 1 prior to registration - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 - Patients must have an anticipated life expectancy greater than 3 months - Acceptable bone marrow, renal and hepatic function within 2 weeks prior to registration as defined in the protocol - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - INCLUSION CRITERIA STEP 2: - Patients must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2 - Patients must have radiographic progressive disease per RECIST v1.1 criteria after >= 2 courses of therapy on Arm A or Arm B - Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1 - Patients must have an ECOG performance status between 0-2 - Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 <= grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs Exclusion Criteria: - EXCLUSION CRITERIA STEP 1: - Patients without sufficient pathology material representative of the patient's cancer (tumor block or 10 unstained slides) - Prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor therapy, Met tyrosine kinase inhibitor therapy, or Met monoclonal antibody (MetMAb); prior antibody therapy such as bevacizumab or cetuximab is allowed with a washout period depending on dosing interval and investigational nature - Prior radiation therapy to the thoracic cavity, abdomen, or pelvis within 3 months prior to registration, to bone or brain metastasis within 14 days prior to registration, or to any other site within 28 days prior to registration - History of the following: Clinically-significant gastrointestinal (GI) bleeding within 6 months prior to registration; Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to registration; Any other signs indicative of pulmonary hemorrhage within 3 months prior to registration - Radiographic or other evidence of the following within 28 days prior to registration: • Tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor; Cavitating pulmonary lesion(s); Tumor in contact with, invading or encasing any major blood vessels - Psychiatric illness/social situations that would limit compliance with study requirements - History of major thrombotic events (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months prior to registration - Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from randomization to documented disease progression or death from any cause, whichever occurred first. Patients who had not experienced an event of interest by the time of analysis were censored at the date of last disease assessment.

Measure: Progression-free Survival (PFS)

Time: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years

Secondary Outcomes

Description: OS is defined as the time from randomization to death from any cause or date of last known alive.

Measure: Overall Survival (OS)

Time: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years

Description: Objective response is defined as complete response (CR) or partial response (PR) evaluated using RECIST v 1.1. CR is defined as disappearance of all lesions and any pathological lymph nodes must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions and persistence of one or more non-target lesion(s).

Measure: Proportion of Patients With Objective Response

Time: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years

Description: Submission of archival tissue for central MET IHC testing was required for this study, and total MET IHC testing was conducted at the Brigham and Women's Hospital using the c-Met clone CVD13 (arabbit polyclonal). Membranous and cytoplasmic staining were individually scored, and positivity was declared if MET was expressed in either the membrane or cytoplasm.

Measure: Proportion of Patients With MET Positivity

Time: Assessed at baseline

Measure: Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher

Time: Assessed every 4 weeks while on treatment and for 30 days after the end of treatment

40 Observational Post-authorization Prospective Study to Characterize the Incidence of Epidermal Growth Factor Receptor (EGFR) Mutation Positive and Advanced Non-small Cell Lung Cancer Patients and Their Clinical Management in Galicia

The present study has been designed in order to characterize the incidence of patients with advanced non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) positive mutations and their clinical management in Galicia.

NCT01717105 Metastatic Non-Small-Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Type of epidermal growth factor receptor (EGFR) mutations: deletion in exon 19, point mutation at codon 858 (L858R) or other (only for EGFR M+ patients). --- L858R ---

Primary Outcomes

Measure: Number of patients with epidermal growth factor receptor (EGFR) positive mutation among advanced or metastatic non-small-cell lung cancer (NSCLC) patients in Galicia

Time: 10 months (recruitment period)

Secondary Outcomes

Measure: Epidermal growth factor receptor (EGFR) mutational status in tumor tissue (primary tumor or metastatic samples) and plasma samples at screening

Time: 1 day (Screening Visit)

Measure: Type of epidermal growth factor receptor (EGFR) mutations: deletion in exon 19, point mutation at codon 858 (L858R) or other (only for EGFR M+ patients)

Time: 1 day (Screening Visit)

Measure: Prescribed first line treatment (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: 1 day (First study visit)

Measure: Tumor response (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: From inclusion until disease progression, death or until 9 months from the inclusion of the last patient in the study have elapsed, whichever is earlier.

Measure: Disease control (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: From inclusion until the end of the study (9 months subsequent to the last patient's inclusion or until lost of follow-up)

Measure: Prescribed second-line treatment after progression (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: 1 day (Progression Visit)

Measure: Progression-free survival and overall survival (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: 1 day (at the end of the study 9 months subsequent to the last patient's inclusion or until lost of follow-up

Measure: Epidermal growth factor receptor (EGFR) mutational status at disease progression in tumor tissue (primary tumor or metastatic samples) and plasma samples (only for EGFR M+ patients)

Time: 1 day (Progresion Visit)

41 Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) in Lung Adenocarcinoma Patients With Acquired Resistance to 1st Generation EGFR Tyrosine Kinase Inhibitors

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a 2nd line monotherapy agent in lung adenocarcinoma patients with acquired resistance to prior EGFR tyrosine kinase inhibitors (TKIs).

NCT01718847 Increased Drug Resistance Drug: NOV120101 (Poziotinib)

Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R ---

Patients who cannot participate in this trial by investigator's judgment Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R ---

Primary Outcomes

Description: The length of time during and after medication or treatment during which the disease being treated (usually cancer) does not get worse.

Measure: Progression free survival (PFS)

Time: By 1 year after enrollment of the last subject

Secondary Outcomes

Description: The proportion of Patients maintaining progress-free status at 16 weeks

Measure: PFS rate at 16 weeks

Time: 16 weeks

Description: The proportion of patients with partial response or complete response at their best tumor treatment evaluation

Measure: Objective response rate (ORR)

Time: By 1 year after enrollment of the last subject

Description: The proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: By 1 year after enrollment of the last subject

Measure: Overall survival (OS)

Time: By 1 year after enrollment of the last subject

Measure: Time to progression (TTP)

Time: By 1 year after enrollment of the last subject

Measure: Time to objective response

Time: By 1 year after enrollment of the last subject

Measure: Duration of objective response

Time: By 1 year after enrollment of the last subject

Measure: Duration of disease control

Time: By 1 year after enrollment of the last subject

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: baseline and the end of treatment, by 1 year after enrollment of the last subject

Other Outcomes

Description: The study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a study drug. Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: By 3 months after enrollment of the last subject

Description: Subgroup analysis, in the context of design and analysis of study drug, refers to looking for pattern in a subset of the subjects according to genotype

Measure: Subgroup analyses with the genetic information

Time: by 1 year after enrollment of the last patient

42 A Phase Ⅱ Randomized Controlled Trial to Compare Chemotherapy Sequenced by EGFR-TKIs and Chemotherapy Combined With EGFR-TKIs for Advanced or Metastatic NSCLC Patients Failed to EGFR-TKIs Therapy

There are two different treatment modes for NSCLC patients who failed to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) after initially responding to EGFR-TKI. One is EGFR-TKI combined with chemotherapy and the other is chemotherapy followed by EGFR-TKI. It is unclear which one is more suitable to this group of lung cancer patients. So this phase Ⅱclinical trial is designed to compare the efficiency and safety of these two different treatment modes.

NCT01746277 Non Small Cell Lung Cancer Drug: combined group Drug: Sequenced group
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria(version3.0) (NCI-CTC).. Inclusion Criteria: - age ≥ 18 years - histologically and cytologically proven non-small cell bronchogenic carcinoma (sputum cytology alone was not acceptable) - clinical stages ⅢB or Ⅳ - recurrent or refractory disease following previous first-line chemotherapy regimens containing platinum and second-line EGFR-TKIs therapy - partial remission (PR) or stable disease (SD) at least for 6 months during previous EGFR-TKI treatment - at least one bidimensionally measurable or radiographically assessable lesion - Eastern cooperative oncology group performance status (ECOG PS) ≤ 2 - life expectancy ≥ 12 weeks - adequate hematological, renal, and hepatic functions Exclusion Criteria: - additional malignancies - uncontrolled systemic disease - any evidence of clinically active interstitial lung disease - newly diagnosed central nervous system (CNS) metastasis and not treated by radiotherapy or surgery - pregnancy or breast feeding phase Inclusion Criteria: - age ≥ 18 years - histologically and cytologically proven non-small cell bronchogenic carcinoma (sputum cytology alone was not acceptable) - clinical stages ⅢB or Ⅳ - recurrent or refractory disease following previous first-line chemotherapy regimens containing platinum and second-line EGFR-TKIs therapy - partial remission (PR) or stable disease (SD) at least for 6 months during previous EGFR-TKI treatment - at least one bidimensionally measurable or radiographically assessable lesion - Eastern cooperative oncology group performance status (ECOG PS) ≤ 2 - life expectancy ≥ 12 weeks - adequate hematological, renal, and hepatic functions Exclusion Criteria: - additional malignancies - uncontrolled systemic disease - any evidence of clinically active interstitial lung disease - newly diagnosed central nervous system (CNS) metastasis and not treated by radiotherapy or surgery - pregnancy or breast feeding phase Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Responses to EGFR-TKIs are quiet dramatic and durable, especially in patients with EGFR gene classic mutations, such as 19 deletion or 21 leucine 858 arginine(L858R). --- L858R ---

Primary Outcomes

Description: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 52 weeks.

Measure: progression free survival

Time: up to 52 weeks (about one year)

Secondary Outcomes

Description: From date of randomization until the date of death from any cause, assessed up to 100 weeks.

Measure: overall survival

Time: up to 100 weeks

Description: The objective response rate includes the complete remission and partial remission rate.

Measure: objective response rate

Time: up to 9 weeks

Description: FACL-L is assessed at different time points.(Date of randomization,1 week after chemotherapy,every cycle of chemotherapy,every month of EGFR-TKI maintain treatment,up to 100 weeks)

Measure: the score of functional assessment of cancer treatment-lung(FACT-L)

Time: up to 100weeks

Description: The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria(version3.0) (NCI-CTC).

Measure: Number of participants with adverse events

Time: Participants will be followed for the duration of treatment, an expected average of 52 weeks.

43 Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of Simotinib Hydrochloride in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

The primary objective is to assess the safety and tolerability of multiple doses of Simotinib Hydrochloride in NSCLC patients. The secondary objective is to determine the pharmacokinetic (PK) profile and explore the preliminary anti-tumor activity.

NCT01772732 Non-small Cell Lung Cancer Drug: Simotinib Hydrochloride
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC, who were previously treated with at least one platinum-based chemotherapy regimen, but had disease relapse; - Patients have ended their chemotherapy or radiotherapy at least 4 weeks prior to study entry and have recovered from any previous toxicity; - EGFR mutation positive (such as E19del, L858R, L861Q, G719X, etc.); - Patients with at least one measurable lesion meeting RECIST; - ECOG performance status 0-2; - Life expectancy ≥12 weeks; - Adequate bone marrow function: ANC ≥1.5 × 109/L, PLT≥80 ×109/L, HB ≥90 g/L; - Adequate hepatic function: serum bilirubin ≤ 2 × ULN, AST and ALT ≤ 2.5 × ULN, and ≤ 5 × ULN are acceptable if the liver has tumor involvement; - Adequate renal function: endogenous creatinine clearance rate (CrCl) ≥ 60 mL/min or serum creatinine ≤ 1.5 × ULN; - Females with childbearing potential must have a negative pregnancy test within 7 days prior to treatment and use an approved contraceptive method during the study; - Males must be surgically sterile or use an approved contraceptive method during the study. --- L858R ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD)

Time: 28 days

Secondary Outcomes

Measure: The maximum plasma concentration (Cmax)

Time: d1,d8,d9,d10,d15

Measure: The time to Cmax (tmax)

Time: d1,d8,d9,d10,d15

Measure: Area under the plasma concentration-time curve (AUC)

Time: d1,d8,d9,d10,d15

Measure: Overall Response Rate (ORR)

Time: 1 year

Measure: Progression-free Survival (PFS)

Time: 1 year

44 ARCHER 1050: A Randomized, Open-Label Phase 3 Efficacy and Safety Study Of Dacomitinib (PF-00299804) Vs. Gefitinib For The First-Line Treatment Of Locally Advanced or Metastatic NSCLC In Subjects With EGFR-Activating Mutations

This is a multinational, multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of treatment with dacomitinib (PF-00299804) to treatment with gefitinib in patients with locally advanced or metastatic non-small cell lung cancer, with epidermal growth factor receptor EGFR-activating mutation (s). Analyses of primary objective (Progression Free Survival) will be done as defined in the protocol.

NCT01774721 Non-small Cell Lung Cancer With EGFR-Activating Mutations Drug: Dacomitinib (PF-00299804) Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration).. Inclusion Criteria: - Evidence of histo or cytopathology confirmed, advanced NSCLC (with known histology) with the presence of EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21). --- L858R ---

- It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study - Minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC - Adequate tissue sample must be available for central analyses. --- T790M --- --- L858R ---

- Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R ---

Inclusion Criteria: - Evidence of histo or cytopathology confirmed, advanced NSCLC (with known histology) with the presence of EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21). --- L858R ---

Primary Outcomes

Description: PFS: time from randomization to date of progression of disease (PD) as determined by IRC review as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Secondary Outcomes

Description: PFS: time from randomization to date of PD as determined by investigator assessment as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: Number of participants with BOR based on IRC review(complete response[CR] or confirmed partial response[PR]) was recorded from randomization until disease progression based on RECISTv1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Number of participants with BOR based on investigator assessment (CR or confirmed PR) was recorded from randomization until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on IRC review recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on investigator assessment recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: DoR was defined as time from first documentation of objective response(CR or PR, whichever occurred first)to date of PD or death from any cause, whichever occurred first. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter used in sum for target nodes, longest diameter used in sum for all other target lesions. PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed(over baseline if no decrease in sum is observed),with a minimum absolute increase of 5 mm. DoR was recorded based on IRC review and investigator's assessment.

Measure: Duration of Response (DoR)

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to 28-35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non- serious adverse events.

Measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Laboratory parameters included haematological and biochemistry parameters. Haematology parameters included anaemia, activated partial thromboplastin time, haemoglobin, international normalized ratio, lymphocyte count, lymphopenia, neutrophils (absolute), platelets, prothrombin time and white blood cells. Biochemistry parameters included alanine aminotransferase (increased), alkaline phosphatase (increased), aspartate aminotransferase (increased), bilirubin (total), creatinine (increased), hypercalcaemia, hyperglycaemia, hyperkalaemia, hypermagnesaemia, hypernatraemia, hypoalbuminaemia, hypocalcaemia, hypoglycaemia, hypokalaemia, hypomagnesaemia, hyponatraemia. Test abnormalities were graded by AEs according to the Common Terminology Criteria for Adverse Events(NCI CTCAE) version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Urinalysis parameter included urine protein, urine blood/haemoglobin, urine glucose and urine sediment. Test abnormalities was defined as deviation from normal range (higher or lower). Normal range of 24-hour urine protein test: less than 150 mg of protein per day, urine glucose: 0 to 0.8 mmol/L (millimole per liter), urine protein: 0 to 20 mg/dL (milligrams per deciliter). Urine blood/haemoglobin abnormality was defined as presence and absence of blood/haemoglobin in urine of participants. Urine sediment abnormality was defined as the presence of any bacteria, casts, crystals, and epithelial cells. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities: Urinalysis

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Criteria for vital signs abnormalities: systolic pulse rate less than (<) 50 beats per minute (bpm) or greater than (>)130 bpm and maximum increase or decrease from baseline in pulse rate of 30 bpm. Systolic blood pressure of maximum increase from baseline (MIB) >=40 millimeters of mercury (mmHg), maximum decrease from baseline (MDB) in systolic blood pressure =<60 mmHg. Diastolic blood pressure of MIB >=20 mmHg and MDB in diastolic blood pressure >40 and =<20 mm Hg. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: ECG parameters included corrected QT interval using Bazett's formula (QTcB) and corrected QT interval using Fridericia's formula (QTcF). ECG criteria for abnormality: absolute value 450 - <480 msec, 480 - <500 msec >=500. The number of participants with potentially clinically significant ECG findings at any visit were reported.

Measure: Number of Participants With Clinically Significant Abnormality in Electrocardiogram (ECG)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: An ejection fraction (EF) was the volumetric fraction of blood ejected from a ventricle of the heart with each heartbeat; it was a measure of the pumping efficiency of the heart. The EF of the left heart, known as the left ventricular ejection fraction, was a measure of the efficiency of pumping into the body's systemic circulation.

Measure: Number of Participants With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

Time: From baseline up to 7 days of Cycle 4 (up to 91 days)

Description: HRQOL was measured by standardized questionnaires (European Organization for Research and Treatment of Cancer (EORTC)) quality of life questionnaires (OLQ-C30) and its lung cancer module (QLQ-LC13). TTD in pain (chest, arm/shoulder), dyspnea, fatigue or cough was defined as time between baseline and first occurrence of increase in score of 10 points or greater from baseline in any of these 4 symptoms for at least two consecutive cycles. For those who had not shown deterioration, the data was censored at the last date when the participants completed an assessment for pain, dyspnea, fatigue or cough.

Measure: Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

Time: Baseline until the end of treatment (up to 48 months)

Description: The Euro Quality of Life-5 dimension (EQ-5D) is a brief self-administered, validated reliable generic health status instrument. EQ-5D general health status can also be measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Measure: Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

Time: From Cycle 1 to 41 (up to 48 months)

Measure: Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Fluctuation coefficient between trough and peak plasma concentration was determined as Cmax-Ctrough divided by Cavg, where Cmax was the maximum observed concentration within the dosing interval, Ctrough was the observed concentration prior to dose administration and Cavg was averaged plasma concentration at steady state.

Measure: Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes).

Measure: Apparent Clearance (CL) of Dacomitinib

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration).

Measure: Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose on Day 1 of Cycle 2, 3, 4, 5 and 6

45 Efficacy of EGFR Tyrosine Kinase Inhibitors (EGFR TKIs) in Patients With EGFR-mutated Non-small Cell Lung Cancer Except Both Exon 19 Deletion and Exon 21 L859R: A Retrospective Analysis

Lung cancer is the leading cause of cancer-related death worldwide and is well known to remain a major health problem. Non-small-cell lung cancer (NSCLC) constitutes more than 80% of all the cases of lung cancer. Today, NSCLC can be defined by various molecular criteria. Especially, somatic mutations within the epidermal growth factor receptor (EGFR) gene itself were discovered in a subset of NSCLC patients. Two activating EGFR mutations are in-frame deletion in exon 19 and the substitutions for L858R in exon 21, which account for 85% of all clinically important mutations related to EGFR TKI sensitivity. Besides two activating EGFR mutations, other EGFR mutations in NSCLC have been discovered. G719 and L861 are reported to have intermediate sensitivity to EGFR TKI. And in-frame insertions within exon 20 and T790, which are known to be resistant to EGFR TKIs. However, there are still other EGFR mutations such as E709 and S768 as well as doublet EGFR mutations are also observed. These rare mutations have not been fully described and data on their correlation with response to EGFR-TKIs are still unclear. Research hypothesis Rare EGFR mutations of unknown clinical significance in NSCLC patients, which are distinguish from mutations such as deletion in exon 19, L858 and insertion in exon 20, have some possibility of EGFR TKI sensitivity. Rationale for conducting this study It has an opportunity to be shown the efficacy of EGFR TKIs in patients with rare EGFR mutation in large number of patients in Korea (Asia) during the short period.

NCT01775943 Lung Neoplasms
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Two activating EGFR mutations are in-frame deletion in exon 19 and the substitutions for L858R in exon 21, which account for 85% of all clinically important mutations related to EGFR TKI sensitivity. --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R --- --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R --- --- L858R --- --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R --- --- L858R --- --- L858R --- --- L858R ---

Primary Outcomes

Measure: the efficacy of EGFR TKIs as defined by objective response rate

Time: up to 1 year

Secondary Outcomes

Measure: the incidence of patients with rare EGFR mutated NSCLC

Time: up to 1 year

Other Outcomes

Measure: the clinical characteristics of patients with rare EGFR mutated NSCLC

Time: up to 1 year

Measure: the efficacy of EGFR TKIs as defined by disease control rate, progression-free survival and overall survival in the patients with rare EGFR mutated NSCLC

Time: up to 1 year

46 Detection of Resistance Genes From Serially Collected Plasma DNA in Non-small Cell Lung Cancer Patients Harboring EGFR Activating Mutation Who Are Being Treated With EGFR TKIs

To detect resistance gene from serially collected plasma DNA in non-small cell lung cancer harbouring EGFR activating mutation who are being treated with EGFR TKIs by using castPCR method.

NCT01776684 EGFR Mutation Positive Non-small Cell Lung Cancer Drug: EGFR TKIs (gefitinib, erlotinib, afatinib, et al)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding EGFR Mutation Positive Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding EGFR Mutation Positive Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L858R ---

Primary Outcomes

Description: To evaluate the efficiency of castPCR method for detection of resistance genes, especially, T790M mutation from serially collected plasma DNA in non-small cell lung cancer patients harboring EGFR activating mutation who are being treated with EGFR TKIs

Measure: detection of resistant gene

Time: 24 months

47 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.

NCT01802632 Advanced Non Small Cell Lung Cancer Advanced (Inoperable) Non Small Cell Lung Cancer Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients (with the exception of 1st line expansion cohort) must fulfil one of the following: - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR - Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI. - Previous treatment with a single-agent EGFR TKI (e.g. --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for Dose Escalation Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for 80mg AZD9291 Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

48 A Prospective, Open-label, Single Arm, Multi-center, Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) as the First-line Treatment Medication in Patients With Harboring EGFR Mutations

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation.

NCT01819428 Adenocarcinoma of Lung Stage IIIB Adenocarcinoma of Lung Stage IV Drug: NOV120101 (Poziotinib)
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarcinoma 3. Documented EGFR mutation (e.g., exon 19 deletion, exon 21 L858R, etc.) with tumor tissue 4. Patients who have 1 or more measurable lesions according to RECIST version 1.1 5. ECOG performance status 2 or less 6. --- L858R ---

Patients who cannot participate in this trial by investigator's judgment Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarcinoma 3. Documented EGFR mutation (e.g., exon 19 deletion, exon 21 L858R, etc.) with tumor tissue 4. Patients who have 1 or more measurable lesions according to RECIST version 1.1 5. ECOG performance status 2 or less 6. --- L858R ---

Primary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR)

Measure: Objective response rate (ORR)

Time: about 3 years

Secondary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR) at 12 months following start of study drug administration.

Measure: Progression free survival (PFS) rate at 12 months

Time: 12 months after enrollment of the last subject

Description: the proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: 3 years

Description: The length of time during and after medication or treatment during which the disease being treated (usually cnacer) does not get worse.

Measure: Progression free survival (PFS)

Time: 3 years

Description: the time from study drug administration until death from any cause

Measure: Overall survival (OS)

Time: 3 years

Description: Change means the end of treatment minus baseline in each patient

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: 3 years

Other Outcomes

Description: to observe pharmacokinetic parameter, inter-individual variability and intra-individual variability considering covariates, demographic factors, influencing PK profile.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: 3 months after enrollment of the last subject

Description: to observe HGF expression status in plasma and T790M mutation induction status from plasma DNA

Measure: Subgroup analyses according to the genetic information

Time: 3 years

49 A Phase Ib Study of Afatinib Plus Nimotuzumab in Non-small Cell Lung Cancer Patients Who Progressed With Reversible EGFR TKI

To find the optimal dose of afatinib and nimotuzumab in patients who acquired resistance to gefitinib or erlotinib.

NCT01861223 NSCLC Drug: afatinib (30 or 40mg) + nimotuzumab (100 or 200mg)

Inclusion Criteria: - Histologically confirmed diagnosis of stage IIIB or IV NSCLC - Presence of EGFR sensitizing mutations (L858R mutation in exon 21 or exon 19 deletion) or response by RECIST on prior gefitinib or erlotinib or stable disease on prior gefitinib or erlotinib for at least 6 months - Disease progression on treatemtn with gefitinib or erlotinib within 30 days - Biopsy on disease progression - Age ≥20 years - ECOG performance status of 0, 1, or 2 - Measurable disease by the criteria of RECIST 1.1 - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL; creatinine clearance ≥ 45 mL/min Exclusion Criteria: - Known interstitial lung disease - Prior treatment with EGFR targeting antibodies or BIBW 2992 - Prior three or more lines of chemotherapy for advanced NSCLC - Significant bowel disease impairing drug absorption - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Have symptomatic, untreated, or uncontrolled central nervous system (CNS) metastases. --- L858R ---

Primary Outcomes

Description: To establish maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) for BIBW 2992 and nimotuzumab in patients with acquired resistance to erlotinib or gefitinib

Measure: Maximal tolerated dose

Time: 4 weeks

50 A Randomized, Controlled Phase 2 Study Evaluating LY2875358 Plus Erlotinib Versus Erlotinib as First-Line Treatment in Metastatic Non-Small Cell Lung Cancer Patients With Activating EGFR Mutations Who Have Disease Control After an 8-Week Lead-In Treatment With Erlotinib

The primary purpose of this study is to compare the efficacy of the study drug LY2875358, given together with erlotinib, against erlotinib, alone. Participants will have Non-Small Cell Lung Cancer (NSCLC) that has advanced to Stage IV. Participants should not have been treated with drugs for Stage IV NSCLC, previously. All participants will get erlotinib alone, for approximately 8 weeks. Participants with radiographic disease control at the end of the erlotinib lead-in study period will be randomly assigned to receive LY2875358 plus erlotinib or erlotinib alone. Participants, who were chosen to receive erlotinib, alone, may cross over to the combination treatment at the time of progression.

NCT01897480 Carcinoma, Non-Small-Cell Lung Biological: LY2875358 Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- L858R ---

Primary Outcomes

Measure: Progression Free Survival (PFS)

Time: Randomization to Objective Disease Progression or Death Due to Any Cause (Estimated 3 Years)

Secondary Outcomes

Measure: Change in Tumor Size (CTS)

Time: Baseline to Measurement with Smallest Tumor Size (Estimated 3 Years)

Measure: Proportion of Participants Exhibiting a Confirmed Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])

Time: Baseline to Objective Disease Progression or Start of New Anticancer Therapy (Estimated 3 Years)

Measure: Duration of Response (DoR)

Time: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Estimated 3 Years)

Measure: Time to Progressive Disease (TTPD)

Time: Randomization to Objective Disease Progression (Estimated 3 Years)

Measure: Proportion of Participants Exhibiting a Stable Disease (SD) or a confirmed CR or PR (Disease Control Rate [DCR])

Time: Baseline to Objective Disease Progression or Participant Stops Study (Estimated 3 Years)

Measure: Overall Survival (OS)

Time: Randomization to Death Due to Any Cause (Estimated 5 Years)

Measure: Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ) C30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13)

Time: Baseline, Objective Disease Progression or Participants Stops Study (Estimated 3 Years)

Measure: Pharmacokinetics (PK): Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) of LY2875358 and Erlotinib

Time: Baseline through Cycle 4 (28 Day Cycle)

Measure: Proportion of Participants with Anti-LY2875358 Antibody Response

Time: Baseline through 30 Day Follow Up (Estimated 3 Years)

51 Phase I Study of INC280 Plus Erlotinib in Patients With C-Met Expressing Non-Small Cell Lung Cancer

This phase I trial studies the side effects and best dose of c-Met inhibitor INCB028060 and erlotinib hydrochloride when given together in treating patients with previously treated non-small cell lung cancer. C-Met inhibitor INCB028060 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01911507 Recurrent Non-small Cell Lung Cancer Drug: INC280 Drug: erlotinib hydrochloride
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

G719X, exon 19 deletion, L858R, L861Q) - Systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or World Health Organization [WHO]) while on continuous treatment with gefitinib or erlotinib - Patients must have measurable disease; disease in previously irradiated sites is considered measurable if there is clear disease progression following radiation therapy - Failed 1-2 prior chemotherapies for advanced disease; prior erlotinib is allowed in the dose finding phase and expansion cohort A (Patients in expansion cohort B must be erlotinib naïve and have v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS] wild type tumor) - Patients must be willing to be off therapy for a minimum of two weeks (In expansion cohort A patients on erlotinib do not have to discontinue treatment) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Life expectancy greater than 3 months - Hemoglobin > 9 g/dL (International System [SI] units: 90 g/L) without transfusion support or growth factors within 10 days of starting INC280 - Platelet count >= 75 x 10^9/L - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L without growth factor support - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) - Serum creatinine =< 2 x ULN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting serum triglyceride level =< 500 mg/dL Exclusion Criteria: - Patients who have had major surgery within 4 weeks of initiation of study medication, excluding the placement of vascular access - Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data - Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia - Severely impaired lung function - Active (acute or chronic) or uncontrolled infection - Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy - Liver disease (i.e. --- L858R ---

Primary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Maximum tolerated dose (MTD) of c-Met inhibitor INCB028060 and erlotinib, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4

Time: Up to 28 days after a full course of therapy

Secondary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Toxicities as measured by NCI CTCAE V4

Time: Up to 30 days

Description: Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.

Measure: Overall response rate among patients with measurable disease, measured by RECIST 1.1

Time: Up to 30 days

Measure: Disease control rate, measured by RECIST 1.1

Time: Up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Progression-free survival

Time: Duration of time from start of treatment to time of progression or death, assessed up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Overall survival

Time: Duration of time from the start of treatment to death from any cause, assessed up to 30 days

Measure: Concentrations of c-Met inhibitor INCB028060 in plasma, measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay

Time: Days 15-16 of course 1, days 1 and 15 of course 2, and day 1 of courses 3-4

52 A Randomized Open-Label Phase II Trial of Pemetrexed and a Platinum (Carboplatin or Cisplatin) With or Without Erlotinib in Patients With Non-Small Cell Lung Cancer Harboring Activating Epidermal Growth Factor Receptor Mutations and Acquired Resistance to First-Line EGFR TKIs, Erlotinib or Gefitinib

This randomized phase II trial studies how well pemetrexed disodium and carboplatin or cisplatin with or without erlotinib hydrochloride work in treating patients with epidermal growth factor receptor (EGFR) mutant positive stage IV non-small cell lung cancer and acquired resistance to first-line therapy with erlotinib hydrochloride or gefitinib. In patients that develop resistance to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs) the drug is usually stopped and the patient is switched to chemotherapy. Drugs used in chemotherapy, such as pemetrexed disodium, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pemetrexed disodium and carboplatin or cisplatin is more effective with or without erlotinib hydrochloride in treating patients with EGFR mutant non-small cell lung cancer and acquired resistance to EGFR TKIs.

NCT01928160 Recurrent Non-small Cell Lung Cancer Stage IV Non-small Cell Lung Cancer Drug: pemetrexed disodium Drug: carboplatin Drug: cisplatin Drug: erlotinib hydrochloride Other: laboratory biomarker analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Age > 18 years - Able and willing to comply with the protocol - Histologically- or cytologically-confirmed Stage IV NSCLC with an EGFR exon-19 deletion or L858R mutation - Must have received at least 6 months of first-line therapy with erlotinib or gefitinib - Clinical evidence of progression on first-line EGFR TKI therapy - Adequate hematological function within 7 days of study treatment initiation: 1. Absolute neutrophil count (ANC) > 1.5 x 109/L AND 2. Platelet count > 100 x 109/L AND 3. Hemoglobin > 9 g/dL (may be transfused to maintain or exceed this level) - Adequate liver function within 7 days of study treatment initiation: 1. --- L858R ---

Primary Outcomes

Description: The Kaplan-Meier approach will be used to estimate the time-to-PFS distribution (and median PFS times) for each treatment arm. The stratified log-rank test will be used to compare the PFS distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Progression free survival using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

Time: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs earlier, assessed up to 1 year

Secondary Outcomes

Description: The Kaplan-Meier approach will be used. The stratified log-rank test will be used to compare the Overall Survival (OS) distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Overall survival

Time: From the date of randomization to the date of death from any cause, assessed up to 1 year

Description: An estimate of the objective response rate and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment arm. The Mantel-Haenszel chi-squared test stratified according to the factors specified by EGFR activating mutation type (exon 19 deletion vs. exon 21 single point mutation), time to progression on first-line EGFR TKI (≤ 1 year vs. > 1 year), and ECOG performance status (0 vs. 1) will be used to compare the response rates between the two treatment arms. An unadjusted Fisher's exact test result will also be provided.

Measure: Objective response rate defined as partial response (PR) and complete response (CR) using RECIST version 1.1

Time: Up to 1 year

Description: Safety will be assessed through summaries of Adverse Events (AEs), Serious Adverse Events (SAEs), deaths, grade 3 or 4 AEs, AEs with incidence rates greater than 10% (all grades), AE of grade 3 or 4 with incidence rates greater 2%, and changes in laboratory test results. Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms

Measure: Number of patients with each worst grade toxicity grades 3-5 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4

Time: Up to 45 days post-treatment

53 Third-line Treatment of Gefitinib in NSCLC Patients Who Had Received First-line Gefitinib With EGFR 19del/L858R Mutation and Tumor Progression After the Second-line Chemotherapy: a Single-arm, Prospective and Multi-center Study

The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy

NCT01933347 Non Small Cell Lung Cancer Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Third-line Treatment of Gefitinib in NSCLC Patients Who Had Received First-line Gefitinib With EGFR 19del/L858R Mutation and Tumor Progression After the Second-line Chemotherapy: a Single-arm, Prospective and Multi-center Study. --- L858R ---

Third-line Treatment of Gefitinib in NSCLC Patients The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy Disease Control Rate (DCR). --- L858R ---

Third-line Treatment of Gefitinib in NSCLC Patients The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy Disease Control Rate (DCR). --- L858R --- --- L858R ---

2. Male or female aged 18 years or older; 3. Subjects were diagnosed with stage IIIB or IV NSCLC before starting the first dose of gefitinib third-line treatment; 4. EGFR exon 19 deletion or exon 21 L858R substitution mutation confirmed; 5. ECOG performance status 0-2; 6. Life expectancy of at least 12 weeks or longer; 7. Has at least one measureable lesion by RECIST 1.1; 8. NSCLC of enrolled subjects previously progressed after first-line gefitinib treatment (PFS ≥ 6 months) and progressed again after second-line chemotherapy (not limited for chemotherapy regimen, ≥ 4 cycles of chemotherapy). --- L858R ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung - Primary Study Objective: To evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy - Secondary Study Objectives: To evaluate objective response rate (ORR), progressive-free survival (PFS), overall survival(OS) and quality of life (QoL) of gefitinib as third-line retreatment in NSCLC patients To evaluate the safety of gefitinib as third-line treatment in NSCLC patients - Exploratory analyses: To dynamically monitor EGFR mutation status and explore the relationship with clinical outcome --- L858R ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung - Primary Study Objective: To evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy - Secondary Study Objectives: To evaluate objective response rate (ORR), progressive-free survival (PFS), overall survival(OS) and quality of life (QoL) of gefitinib as third-line retreatment in NSCLC patients To evaluate the safety of gefitinib as third-line treatment in NSCLC patients - Exploratory analyses: To dynamically monitor EGFR mutation status and explore the relationship with clinical outcome --- L858R --- --- L858R ---

Primary Outcomes

Measure: Disease Control Rate (DCR)

Time: week 8

Secondary Outcomes

Measure: objective response rate (ORR), progressive-free survival (PFS), overall survival(OS)

Time: until the death of last subject or 2 years after enrollment

54 A Single-arm Phase II Study to Determine the Efficacy of Preemptive Local Ablative Therapy to Residual Metabolic Active Oligo-metastases in Those EGFR Mutation Positive Non-small Cell Lung Cancer Patients Who Have Achieved a Good Partial Response With First-line EGFR TKI (ATOM)

To determine the efficacy of preemptive local ablative therapy in NSCLC patients with activating EGFR mutation who have oligometastatic residual metabolic-active disease after first-line EGFR TKI, as measured by PFS rate at 1 year from the trial enrollment.

NCT01941654 NSCLC Activating EGFR Mutation Radiation: preemptive local ablative therapy Drug: Oral TKI

Inclusion Criteria: 1. Pathologically confirmed UICC 7th edition Stage IIIB (not amenable for curative intent local radiotherapy)/IV (metastatic or recurrent) non-small cell carcinoma of lung 2. Documented activating EGFR mutation (exon 19 deletion or exon 21 L858R only) in tumor tissues 3. Treated with first-line EGFR TKI for 3 months and achieved good radiological partial response that was documented with a CT scan 4. --- L858R ---

Non-compliance to the study procedure Inclusion Criteria: 1. Pathologically confirmed UICC 7th edition Stage IIIB (not amenable for curative intent local radiotherapy)/IV (metastatic or recurrent) non-small cell carcinoma of lung 2. Documented activating EGFR mutation (exon 19 deletion or exon 21 L858R only) in tumor tissues 3. Treated with first-line EGFR TKI for 3 months and achieved good radiological partial response that was documented with a CT scan 4. --- L858R ---

Primary Outcomes

Measure: PFS rate at 1 year

Time: 2 years

Secondary Outcomes

Measure: Overall survival

Time: 2 years

Measure: Progression-free survival

Time: 2 years

Measure: radiologic change on PET-CT scan 3 months after SABR

Time: 3 months

Measure: Number of Participants with Adverse Events as a Measure of safety

Time: 2 years

55 A Randomized, Open-label Phase II Trial of Erlotinib 100mg Daily Versus Gefitinib 250mg Daily in Patients With Advanced Non-small Cell Lung Cancer Who Harbor EGFR Mutations.

This study is a multicenter, randomized, open-label Phase II trial that compares reduced dose erlotinib 100mg daily and standard dose gefitinib 250mg daily in patients with advanced non-small cell lung cancer who harbor EGFR mutations. The primary endpoint is disease control rate (DCR) and the key secondary endpoint is progression free survival (PFS). A total of 224 eligible patients will be randomized to receive either erlotinib 100mg daily or gefitinib 250mg daily in a 1:1 ratio until patients experience disease progression. Independent assessment of the major endpoints will be completed in a treatment-blinded manner. Randomization will be stratified based on treatment-lines (first-line vs. maintenance vs. second-line therapy). Tumor response and progression will be assessed according to RECIST 1.1.

NCT01955421 Advanced Stage Non Small Cell Lung Cancer Drug: Erlotinib 100mg qd Drug: Gefitinib 250mg qd
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Harboring a PCR-confirmed activating mutation of EGFR, including an exon 19 deletion or an exon 21 L858R point mutation. --- L858R ---

Primary Outcomes

Measure: disease control rate

Time: 2 years

Secondary Outcomes

Measure: progression free survival

Time: 2 years

Description: rash, diarrhea, ILD, etc.

Measure: adverse events

Time: 2 years

56 A Phase IB/II, Open Label, Multicenter Study of Selumetinib Administered Orally in Combination With Gefitinib in Patients With EGFR-mutated Non-small Cell Lung Cancer Who Have Developed Acquired Resistance of EGFR Inhibitor Treatment

This is an open-label, non-randomized, multicenter phase Ib/II study, which is composed of a phase Ib dose escalation part and a phase II dose expansion part. Patients will receive selumetinib in combination with gefitinib 250mg daily. This study will enroll EGFR-mutated NSCLC patients who have developed acquired resistance to EGFR TKI treatment.

NCT02025114 Non-small Cell Lung Cancer (NSCLC) Drug: selumetinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A tumor harboring an EGFR mutation known to be associated with drug sensitivity (ie, exon 19 deletion , L858R, L861Q, G719X etc.). --- L858R ---

Primary Outcomes

Description: Frequency and characteristics of DLTs to the selumetinib and gefitinib combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. (an expected average of 18 weeks) If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, then dose escalation may occur.

Measure: To determine the MTD and/or RP2D

Time: an expected average of 18 weeks

Secondary Outcomes

Description: to estimate overall clinical activity of selumetinib combined with gefitinib in EGFR-mutated NSCLC patients who have acquired resistance to EGFR TKIs

Measure: Overall Response Rate (ORR)

Time: Patients will be followed up for 2 years(post disease progression)

57 An Open-label, Randomized, Phase II Study of Erlotinib Monotherapy Versus Docetaxel and Cisplatin as Neoadjuvant Therapy in Patients of Stage IIIA Lung Adenocarcinoma With Epidermal Growth Factor Receptor Gene Mutation.

To compare clinical response (complete response and partial response) by RECIST) rates by RECIST between erlotinib monotherapy and docetaxel plus cisplatin chemotherapy

NCT02036359 Non-small Cell Lung Cancer(NSCLC) Drug: erlotinib Drug: docetaxel
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Life expectancy > 12 weeks - Tumor specimen with EGFR gene mutation of exon 19 deletion and L858R, G719X, L861Q mutation - Adequate hematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL - Data of INR and PTT should be available in patients taking anticoagulants concomitantly, with INR ≤ 1.5 and PTT ≤ 1.5 times the upper limit of normal (x ULN ) within 7 days prior to starting study treatment - Adequate liver function: serum bilirubin ≤ 1.5 x ULN; transaminases ≤ 2.5 x ULN - Adequate renal function: 24-hour urine creatinine clearance or creatinine clearance measured and calculated according to the formula of Cockroft and Gault ≥ 60ml/min - Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women - Written informed consent. --- L858R ---

Those with exon 19 deletion and L858R, G719X, L861Q mutation were randomized as erlotinib monotherapy or docetaxel plus cisplatin chemotherapy. --- L858R ---

Primary Outcomes

Measure: Number of Adverse Event

Time: Within 28 days of last study dose

58 Phase I, Open-label, Safety, Tolerability and Preliminary Efficacy Study of Tremelimumab in Combination With Gefitinib in EGFR Mutant NSCLC Patients

This is an open-label phase 1, safety, PK, and preliminary efficacy study of oral Gefitinib and IV Tremelimumab in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as Erlotinib or Gefitinib. The primary objective of this phase I, is to determine the safety and tolerability of oral Gefitinib in combination with escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Secondary objectives include evaluation of, pharmacokinetics, immunogenicity, antitumor activity of Gefitinib and Tremelimumab combination. The exploratory objectives are to evaluate biomarkers that may correlate with activity or prospectively identify patients likely to respond to Tremelimumab and Gefitinib. The biological rationale for such a study is that even though the disease is progressing it is likely that EGFR sensitive clones, although diminished under the pressure from the EGFR TKI, are still present. Therefore, withdrawing the inhibitory pressure of the EGFR TKI can potentially allow regrowth of the EGFR sensitive cells. On the other hand, the proliferation of EGFR resistant clones needs to be suppressed by another therapeutic approach. Until today no association of chemotherapy and TKI EGFR has demonstrated clinical benefit. Moreover, patients may have received chemotherapy and the likelihood of chemosensitivity is very low. So, the association of Gefitinib with immune checkpoint blockade is very attractive and may result in clinical benefit in NSCLC with EGFRmut.

NCT02040064 Non Small Cell Lung Cancer Drug: Gefitinib Drug: Tremelimumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R ---

- Previous allogenic bone marrow transplant Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R ---

Primary Outcomes

Description: The primary objective of this phase 1 study is to determine the safety and tolerability of oral Gefitinib in combination with three escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Overall safety profile will be characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCICTCAE] Version 4.03), timing of adverse events and laboratory abnormalities in the first and in the following cycles

Measure: safety and tolerability of the association between Gefitinib (fixed dose) and Tremelimumab (dose escalation)

Time: Up to 42 days

Secondary Outcomes

Description: To obtain a preliminary assessment of the anti-tumour activity of Gefitinib + Tremelimumab by evaluation of tumour response using modified Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and evaluation of Disease control rate and PFS

Measure: Anti-tumour activity of Gefitinib + Tremelimumab

Time: From day 1 cycle 1 every 8 weeks for 24 weeks and then every 6 weeks until progression or death whichever comes first assessed up to 30 months

Description: Immunogenicity results will be analyzed descriptively by summarizing the number and percentage of subjects who develop detectable anti-Tremelimumab antibodies. The immunogenicity titer will be reported for samples confirmed positive for the presence of anti-Tremelimumab antibodies.

Measure: Immunogenicity of Tremelimumab in combination with Gefitinib

Time: At day 1 cycle 1 and then every 8 weeks from day 1 cycle 2 until progression or death whichever comes first assessed up to 30 months

Description: Gefitinib pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)

Measure: Pharmacokinetics of Gefitinib

Time: At first Tremelimumab administration and then every 4 weeks until progression or death whichever comes first assessed up to 30 months

Description: Tremelimumab pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)

Measure: Pharmacokinetics of Tremelimumab

Time: Before and after injection of Tremelimumab at day 1 cycle 1 and at day 8 and day 15 of cycle 1 and then before and after injection at day 1 for every cycle (4 weeks) until progression or death whichever comes first assessed up to 30 months

59 Erlotinib Treatment Beyond Progression in EGFR Mutant or Patients Who Have Responded EGFR TKI in Stage IIIB/IV NSCLC

The purpose of this study is to determine whether continuing erlotinib beyond disease progression in combination with chemotherapy is beneficial for NSCLC patients who have EGFR mutant disease or who have responded to EGFR TKI.

NCT02064491 Non-small Cell Lung Cancer Drug: Erlotinib Drug: Chemotherapy
MeSH:Carcinoma, Non-Small-Cell Lung Disease Progression
HPO:Non-small cell lung carcinoma

- Investigator confirmed progression according RECIST 1.1 during EGFR TKI treatment within 28 days of the randomization - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Performance status: WHO 0-2 - Measurable disease according to RECIST 1.1 - Patients must be able to comply with study treatments - Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study - Neutrophils ≥ 1'000/μl, Platelets ≥ 100'000/μl, Alanine amino transferase ≤ 2.5 × Upper limit of normal (ULN) (< 5 × ULN if liver metastases), Alkaline phosphatase ≤ 2.5 × ULN (< 5 × ULN if liver metastases), Serum bilirubin ≤ 1.5 × ULN, Serum Creatinine ≤ 1.5 × ULN. - Patient must be able to comply with the protocol Exclusion Criteria: - RECIST 1.1 defined disease progression for more than 28 days while on previous EGFR TKI treatment. --- G719A --- --- L858R ---

Primary Outcomes

Measure: Progression-free survival of the whole study population and in the strata 1-2

Time: An expected average of 36 weeks after last subject enrolled into our study

Secondary Outcomes

Measure: Overall Survival

Time: An expected average of 52 weeks after last subject enrolled into our study

Measure: Overall Response Rate

Time: An expected average of 36 weeks after last subject enrolled into our study

Measure: Rate of non-progression at 9 and 18 weeks

Time: 18 weeks after date of randomization of a last patient

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety and toxicity

Time: An expected average of 52 weeks after last subject enrolled into our study

60 A Multi-center, Open-labeled Phase 2 Study of First Line Intermittent and Maintenance of Erlotinib in Combination With Pemetrexed/Carboplatin in ⅢB/IV Non Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Mutation

EGFR-tyrosine kinase inhibitor(TKI)- ie, erlotinib, gefitinib, has been recommended as the first option for EGFR-mutated IIIb/IV NSCLC by serial trials as it prolonged patients' progression-free survival. The OPTIMAl trial indicated that those who received TKI and chemotherapy during the whole treatment window survived longest. Unfortunately, previous studies(INTACT, TRIBUTE et al) that concurrently combined TKI and cytotoxic regimens failed to improve survival in unselected patients. To avoid the potential synergistic antagonism, the FAST-ACT II trial committed a sequential strategy and find a superiority in the combination arm upon chemotherapy even in EGFR-mutated group. However, pharmaceutically, the continuous administration of an EGFR-TKI before subsequent chemotherapy in FAST-ACT II could obviate the effects of cytotoxic agents due to the erlotinib-induced G1 arrest. On the basis of these and other studies, the investigators hypothesized that a better sequential combination strategy of EGFR-TKI and chemotherapy (adding a EGFR-TKI wash-out window before chemotherapy) would be more efficacious than chemotherapy alone. In this study, the investigators investigate the efficacy(PFS:progression free survival), safety, and adverse-event profile of chemotherapy plus intermittent and maintenance of erlotinib, when these drugs were used as first-line treatment in who had non-squamous lung carcinoma with EGFR gene mutation in China.

NCT02066038 Lung, Carcinoma Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmed activating mutation of EGFR—ie, an exon 19 deletion or an exon 21 L858R point mutation. --- L858R ---

Primary Outcomes

Description: Patients were imaged with computed tomography (CT) scan

Measure: Response Evaluation Criteria in Solid Tumors(RECIST) 1.1

Time: eight weeks

61 A Phase IIIb/IV Safety Trial of Nivolumab (BMS-936558) in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed During or After Receiving At Least One Prior Systemic Regimen

The purpose of this study is to estimate the incidence and characterize the outcome of high grade, select adverse events in subjects with advanced or metastatic NSCLC treated with Nivolumab.

NCT02066636 Non Small Cell Lung Cancer (NSCLC) Drug: Nivolumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A switch of an agent within a regimen in order to manage toxicity does not define the start of a new line of therapy - Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate regimen of therapy - Subjects who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible - Subjects with recurrent disease >6 months after platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, who also subsequently progressed during or after a platinum doublet-based regimen given to treat the recurrence are eligible - Subjects with non-squamous histology must be tested for Epithelial Growth Factor Receptor (EGFR) mutations (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution) and Anaplastic Lymphoma Kinase (ALK) rearrangement if tests have not been previously performed. --- L858R ---

Primary Outcomes

Measure: Incidence for high grade (Grade 3-4 and Grade 5) treatment related select adverse events (AEs)

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

Secondary Outcomes

Measure: Incidence for high grade (Grade 3-4 and Grade 5) select AEs

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

Measure: Median time to onset and median time to resolution (Grade 3-4)

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

Description: Immune modulating medication (e.g. corticosteroids, Infliximab, Cyclophosphamide, intravenous immune globulin (IVIG), and Mycophenolate Mofetil)

Measure: Percentage of subjects who received immune modulating medication or hormonal replacement therapy, percentage of subjects who received ≥40 mg Prednisone equivalents, total duration of all immune modulating medications given for select event

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

62 My Pathway: An Open-Label Phase IIa Study Evaluating Trastuzumab/Pertuzumab, Erlotinib, Vemurafenib/Cobimetinib, Vismodegib, Alectinib, and Atezolizumab in Patients Who Have Advanced Solid Tumors With Mutations or Gene Expression Abnormalities Predictive of Response to One of These Agents

This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.

NCT02091141 Neoplasms Solid Tumors Biliary Cancer Salivary Cancer Bladder Cancer Drug: Trastuzumab Drug: Pertuzumab Drug: Erlotinib Drug: Vemurafenib Drug: Cobimetinib Drug: Vismodegib Drug: Alectinib Drug: Atezolizumab

The tissue sample must be submitted within 4 weeks after enrollment General Exclusion Criteria: - Participants with hematologic malignancies - Concurrent administration of any other anti-cancer therapy (except male participants with prostate cancer receiving androgen blockade): Bisphosphonates and denosumab are allowed; Most recent anti-cancer therapy ≤28 days and have not recovered from the side effects, excluding alopecia; Radiation therapy within ≤14 days - Active or untreated brain metastases - History of carcinomatous meningitis - Uncontrolled concurrent malignancy (early stage is allowed if not requiring active therapy or intervention) - Pregnant or breastfeeding women, or intending to become pregnant during the study - Any significant cardiovascular events within 6 months prior to study entry - Pulmonary embolism within 30 days prior to study entry - History or presence of clinically significant ventricular or atrial dysrhythmia >Grade 2 per NCI CTCAE v4.0 - Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results - Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol Study-Drug Specific Exclusion Criteria: Trastuzumab plus Pertuzumab - Previous treatment with any HER2-targeted therapy Erlotinib - Non-small cell lung cancer (NSCLC) or pancreatic cancer identified by exon 19 deletions or exon 21 L858R substitution mutations - EGFR amplifications in the absence of EGFR-activating mutations - Cancers with exon 20 mutations - Previous treatment with erlotinib or any other EGFR inhibitor - Inability to swallow pills - Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of erlotinib Vemurafenib plus Cobimetinib - Malignant melanoma, papillary thyroid cancer, colorectal cancer, or hematologic malignancy including multiple myeloma - LVEF below institutional lower level of normal (LLN) or below 50%, whichever is lower - History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration - Presence of any of the following conditions, which are risk factors for RVO: Uncontrolled glaucoma with intraocular pressure >21 millimetres of mercury (mm Hg); Serum cholesterol ≥Grade 2; Hypertriglyceridemia ≥Grade 2; Hyperglycemia (fasting) ≥Grade 2; Grade ≥2 uncontrolled hypertension (participants with a history of hypertension controlled with anti-hypertensive medication to Grade L858R ---

Primary Outcomes

Description: Tumor response will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for all arms.

Measure: Percentage of Participants in All Tumor-Pathway Cohorts With Overall Response, as Assessed by the Investigator

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants With Tissue Tumor Mutational Burden (tTMB) ≥16 Mutations/Mb With Overall Response, as Assessed by the Independent Review Committee (IRC)

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Secondary Outcomes

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Percentage of Participants With Disease Control

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Progression-Free Survival (PFS)

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Measure: Percentage of Participants who are Alive at Year 1

Time: 1 year

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Duration of Response

Time: From the date of first documented response (complete response [CR] or partial response [PR]) to the time of disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants with tTMB ≥10 Mutations/Mb and <16 Mutations/Mb With Overall Response, as Assessed by the Investigator

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants with Blood Tumor Mutational Burden (bTMB) ≥16 Mutations With Overall Response, as Assessed by the IRC

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Measure: Percentage of Participants With Adverse Events

Time: From first study treatment administration to 30 days (45 days for vismodegib, 90 days for atezolizumab) after the last dose (up to approximately 5 years)

63 Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

NCT02094261 Non Small Cell Lung Cancer Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

64 Intercalated Combination of Chemotherapy and Erlotinib in 1st Line Setting for Patients Advanced Stage Non-small-cell Lung Cancer With Low Abundant Activating EGFR Mutation(INNOVATE)

This is a single arm phase II clinical trial, which aims to evaluate the effectiveness of intercalated combination of doublet chemotherapy of paclitaxel plus carboplatin and erlotinib on patients with advanced stage non-small-cell lung cancer with low abundant activating EGFR mutation.

NCT02095782 Non-small-cell Lung Cancer Drug: Intercalated combination of chemotherapy and erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Low abundant activating EGFR mutation: EGFR exon 19 deletion or exon 21 L858R, which are positive by real-time PCR methods and negative by standard sequencing methods. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy untill progression or death

Measure: Progression free survival defined by imagery methods

Time: 8 weeks

Secondary Outcomes

Description: From start of anti-cancer therapy till progression of death

Measure: Toxicities related to anti-cancer therapy

Time: 8 weeks

65 Second Line Erlitinib Combination With Gemcitabine Cisplatinum in Non-small Cell Lung Cancer Patients Who Harbored EGFR Sensitive Mutation Developed Resistance After First Line TKI Treatment

Numerous evidences verified that erlotinib could dramatically improve the PFS and OS of non-small cell lung cancers who harbor EGFR sensitive mutations, however, primary or secondary resistance will be developed after TKI treatment, doctors do plenty of researches to overcome TKI resistance. FAST ACT-2 study present that, first line erlotinib combined with chemotherapy could improved mOS to more than 30 months in NSCLCs who harbor EGFR sensitive mutations, several study shows that sensitive mutations still exist after TKI resistance, because of the next generation TKIs(such as BIBW2992) are not avaliable at present, agents for met amplification(such as Crizotinib) are so expensive that many Chinese patients could not support. Thus, the investigators hypothesis that, after first line TKI treatment, the patients who developed TKI resistance could still benefit from second line TKI combined with chemotherapy.

NCT02098954 Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Drug: Gemcitabine platinum combined with erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Carcinoma, Non-Small-Cell Lung The investigators will enroll patients diagnosed with advanced non-squamous,non-small cell lung cancer, patients with EGFR TKI sensitive mutations and developed TKI resistance in first line treatment. --- L858R ---

Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Carcinoma, Non-Small-Cell Lung The investigators will enroll patients diagnosed with advanced non-squamous,non-small cell lung cancer, patients with EGFR TKI sensitive mutations and developed TKI resistance in first line treatment. --- L858R --- --- L858R ---

Primary Outcomes

Description: mean progression free survival(mPFS) will be recorded in enroll patients who received second line gemcitabine platinum combined with erlotinib. mPFS should be measured before second line treatment, before the third combined chemotherapy, after the fourth combined chemotherapy, every 3 months during erlotinib treatment, mPFS should be measured up to two years or every time progression disease occurs within two years.

Measure: mean progression free survival(mPFS)

Time: after patients receive treatment, mPFS should be measured before the third cycle of chemotherapy, after the fourth cycle, mPFS should be measured every 3 months up to two years

Secondary Outcomes

Description: mOS should be measured since enrollment, every 3 months we will contact patients to find out detail survival data of each patient until 3 years, or within 3 years if all survival data is obtained.

Measure: mean overall survival(mOS)

Time: every 3 months up to 3 years, or until all the survival data is obtained

Description: 8 week ORR should be measured after enrollment, after combined chemotherapy for 8 weeks, the exact time point should be the ninth week during combined chemotherapy. CR, PR, SD shoud be measured according to RESICT 1.1

Measure: 8 week overall response rate(8 week ORR)

Time: 8 week ORR should be measured after enrollment, the exact time point should be the ninth week after combined chemotherapy

66 A Multicenter, Phase 1/1b, Open-Label, Dose-Escalation Study of ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors

This is a Phase 1/1b open-label study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of ABBV-399 as monotherapy and in combination with osimertinib, erlotinib, and nivolumab in subjects with advanced solid tumors likely to express c-Met. Enrollment is closed for the monotherapy arms, Arm A, and Arm D.

NCT02099058 Advanced Solid Tumors Cancer Drug: Osimertinib Drug: Nivolumab Drug: Telisotuzumab vedotin Drug: Telisotuzumab vedotin Drug: Erlotinib
MeSH:Neoplasms
HPO:Neoplasm

- Participant must have metastatic NSCLC with documented Epidermal Growth Factor Receptor (EGFR) mutation(s) known to be sensitive to osimertinib, including del19, L858R, G719X or L861Q. --- L858R ---

Primary Outcomes

Description: AUC (0-t) = Area under the serum concentration versus time curve from time zero (pre-dose) to the time of the last measurable concentration.

Measure: Area under the curve (AUC) from time zero to the last measurable concentration AUC (0-t)

Time: Up to 24 months

Description: Maximum observed plasma concentration (Cmax)

Measure: Maximum observed plasma concentration (Cmax)

Time: Up to 24 months

Description: Time to Cmax (Tmax)

Measure: Time to Cmax (Tmax)

Time: Up to 24 months

Measure: Terminal elimination half life

Time: Up to 24 months

Secondary Outcomes

Description: ORR is defined as the proportion of the subjects who have a complete response (CR) or partial response (PR).

Measure: Objective response rate (ORR)

Time: Up to 24 months

Description: PFS is defined as the time from the first dose date of ABBV-399 to either disease progression or death, whichever occurs first.

Measure: Progression free survival (PFS)

Time: Up to 24 months

Description: DOR is defined as the time from the subject's initial CR or PR to the time of disease progression.

Measure: Duration of overall response (DOR)

Time: Up to 24 months

67 Sequential Icotinib Plus Chemotherapy Versus Icotinib Alone as First-line Treatment in Stage IIIB/IV Lung Adenocarcinoma: a Randomized, Open-label, Multicenter Study

This randomised, controlled, multicentre trial is designed to assess the efficacy and safety of sequential icotinib plus chemotherapy versus single icotinib as first-line treatment in stage IIIB/IV lung adenocarcinoma patients with EGFR mutation.

NCT02103257 EGFR Positive Non-small Cell Lung Cancer Adenocarcinoma Drug: Sequential Icotinib Plus Chemotherapy Drug: Icotinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

The number of patients who suffered adverse events, which is graded by NCI CTCAE version 4.0.. Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease EGFR Positive Non-small Cell Lung Cancer Adenocarcinoma Adenocarcinoma Adenocarcinoma of Lung null --- L858R ---

The number of patients who suffered adverse events, which is graded by NCI CTCAE version 4.0.. Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease EGFR Positive Non-small Cell Lung Cancer Adenocarcinoma Adenocarcinoma Adenocarcinoma of Lung null --- L858R --- --- L858R ---

Primary Outcomes

Description: A duration from randomization date to disease progression(as defined by RECIST) or death. If a participant are known to have progressed, the time to progression is defined as the time from the date of randomization to the date of progression. Otherwise, a participant will be censored at the last date they are known not to be progressed.

Measure: Progression Free Survival

Time: 15 months

Secondary Outcomes

Description: Overall Survival is assessed via calculation of the time to death due to any cause. If a participant is known to have died, the time to death is defined as the time from the date of randomization to the date of death. Otherwise, a participant will be censored at the last date they are known to be alive.

Measure: Overall survival

Time: 24 months

Description: Number of subjects with confirmed objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Measure: Objective response rate

Time: 15 months

Description: The number of patients who suffered adverse events, which is graded by NCI CTCAE version 4.0.

Measure: Adverse events

Time: 24 months

68 Randomized, Double-Blind, Multicenter, Phase 3 Study Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Advanced or Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)

This is a 2 arm Phase 3 study to evaluate the safety and efficacy of the addition of veliparib plus carboplatin and paclitaxel versus the addition of placebo plus carboplatin and paclitaxel in subjects with advanced or metastatic squamous NSCLC.

NCT02106546 Squamous Non-Small Cell Lung Cancer Drug: carboplatin Drug: veliparib Drug: paclitaxel Drug: placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Subject has peripheral neuropathy >= grade 2. 4. Subject has non-squamous NSCLC, or a known Epidermal Growth Factor Receptor (EGFR) mutation of exon 19 deletion or L858R mutation in exon 21, or a known Anaplastic Lymphoma Kinase (ALK) gene rearrangement. --- L858R ---

Primary Outcomes

Description: Time to death for a given subject will be defined as the number of days from the date that the subject was randomized to the date of the subject's death.

Measure: Overall Survival (OS) in current smokers

Time: Up to 3 years from first dose of study drug

Secondary Outcomes

Description: Time to death for a given subject will be defined as the number of days from the date that the subject was randomized to the date of the subject's death.

Measure: Overall Survival (OS) in all subjects

Time: Up to 3 years from first dose of study drug

Description: Defined as the number of days from the date that the subject was randomized to the date the subject experiences an event of disease progression or to the date of death (all causes of mortality) if disease progression is not reached.

Measure: Progressive-Free Survival (PFS) in current smokers and in all subjects

Time: Up to 3 years from first dose of study drug

Description: Objective response rate is defined as the proportion of subjects with complete or partial response as determined by the investigator per RECIST (version 1.1)

Measure: Objective Response Rate (ORR) in current smokers and in all subjects

Time: Up to 3 years from first dose of study drug

Other Outcomes

Measure: Change in Quality of Life: European Organisation for Research and Treatment of Cancer Quality of Life Core 30 Question Questionnaire (EORTC-QLQ-C30).

Time: From Screening (prior to dosing) up to 2 years

Measure: Change in Quality of Life: European Organisation for Research and Treatment of Cancer Quality of Life Lung Cancer 13 Question Questionnaire (EORTC-LC13).

Time: From Screening (prior to dosing) up to 2 years

Measure: Change in Eastern Cooperative Oncology Group (ECOG) Performance Status

Time: From Screening (prior to dosing) up to 2 years

Measure: Change in Quality of Life: European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L)

Time: From Screening (prior to dosing) up to 2 years

Description: The duration of overall response for a given subject will be defined as the number of days from the day the criteria are met for Complete or Partial Response (whichever is recorded first) to the date that Progressive Disease (PD) is objectively documented.

Measure: Duration of Response

Time: From complete or partial response to disease progression (up to 3 years from randomization).

69 An Open-label, Phase 1 Dose Escalation Study of Oral ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations

The purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.

NCT02113813 Non-Small-Cell Lung Cancer (NSCLC) Epidermal Growth Factor Receptor Mutations Drug: naquotinib Drug: midazolam
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.. Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R ---

Exclusion Criteria: - Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment - Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days - Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV) - Symptomatic Central Nervous System (CNS) metastasis - Active infection requiring systemic therapy within 14 days - Severe or uncontrolled systemic diseases including uncontrolled hypertension - History of or active interstitial lung disease - Screening QTcF >450 msec or current medication known to prolong QT - ≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months - History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction - Concurrent corneal disorder or ophthalmologic condition making subject unsuitable - RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days - Any other malignancy requiring treatment Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03.

Measure: Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)

Time: up to 18 months

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Measure: Safety and tolerability as assessed by adverse events (AEs)

Time: up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.

Measure: Safety and tolerability as assessed by laboratory tests

Time: up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature.

Measure: Safety and tolerability as assessed by vital signs

Time: up to 18 months

Measure: Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)

Time: up to 18 months

Secondary Outcomes

Description: Maximum concentration (Cmax), the time after dosing when Cmax occurs (tmax), area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast), area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf), apparent terminal elimination half-life (t1/2), apparent oral systemic clearance (CL/F), Apparent volume of distribution (Vz/F)

Measure: Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3

Measure: Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2

Description: Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.

Measure: Best overall response rate

Time: Up to 18 months

Description: Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.

Measure: Disease control rate

Time: Up to 18 months

Description: Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.

Measure: Progression free survival

Time: Up to 18 months

70 A Single-Arm Phase II Clinical Trial of Cabozantinib (XL184) in Patients With Previously Treated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases With and Without C Met Amplification

This is an open-label phase II clinical trial designed to allow a preliminary assessment of the efficacy and safety of cabozantinib in unselected Non-Small Cell Lung Cancer (NSCLC) patients with metastases to the brain and in the subset of patients with c-MET amplified Non-Small Cell Lung Cancer with metastases to the brain. Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial. Patients with clinically asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating investigator. Patients who have undergone treatment for their brain metastases with Whole-Brain Radiation Therapy (WBRT), stereotactic radiosurgery (SRS) or surgery must be clinically stable and recovered from all procedures at the time of study enrollment.

NCT02132598 Non Small Cell Lung Cancer (NSCLC) Metastases to the Brain Drug: cabozantinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients must agree to submission of these specimens as defined in Section 9. - c-MET amplification will be determined by FISH ratio (c-MET/CEP7) > 2.0, based on testing of the primary tumor and/or site of metastatic disease - Patients' tumors must undergo testing for Epidermal Growth Factor Receptor (EGFR) exon 19 deletion, EGFR exon 21 L858R substitution, and anaplastic lymphoma kinase (ALK) rearrangements. --- L858R ---

Primary Outcomes

Measure: To assess the Overall Response Rate (ORR)

Time: 12 months

Secondary Outcomes

Measure: To assess the Disease Control Rate (DCR)

Time: 16 weeks

Measure: To assess the Progression-free Survival (PFS)

Time: 12 months

Measure: To assess the Overall Survival (OS)

Time: 24 months

Description: Seriousness, severity/ grade and relationship to study treatment will be assessed by the investigator. Severity/ grade will be defined by the National Cancer Institute (NCI) CTCAE v4.0. Subjects will be monitored continuously for Adverse Events (AE's) throughout the study and for 30 days after the last dose of study treatment and for any serious adverse event (SAE) assessed as related to study treatment or study procedures, even if the SAE occurs more than 30 days after the last dose of study treatment.

Measure: Number of Participants with Serious and Non-Serious Adverse Events

Time: Monitor AE's continuously during study and for 30 days after the last dose of study treatment and SAE's assessed as related to study treatment until resolution

Description: For this study, computed tomography scans will be performed every 8 weeks for assessment of extra-cranial disease. An MRI of the brain with contrast (or CT brain with contrast in patients who are unable to obtain an MRI, e.g., has a pacemaker) will be performed every 8 weeks to assess intracranial disease. In patients whose first site of disease progression is extra-cranial disease, a brain MRI (or CT brain with contrast in patients who are unable to obtain an MRI) will be performed at the time of extra-cranial disease progression and every 12 weeks in the study follow-up period. Subjects continuing to show benefit, (complete response [CR], partial response [PR], or stable disease [SD]) as defined by RECIST v1.1 may continue on study. Subjects with PD as defined by RECIST v1.1 should have their treatment discontinued, and they should enter the post-treatment phase of the study. The same method for tumor assessment should be employed at every assessment

Measure: Time to Progression (TTP) of intra-cranial disease

Time: Baseline at 28 days prior to 1st dose, then every 8 weeks till Progressive Disease followed by every 12 weeks for 5 years

71 Phase 3, Randomized, Placebo-Controlled, Double-Blind, Multi-Center, Two-Part Study of Patritumab (U3-1287) In Combination With Erlotinib in EGFR Wild-type Subjects With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Who Have Progressed on at Least One Prior Systemic Therapy

1. Part A: Subjects will receive Patritumab or placebo with erlotinib. Progression-free survival will be the primary outcome. Subjects will need to have Epidermal Growth Factor Receptor (EGFR) wild-type, locally advance or metastatic NSCLC and have their cancer progressed after at least one prior systemic anti-cancer therapy, available recent or archival tumor specimen and may not have had previous EGFR-targeted regimen, anti-HER2 (Human Epidermal Growth Factor Receptor 2), anti-HER3, or anti-HER4 therapy. Subjects may have high heregulin or low heregulin. 2. Part B: Subjects will receive Patritumab or placebo with erlotinib. Overall survival will be the primary outcome. Subjects will need to have EGFR wild-type, locally advance or metastatic NSCLC and have their cancer progressed after at least one prior systemic anti-cancer therapy, available recent or archival tumor specimen and may not have had previous EGFR-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy. Only subjects with high heregulin will be enrolled.

NCT02134015 Lung Cancer Non-small Cell Lung Cancer Drug: Patritumab Drug: Erlotinib Drug: Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

If tumor histology is adenocarcinoma, must have wild-type EGFR genotype as assessed by a validated assay that includes exon 19 deletion and exon 21 (L858R) substitution. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table.

Measure: Part A: Progression Free Survival (PFS) in Heregulin-high Participants

Time: by trial termination (at 20 months)

Description: PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table.

Measure: Part A: Progression Free Survival (PFS) in Heregulin-low Participants

Time: by trial termination (at 20 months)

Description: Percentage of participants still alive at the end of Part B

Measure: Part B: Overall Survival

Time: 4 years

Secondary Outcomes

Description: Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial

Measure: Part A: Overall Survival in HRG High Participants

Time: by trial termination (at 20 months)

Description: Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial

Measure: Part A: Key Secondary Efficacy Endpoint: Overall Survival in HRG Low Participants

Time: by trial termination (at 20 months)

Description: PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (TTD, as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause.

Measure: Part B: Key Secondary Efficacy Endpoint: PFS, TTD

Time: 4 years

Description: Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response (CR) or partial response (PR) Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response [in the order of CR, PR, stable disease (SD), and progressive disease (PD)] among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable.

Measure: Part A: Objective Response Rate (ORR) in HRG High Participants

Time: by trial termination (at 20 months)

Description: Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response or partial response Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response (in the order of CR, PR, SD, and PD) among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable.

Measure: Part A: Objective Response Rate (ORR) in HRG Low Participants

Time: by trial termination (at 20 months)

72 Phase 3 Study of Erlotinib 100mg or 150mg in Treating EGFR Mutated Patients With Non-small Cell Lung Cancer

The purpose of this study is to determine whether 100mg erlotinib had similar effect compared with 150mg erlotinib in NSCLC patients with EGFR mutation in China.

NCT02140333 NSCLC EGFR Mutation Drug: Erlotinib

Inclusion Criteria: 1. Histological diagnosis of NSCLC with phase IIIB or IV disease; 2. Sensitive mutation EGFR gene (18, 19 del, 21 L858R gene mutation) (mutation detection methods:ARMS-PCR, sequence method) 3. Never received anti-tumor therapies for the advanced stage; 4. Never used EGFR inhibitors; 5. Measurable disease by RECIST criteria; 6. --- L858R ---

Primary Outcomes

Measure: Progression free survival

Time: 2 years after the initial dose

Secondary Outcomes

Measure: The objective response rate

Time: Patients will be followed for an expected average of 6 months

Other Outcomes

Measure: Overall survival

Time: 3 year after the initial dose

Measure: Adverse events

Time: 1 year

73 A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety,Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm+ Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON).

The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer.

NCT02143466 Advanced Non Small Cell Lung Cancer Drug: Part A - AZD9291 in combination with AZD6094 Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects) Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects) Drug: Part A - AZD9291 in combination with intermittent selumetinib Drug: Part A - AZD9291 in combination with MEDI4736 Drug: Part B - AZD9291 in combination with AZD6094 Drug: Part B - AZD9291 in combination with selumetinib Drug: Part B - AZD9291 in combination with MEDI4736 Drug: Part C - AZD6094 monotherapy (Japan only) Drug: Part C - AZD9291 in combination with AZD6094 (Japan only) Drug: Part D - AZD9291 in combination with AZD6094
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including exon 19 deletion and L858R). --- L858R ---

Primary Outcomes

Description: Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.

Measure: Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Description: Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent. Part C monotherapy cohort (Japan only): To investigate and confirm the safety and tolerability of AZD6094 when given orally to Japanese patients with advanced solid malignancies. Part C combination cohort (Japan only): To investigate the safety and tolerability of AZD9291 when given orally to Japanese patients with EGFRm+ NSCLC in combination with AZD6094 who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation. Part D: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 (300 mg OD) in patients with locally advanced or metastatic EGFRm+ NSCLC.

Measure: Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Secondary Outcomes

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-t after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-24 after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Terminal half life after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CL/f after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Volume of distribution after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmin after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times for the duration of treatment.

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUCss after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CLss/f after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Rac after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Time dependency of PK after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1.

Measure: Objective response rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Disease control rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Duration of response

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Percentage change in tumour size

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1 Expansion phase only

Measure: Progression free survival

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.

Measure: Overall survival

Time: Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first.

74 Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer

- Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, 20-30% of patients with EGFR-activating mutations show intrinsic resistance to EGFR-TKI. - EGFR-mutant non-small cell lung cancer (NSCLC) cells with BIM (BCL2L11) deletion polymorphism show the impaired generation of BIM with the proapoptotic BH3 domain, as well as resistance to EGFR-TKI-induced apoptosis. - Both BIM polymorphism (12.9%) and EGFR mutations (50% in lung adenocarcinoma) are more prevalent in the East Asian than in Caucasian populations. BIM is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGFR-TKI in EGFR-mutant NSCLC. - Vorinostat (suberoylanilide hydroxamic acid [SAHA]) is a small-molecule inhibitor of histone deacetylase (HDAC) and induces cell differentiation, cell cycle arrest, and apoptosis in several tumor cells. HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in patients with EGFR-mutant NSCLC in whom resistance to EGFR-TKI is associated with a common BIM polymorphism. EGFR-TKI resistance due to the BIM polymorphism may be able to be circumvented in combination with HDAC inhibition of vorinostat with gefitinib in NSCLC.

NCT02151721 Non-Small-Cell Lung Carcinoma Drug: Vorinostat, gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.. Inclusion Criteria: - Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma) - NSCLC of clinicopathologic stage IIIB or IV for which radical radiation therapy is impracticable, or recurrence after surgery - EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance - Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment - Having a history of treatment with cytotoxic anticancer agents (not including pre- or postoperative chemotherapy that has passed 1 or more year from the day of final administration) - Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory - Having a lesion measureable according to the RECIST guidelines revised version 1.1 (20 mm or larger in 10-mm slice CT, 10 mm or larger in 5-mm slice CT, 15 mm or larger in the minor axis of a lymph node). --- L858R ---

- Verified HBs antigen positivity or HCV antibody positivity (excluding the case of confirmed HCV-RNA negativity) Inclusion Criteria: - Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma) - NSCLC of clinicopathologic stage IIIB or IV for which radical radiation therapy is impracticable, or recurrence after surgery - EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance - Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment - Having a history of treatment with cytotoxic anticancer agents (not including pre- or postoperative chemotherapy that has passed 1 or more year from the day of final administration) - Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory - Having a lesion measureable according to the RECIST guidelines revised version 1.1 (20 mm or larger in 10-mm slice CT, 10 mm or larger in 5-mm slice CT, 15 mm or larger in the minor axis of a lymph node). --- L858R ---

Primary Outcomes

Description: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Measure: MTD (Maximum Tolerated Dose)

Time: Second cycle (Day 28)

75 A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients With EGFR-mutant Lung Adenocarcinoma With Acquired Resistance to Erlotinib

This is a phase 2 study. The goal of this study is to find out what effects, good and/or bad, taking erlotinib and ruxolitinib has on the patients and on lung cancer. Erlotinib and ruxolitinib are FDA approved for other indications, but the use of erlotinib and ruxolitinib together has not been studied before and is not FDA-approved.

NCT02155465 Lung Cancer Drug: Ruxolitinib Drug: Erlotinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - Pathologic evidence of advanced (non-operable or metastatic) biopsy-proven stage IV or recurrent lung cancer reviewed at MSKCC. - a documented somatic activating mutation in EGFR (including but not limited to Exon 19 deletion or L858R) - Radiographic progression during treatment with erlotinib. --- L858R ---

Primary Outcomes

Measure: Maximally Tolerated Dose (MTD) (Phase I)

Time: 1 year

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD), at least a 20% increase in the sum of the diameter of the target lesions or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD

Measure: Assess Overall Response Rate

Time: 1 year

Secondary Outcomes

Description: Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0.

Measure: Number of Participants With NCI CTCAE Toxicity

Time: 2 years

Measure: Progression-free Survival

Time: 2 years

76 A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of a Single Oral Dose of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2 part study in patients with EGFRm+ non small cell lung cancer (NSCLC), whose disease has progressed on an EGFRm TKI, who are refractory or resistant to standard therapy. Part A will assess the effect of multiple oral doses of itraconazole on the single dose pharmacokinetic (PK) parameters of AZD9291. On completion of Part A, patients may continue to take AZD9291 tablets (Part B) following the collection of the 216 hour sample on Day 19 if they and the Investigator deem it appropriate, until such time as their disease progresses, the Investigator believes they are no longer deriving clinical benefit, or they stop taking AZD9291 for any other reason.

NCT02157883 Advanced Non Small Cell Lung Cancer Advanced (Inoperable) Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling Drug: AZD9291 Drug: Itraconazole
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. ECOG performance status 0-1 with no deterioration over the previous 2 weeks. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Secondary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours

Measure: AUC(0-120) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration curve from time zero to last quantifiable dose

Measure: AUC(0-t) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax

Measure: Tmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life

Measure: t1/2 of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution

Measure: Vz/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of maximum plasma AZ5104 concentration

Measure: Cmax of AZ5104

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of maximum plasma AZ7550 concentration

Measure: Cmax of AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

77 An Open-label, Randomised, Phase I, Study to Determine the Effect of Food on the Pharmacokinetics of Single Oral Doses of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2-part study in patients with epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung cancer (NSCLC) whose disease has progressed on treatment with an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI): Part A will determine the effect of food on the pharmacokinetics (PK) of AZD9291; Part B will allow patients further access to AZD9291 and will provide for additional safety data collection. Part A is a randomised, open-label, 2 treatment period crossover study in which patients will each receive a single oral dose of AZD9291 (1 x 80 mg tablet) at breakfast time (approximately 0800) in each of 2 treatment periods (once immediately following a high fat meal [fed], and once in the fasted state [fasted]), with a washout period of 9 days between doses. Approximately 38 patients are planned to be enrolled and dosed; at least 30 evaluable patients will be required to complete Part A (ie, the last PK sample in Treatment Period 2 [TP 2] has been collected). Additional patients may be enrolled to allow for at least 30 evaluable patients.

NCT02163733 Advanced Non Small Cell Lung Cancer Advanced (Inoperable) Non Small Cell Lung Cancer Drug: AZD9291 tablets Procedure: Pharmacokinetic sampling - AZD9291 Other: Dietary Fasted Other: Dietary High Fat Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 72 hours.

Measure: AUC(0-72) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration.

Measure: Cmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Secondary Outcomes

Description: Area under the plasma concentration curve from zero extrapolated to infinity.

Measure: AUC of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Area under the plasma concentration curve from time zero to last quantifiable dose.

Measure: AUC(0-t) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours.

Measure: AUC(0-120) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax.

Measure: Tmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life.

Measure: t1/2 of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration.

Measure: CL/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution.

Measure: Vz/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 72 hours.

Measure: AUC(0-72) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of maximum plasma concentration.

Measure: Cmax of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Area under the plasma concentration curve from time zero to last quantifiable dose for AZ5104 and AZ7550 (metabolites to AZD9291).

Measure: AUC(0-t) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 120 hours.

Measure: AUC(0-120) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of time to Cmax.

Measure: Tmax of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of the terminal half-life.

Measure: t1/2 of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

78 A Multicenter Randomized Phase III Study Comparing Second-line Treatment With Chemotherapy Associated or Not to Erlotinib in NSCLC Patients With Secondary Resistance to TKI-EGFR

The current first line treatment of patients with EGFR activating mutation lung cancer is EGFR TKI. Compared to platinum-based chemotherapy, EGFR-TKIs are superior in terms of response rate and progression-free survival. However, an acquired resistance occurs almost constantly. The second-line treatment includes platinum-based chemotherapy in the absence of contraindication. This chemotherapy is then administered after discontinuing EGFR TKIs. However, a rebound phenomenon of the disease was described in patients who discontinued EGFR TKIs. Some clinical teams therefore recommend, as a precaution, in order to avoid any withdrawal phenomenon, to never discontinue EGFR TKIs in patients developing an EGFR TKI acquired resistance. It seems therefore useful to conduct a study to better define the therapeutic strategy to adopt in patients developing an acquired resistance after having received EGFR TKIs as first line treatment.

NCT02178397 NSCLC Patients With EGFR Activating Mutation Drug: ERLOTINIB WITH CHEMOTHERAPY Drug: CHEMOTHERAPY ONLY
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Presence of one of the EGFR activating mutations in the tumor (exon 19 deletion or L858R, G719X or L861Q) - One additional line of previous chemotherapy is allowed if administered in adjuvant or neoadjuvant setting and received more than six months before. --- L858R ---

Primary Outcomes

Description: Efficacy will be assessed by the PFS, define as time between randomization of the patient in the study and disease progression (local, regional, distant and second cancer) or death (all causes). Alive patients free of progression will be censored at the last follow-up.

Measure: Efficacy by PFS

Time: From date of randomization until the date of first documented progression evaluated every 6-9 weeks

Secondary Outcomes

Description: difference between the scores of QoL at baseline and at 4 months after inclusion for the three targeted dimensions of EORTC QLQ-C30 (global quality of life, fatigue and physical functioning). A difference or 10 points or more at 4 months after inclusion for one score between the 2 arms will be considered as clinically relevant.

Measure: scores of QoL

Time: at 4 months after inclusion

Description: Overall survival defined as time interval between randomization and death (all causes). Alive patients will be censored at the last date of news or data cut off

Measure: Overall survival

Time: From date of randomization until the date of death from any cause, whichever came first, assessed up to 100 months

Description: Tumoral response (complete response, partial response, stable disease, progression) according to RECIST 1.1

Measure: Tumoral response

Time: every 6-9 weeks

Description: Toxicities according to NCI-CTC-AE v.4

Measure: Toxicities

Time: From date of randomization until study participation, assessed up to 100 months

Description: Rebound phenomenon (flare) defined by a hospitalization or a death within 3 weeks for disease progression after the end of TKI EGFR treatment (in the arm without EGFR TKI) and date of onset

Measure: Rebound phenomenon (flare)

Time: within 3 weeks after disease progression before inclusion

79 A Pilot Study Testing the Detection of Oncogenic Tumor Mutations in the Urine and Blood of Lung and Colorectal Cancer Patients

The purpose of this study is to see whether gene mutations can be found in the urine or blood of lung cancer patients and urine of colorectal cancer patients. Gene mutations are when DNA in a gene is damaged in a way that changes the genetic message carried by that gene. Gene mutations can sometimes cause lung cancers. These gene mutations are only found in lung and colorectal cancer cells, not the normal cells in your body. All lung cancer tumors and colorectal cancer tumors are now tested for different gene mutations as their presence affects lung cancer treatment. Tumor samples obtained from a biopsy or surgery are typically tested for these gene mutations.

NCT02186236 Lung Cancer Colorectal Cancer
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

- Patients must have had or intend to have EGFR mutation testing (specifically including exon 19 deletions and L858R) performed on their tumor with results available from a CLIA certified laboratory. --- L858R ---

- Patients must have a confirmed EGFR mutant lung cancer (exon 19 deletions and L858R) with molecular testing results available from a CLIA certified laboratory. --- L858R ---

Primary Outcomes

Description: The Trovagene urine-based assay will test to determine the presence of EGFR mutation in cfDNA or RAS/RAF mutation in colorectal cancer

Measure: EGFR detection in urinary cell free DNA [cfDNA]

Time: 2 years

Description: urine assay to identify EGFR mutations as compared to the gold standard of tumor tissue.

Measure: To validate the Trovagene urine assay

Time: 2 years

Secondary Outcomes

Description: The plasma-based assay will test to determine the presence of EGFR mutation in CTC and in cfDNA.

Measure: EGFR detection in plasma circulating tumor cells [CTC] and plasma cfDNA)

Time: 2 years

80 A Phase Ib Open-label Clinical Trial of Once Daily Oral Treatment of Afatinib Plus Weekly Intravenous Infusion of Xentuzumab (BI 836845) in Patients With EGFR Mutant Non-small Cell Lung Cancer With Progression Following Prior EGFR Tyrosine Kinase Inhibitors

Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy). Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs. Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

NCT02191891 Carcinoma, Non-Small-Cell Lung Drug: BI 836845 Drug: afatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R ---

AZD9291 or CO-1686) Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD) of BI 836845 in combination with afatinib - part A

Time: up to 12 months

Measure: Dose limiting toxicity (DLT) during the first treatment course - part A

Time: up to 28 days

Measure: Objective response (OR), defined as complete response (CR) or partial response (PR)

Time: up to 12 months

Secondary Outcomes

Measure: Disease control (DC), defined as complete response (CR), partial response (PR) or stable disease (SD)

Time: up to 12 months

Measure: Time to objective response, defined as the duration of time from the date of first treatment administration until objective response

Time: up to 12 months

Measure: Duration of objective response, defined as the duration of time from first objective response to the date of first objective tumour progression or death due to any cause

Time: up to 12 months

81 An Open-label Study of the Oral Administration of ASP8273 in Patients With Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

Purpose of the study is to determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. - the safety and tolerability of ASP8273. - the pharmacokinetics (PK) of ASP8273. - the antitumor activity of ASP8273.

NCT02192697 Non-small Cell Lung Cancer Drug: ASP8273
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the del ex19, L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using the Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE ver 4.0 - JCOG)

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by Dose Limiting Toxicities (DLTs)

Time: Up to Day 23

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR) at Week 24

Time: Week 24

Secondary Outcomes

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Measure: Phase I: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase I: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase I: Overall response rate (CR+PR)

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase I: Disease control rate (CR+PR+SD)

Time: Up to 18 months

Measure: Phase II: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase II: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase II: Disease control rate

Time: Up to 18 months

Measure: Phase II: Progression-free survival (PFS)

Time: Up to 18 months

Measure: Phase II: Overall survival (OS)

Time: Up to 18 months

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR)

Time: Up to 18 months

82 Randomized Study of Erlotinib vs Observation in Patients With Completely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase III ALCHEMIST trial studies how well erlotinib hydrochloride compared to observation works in treating patients with stage IB-IIIA non-small cell lung cancer that has been completely removed by surgery. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02193282 Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Other: Clinical Observation Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Other: Placebo Administration
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib (erlotinib hydrochloride) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R ---

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib (erlotinib hydrochloride) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Estimated using the method of Kaplan-Meier survival curves and a 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare OS between the two arms. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess whether the distribution of OS times differ with respect to treatment regimen after having adjusted for the stratification factors as well as other potential prognostic and treatment covariates.

Measure: Overall survival (OS)

Time: The time from randomization until death, assessed up to 10 years

Secondary Outcomes

Description: DFS will be defined as the proportion of patients alive and disease free at 2 years from the date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Disease free survival (DFS) rate

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed at 2 years

Description: Will be defined as the proportion of patients alive at 5 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 5 years

Time: At 5 years

Description: Will be defined as the proportion of patients alive at 10 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 10 years

Time: At 10 years

Description: Estimated using the method of Kaplan-Meier survival curves (21). A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall disease free survival (DFS) between the erlotinib hydrochloride and observation arms

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed up to 10 years

Description: The maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. All adverse events analysis will entail comparisons between the arms within Arms A and B, respectively. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.

Measure: Incidence of adverse events associated with each treatment arm

Time: Up to 10 years

83 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Simvastatin (a Sensitive CYP3A4 Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197234 Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling - AZD9291 Drug: Simvastatin Drug: AZD9291 tablet dosing Procedure: Pharmacokinetic sampling - simvastatin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration

Measure: Cmax of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Secondary Outcomes

Description: Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax

Measure: Tmax of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration

Measure: CL/F of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration

Measure: Cmax of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose

Measure: AUC(0-t) of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

84 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of Rifampicin (a CYP3A4 Inducer) on the Pharmacokinetics of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of rifampicin on the pharmacokinetic (PK) parameters of AZD9291 and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients who complete Part A will be able to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197247 Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling - AZD9291 Drug: Rifampicin Drug: AZD9291 tablet dosing Procedure: Pharmacokinetic sampling - rifampicin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of Css,Max for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of AUCtau for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of AUCtau for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Tss,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Min for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of CLss/F for AZD9291

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of CLss/F for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

85 A Phase 1b Study of Erlotinib and Momelotinib for the Treatment of Epidermal Growth Factor Receptor (EGFR) Mutated EGFR Tyrosine Kinase Inhibitor (TKI) Naïve Metastatic Non-Small Cell Lung Cancer (NSCLC)

This study will evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) of momelotinib (MMB) and erlotinib, as well as define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with erlotinib in adults with epidermal growth factor receptor (EGFR)-mutated, EGFR tyrosine kinase inhibitor (TKI) naive metastatic non-small cell lung cancer (NSCLC). Participants will be sequentially enrolled to receive progressively increasing doses of momelotinib (MMB) in combination with erlotinib. Escalation of momelotinib (MMB) doses will proceed to the MTD, defined as the highest tested dose associated with dose-limiting toxicities (DLT) during the first 28 days of combined erlotinib and momelotinib (MMB) treatment. There will be four dose levels and each treatment cycle will consist of 28 days.

NCT02206763 EGFR Mutated EGFR TKI Naive Metastatic NSCLC Drug: Momelotinib (MMB) Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).. Key Inclusion Criteria: - Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation - Treatment naive OR one prior standard chemotherapy that is platinum-based - Adequate organ function defined as follows: - Hepatic: Total bilirubin < upper limit of the normal range (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN - Hematological: absolute neutrophil count (ANC) ≥1500 cells/mm^3, platelet ≥ 100,000 cells/mm^3, hemoglobin ≥ 9.0 g/dL - Renal: Serum creatinine < ULN OR calculated creatinine clearance (CLcr) of ≥ 60 ml/min - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Key Exclusion Criteria: - Known positive status for human immunodeficiency virus (HIV) - Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C) - Presence of > Grade 1 peripheral neuropathy - Symptomatic leptomeningeal, brain metastases, or spinal cord compression. --- L858R ---

Key Inclusion Criteria: - Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation - Treatment naive OR one prior standard chemotherapy that is platinum-based - Adequate organ function defined as follows: - Hepatic: Total bilirubin < upper limit of the normal range (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN - Hematological: absolute neutrophil count (ANC) ≥1500 cells/mm^3, platelet ≥ 100,000 cells/mm^3, hemoglobin ≥ 9.0 g/dL - Renal: Serum creatinine < ULN OR calculated creatinine clearance (CLcr) of ≥ 60 ml/min - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Key Exclusion Criteria: - Known positive status for human immunodeficiency virus (HIV) - Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C) - Presence of > Grade 1 peripheral neuropathy - Symptomatic leptomeningeal, brain metastases, or spinal cord compression. --- L858R ---

Primary Outcomes

Description: Dose limiting toxicities refer to toxicities experienced during the first 28 days of combined erlotinib and momelotinib (MMB) treatment that have been judged to be clinically significant and related to study treatment.

Measure: Incidence of Dose Limiting Toxicities (DLTs)

Time: Up to 28 days

Measure: Safety as Assessed by the Incidence of Adverse Events (AEs)

Time: Up to 2 years plus 30 days

Measure: Safety as Assessed by the Percentage of Participants Experiencing Treatment-Emergent Graded Lab Abnormalities (including Chemistry, Coagulation, Hematology, and Urinalysis)

Time: Up to 2 years plus 30 days

Measure: Change from Baseline in Vital Signs

Time: Up to 2 years

Secondary Outcomes

Description: Progression-free survival is defined as the interval from first dose date of study drug (MMB/erlotinib) to the earlier of the first documentation of definitive disease progression or death from any cause; definitive disease progression is progression based on RECIST criteria v1.1.

Measure: Progression-Free Survival

Time: Until disease progression (up to 2 years)

Description: Overall survival is defined as the interval from first dose date of study drug (MMB/erlotinib) to death from any cause.

Measure: Overall Survival

Time: Until disease progression (up to 2 years)

Description: Overall response rate is defined as the proportion of participants who achieve a complete response or partial response.

Measure: Overall Response Rate

Time: Until disease progression (up to 2 years)

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: Pharmacokinetic (PK) Parameter: Cmax of momelotinib (MMB)

Time: Predose and up to 24 hours postdose

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of momelotinib (MMB)

Time: Predose and up to 24 hours postdose

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: PK Parameter: Cmax of Erlotinib

Time: Predose and up to 24 hours postdose

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of Erlotinib

Time: Predose and up to 24 hours postdose

86 An Open Label, Single-arm Phase IV Study to Assess the Efficacy and Safety of Afatinib as Second-line Therapy for Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harbouring an EGFR Mutation (Del19 or L858R) Who Have Failed First-line Treatment With Platinum-based Chemotherapy

The objectives of this single-arm, open-label trial are to assess the efficacy and safety of afatinib as second line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring a common EGFR mutation who have failed first-line platinum-based chemotherapy and to demonstrate that the efficacy and safety are comparable to the results seen in previous trials.

NCT02208843 Carcinoma, Non-Small-Cell Lung Drug: Afatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

An Open Label, Single-arm Phase IV Study to Assess the Efficacy and Safety of Afatinib as Second-line Therapy for Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harbouring an EGFR Mutation (Del19 or L858R) Who Have Failed First-line Treatment With Platinum-based Chemotherapy. --- L858R ---

2. Documented EGFR mutation (L858R and/or Deletion 19) with no other known EGFR mutation. --- L858R ---

Primary Outcomes

Description: As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions

Measure: Objective Tumour Response (Complete Response [CR], Partial Response [PR]) as Assessed by the Investigator According to the RECIST Version 1.1

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

Secondary Outcomes

Description: Progression-free survival (PFS) is the time from treatment start to disease progression (or death if the patient died before progression). PFS as assessed based on investigator review according to the response evaluation criteria in solid tumours (RECIST) version 1.1.

Measure: Progression-free Survival (PFS) as Assessed by the Investigator According to RECIST 1.1.

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

Description: As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

Measure: Disease Control (CR, PR, Stable Disease [SD]) as Assessed by the Investigator According to RECIST 1.1

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

87 A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients With EGFR Mutation Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC)

This is the first time in patient study to assess the safety, tolerability and preliminary efficacy of AZD3759 in patients with advanced Non Small Cell Lung Cancer (NSCLC) In this study, patients with Leptomeningeal Metastasis and Brain Metastasis may also be enrolled to assess the anti-tumour efficacy, safety, pharmacokinetics and potential biological activity of AZD9291

NCT02228369 EGFR Mutation Positive Advanced Non Small Cell Lung Cancer Drug: AZD3759 Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del). --- L858R ---

Primary Outcomes

Description: Adverse events will be collected from Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.Physical exam (screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation). ECG and vital signs (screening, Day 1 and 2 of Cycle 0 for AZD3759 cohorts, Day 8 of Cycle 1 for AZD3759 cohorts, Day 1 of every 3-week cycle, treatment discontinuation, and if occurrence of any cardiac adverse event). Lab variables (screening, first dosing day, Day 1, 8 and 15 of multiple dosing, Day 1 of every 3-week cycle and treatment discontinuation). Eye exam (at screening and study drug discontinuation and upon occurrence of any visual AE). Echocardiogram or multigated radionuclide angiography (at screening,whenever necessary as clinically indicated throughout the study for AZD3759 cohorts.

Measure: Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)

Time: From Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.

Secondary Outcomes

Description: The parent drug and N-demethylated metabolite in plasma samples will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, hour in Day 1; 24hour in Day 2 and 48hour in Day 3. AUC: Area Under Curve

Measure: Plasma concentration of AZD3759 and metabolite and pharmacokinetics parameters after single dose of AZD3759(Cmax, tmax, terminal rate constant, half life, AUC, clearance, volume of distribution, mean residence time)

Time: Cycle 0 Day 1 to 3 in Part A patients.

Description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1 . The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients. AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma,urine,cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).

Time: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A. CSF samples: pre-dose of Cycle 1 Day 8 in BM; Pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in LM

Description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1. The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients.

Measure: Plasma,urine, cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)

Time: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A patients. CSF samples: pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in Part B patients .

Description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolite and pharmacokinetics parameters after multiple dose of AZD9291(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).

Time: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.

Description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolites and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)

Time: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.

Description: After 28-day follow-up visit, patients will be followed for overall survival via telephone every 6 weeks until death, lost to follow-up or consent withdrawal

Measure: Overall survival follow up for all expansion patients

Time: Every 6 weeks after the 28- day safety follow-up visit

Description: Blood collection at pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15 to evaluate if AZD3759 affects 4b-hydroxy cholesterol which is an endogenous marker of CYP enzyme induction

Measure: 4b-hydroxy cholesterol in Part B patients with BM

Time: pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15

Description: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hour of Cycle 0 Day 1and Day 4; 24 hour of Cycle 0 Day 2 and Day 4.A Mixed Effects model with treatment (fed/fasted) and period as fixed effects and patient as a random effect will be used to compare AUC/Cmax in the fed state with AUC/Cmax in the fasted state.

Measure: The effect of food on the pharmacokinetics of a single dose of AZD3759 in plasma

Time: Cycle 0 Day 1 to Day 4 in Part B patients with BM

Description: Cerebrospinal fluid collection at screening and every 6 weeks until progression to evaluate the cerebrospinal fluid response rate which is defined as the percentage of leptomeningeal metastasis patients who have at least one cerebrospinal fluid response (100% clearance of tumour cells from cerebrospinal

Measure: Cerebrospinal fluid response rate for patients with LM and/or BM

Time: Screening and every 6 weeks (relative to first dose of multiple dosing) until progression, expected average 6 months

Description: Quality of life questionnaire-Brain Cancer 20 questionnaire completed by patients at screening, Day 1 of every 3-week cycle and treatment discontinuation. Use relevant symptom questions to evaluate improvement of central nervous system symptoms.

Measure: Changes from baseline in central nervous system symptoms (analyzed from QLQ-BN20) in patients with LM treated with AZD3759 /AZD9291

Time: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.

Description: Neurological exam will be performed: screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation

Measure: Changes from baseline in neurological exam in patients with LM treated with AZD3759 /AZD9291

Time: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.

Description: ORR assessed through the number of patients who achieve a disease response (i.e. complete response or partial response) assessed according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease and overall disease

Measure: Measurement of Objective Response Rate (ORR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: DCR assessed through the number of patients who achieve a best response of confirmed CR, confirmed PR or responding, or stable disease according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease, leptomeningeal disease and overall disease

Measure: Measurement of Disease Control Rate (DCR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: RR assessed through the number of patients who have at least one confirmed response of Complete Response or Responding prior to any evidence of progression according to modified RECIST 1.1 criteria for leptomeningeal disease

Measure: Measurement of Response Rate (RR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: PFS assessed through change in tumour size (as well as assessment of non-target lesions and appearance of any new lesions) according to modified RECIST 1.1 criteria for Part B patients with brain metastasis and patients with leptomeningeal metastasis

Measure: Measurement of Progression Free Survival (PFS)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: Best LM assessment via LANO criteria through the number of patients with LM present at baseline, without a requirement for confirmation. LANO assessments will be mapped to RECIST-like scores and performed via central imaging reading.

Measure: Best Leptomeningeal Metastasis (LM) assessment for AZD9291 LM patients

Time: Screening within 28days

88 A Phase 2, Open-Label, Multi-Center Study to Assess Safety and Efficacy of Second/Third-Line Treatment With NAB®-Paclitaxel (ABI-007) In Combination With Epigenetic Modifying Therapy Of CC-486, Or Immunotherapy of Durvalumab (MEDI4736), Or As Monotherapy In Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC): Abound.2L+

This is a Phase 2, open-label, multicenter study to assess the efficacy and safety of second/third-line treatment with nab-paclitaxel in combination with the epigenetic modifying therapy of CC-486 or immunotherapy of durvalumab, and nab-paclitaxel monotherapy in subjects with advanced non-small cell lung cancer (NSCLC).

NCT02250326 Carcinoma, Non-Small-Cell Lung Drug: nab-paclitaxel IV Drug: CC-486 Drug: Duravalumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Known activating EGFR mutations (such as exon 19 deletions or L858R). 5. Known activating EML4-ALK mutations. --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time in months from the date of randomization/assignment to the date of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria documented by computed tomography (CT) scan, not including symptomatic deterioration, or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. Participants who did not have disease progression and had not died, regardless of whether they were discontinued from treatment, were censored at the date of last tumor assessment, on or prior to the clinical cut-off date that the participant was progression free. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions from nadir.

Measure: Kaplan Meier Estimate of Progression-Free Survival (PFS) as Assessed by the Investigator

Time: From date of first dose of IP to DP; up to data cut-off date of 30 August (Aug) 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 December (Dec) 2017 for Durva + nab-paclitaxel; participants were followed for PFS for up to 18 months

Secondary Outcomes

Description: Disease control rate was defined as the percentage of participants who had a CR, PR or SD during the course of the study, according to RECIST version 1.1 criteria, as evaluated by the investigator. RECIST Version 1.1 criteria is defined as follows: Complete Response is the disappearance of all target lesions; Partial Response is at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. Responses were evaluated every 6 weeks.

Measure: Percentage of Participants Who Achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) According to RECIST V 1.1 Criteria

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Overall Response was defined as percentage of participants who achieved a radiologic confirmed complete response or partial response according to RECIST V 1.1 criteria and compared with baseline among all tumor assessments, where baseline was the last CT obtained prior to or on Day 1 of treatment. Per RECIST V 1.1 criteria, a CR is defined as a disappearance of all target lesions; a PR is defined as having at least a 30% decrease in the sum of diameters of target lesions from baseline. Responses were evaluated every 6 weeks.

Measure: Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response According to RECIST V 1.1 Criteria

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Overall survival was defined as the time in months between randomization/treatment assignment and death from any cause. Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact.

Measure: Kaplan Meier Estimate of Overall Survival (OS)

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; participants were followed for overall survival up to 30 months

Description: TEAEs were defined as any adverse event or serious adverse event that occurred or worsened on or after the day of the first dose of the IP through 28 days after the last dose of IP for Arms A and C or up to 90 days after the last dose for Arm B, and those SAEs made known to the investigator at any time thereafter that are suspected of being related to IP. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild l intervention/therapy required Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death.

Measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Entire Treatment Period

Time: TEAEs were collected up to 4 weeks after receiving last dose of IP for nab-paclitaxel and CC-486 + nab-paclitaxel, and up to 90 days after the last IP dose for Durva + nab-paclitaxel; TEAEs were collected up to 86.1 weeks

Description: The discontinuation rate was defined as the percentage of participants who had study drug discontinued and was assessed throughout the conduct of the study.

Measure: Percentage of Participants Who Discontinued Study Treatment

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks.

Measure: Dose Intensity Per Week of Nab-Paclitaxel

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks.

Measure: Dose Intensity Per Week of CC-486

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks).

Measure: Dose Intensity Per Week of Durvalumab

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: A dose reduction occurred when the dose assigned at a visit was lower than the dose assigned at the previous visit. Dose reductions were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities.

Measure: Percentage of Participants With Study Drug Dose Reductions

Time: Up to 16 Jan 2017 for CC-486 + nab-paclitaxel and up to 23 Dec 2017 for nab-paclitaxel and Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

89 A Randomized, Open-Label, Multicenter, Phase 3 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Subjects Receiving First Cytotoxic Chemotherapy for Metastatic or Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) and Who Are Current or Former Smokers

This is a 2-arm, Phase 3 study to evaluate the safety and efficacy of veliparib plus carboplatin and paclitaxel versus the Investigator's choice of standard chemotherapy in Lung Subtype Panel (LSP) positive subjects with metastatic or advanced non-squamous non-small cell lung cancer.

NCT02264990 Non-squamous Non-small Cell Lung Cancer Drug: Paclitaxel Drug: Pemetrexed Drug: Carboplatin Drug: Cisplatin Drug: Veliparib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Subject has peripheral neuropathy ≥ grade 2. - Subject has squamous NSCLC, or an untreated known EGFR mutation of exon 19 deletion or L858R mutation in exon 21, or a known ALK gene rearrangement. --- L858R ---

Primary Outcomes

Description: Overall survival is defined as the number of days from the date that the participant was randomized to the date of the participant's death.

Measure: Overall Survival (OS) in the LSP (Lung Subtype Panel) positive subgroup

Time: Up to 3 years from first dose of study drug.

Secondary Outcomes

Description: Objective response rate is defined as the proportion of participants with complete or partial response as determined by the investigator per Response Evaluation Criteria In Solid Tumors (version 1.1).

Measure: Objective Response Rate (ORR) in the LSP (Lung Subtype Panel) positive subgroup and all participants

Time: Up to 3 years from first dose of study drug

Description: Progression-free survival is defined as the number of days from participant randomization to the date the participant experiences an event of disease progression (PD) or death (all causes of mortality), if PD is not reached.

Measure: Progression Free Survival (PFS) in the LSP (Lung Subtype Panel) positive subgroup and all participants

Time: Up to 5 years from first dose of study drug

Description: Overall survival is defined as the number of days from the date that the participant was randomized to the date of the participant's death.

Measure: Overall Survival (OS) in all participants

Time: Up to 5 years from first dose of study drug.

Other Outcomes

Description: Participants will answer the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L) and the Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 questionnaire.

Measure: Change in Quality of Life in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: From Screening (prior to dosing) up to 2 years

Description: The duration of overall response for a participant is defined as the number of days from when the criteria is met for a complete or partial response (whichever occurs first), to the date that progressive disease (PD) is objectively documented.

Measure: Duration of overall response (DOR) in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: Up to 3 years from randomization.

Measure: Change in Eastern Cooperative Oncology Group (ECOG) Performance Status in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: From Screening (prior to dosing) up to 2 years

90 Phase II Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment of HER2 Amplified Advanced Gastric, Gastroesophageal Junction and Esophageal Cancer

The investigators are doing this research program to find out if the investigational drug, afatinib which is a medication known to block the function of the ErbB2 protein might help standard chemotherapy, in particular paclitaxel, work better. Afatinib (GILOTRIF) is a highly potent, irreversible inhibitor of the EGFR and HER2. On July 12, 2013 the United States Food and Drug Administration (US FDA) approved afatinib for the first-line treatment of patients with metastatic non-small cell lung cancer whose tumors had specific EGFR gene mutations (exon 19 deletions or exon 21 i.e. L858R substitution mutations) as detected by an FDA approved test. Paclitaxel is a standard, anti-cancer medicine that has been approved by the US Food and Drug Administration (FDA) for the treatment of lung cancer. The combination of Afatinib and Paclitaxel are considered investigational when used in this research program. An investigational drug is a drug that is not approved by the FDA for its indication.

NCT02274012 HER-2 Positive Gastric Cancer Gastrooesophageal Cancer Esophageal Cancer Drug: Afatinib Drug: Paclitaxel
MeSH:Esophageal Neoplasms
HPO:Esophageal neoplasm

L858R substitution mutations) as detected by an FDA approved test. --- L858R ---

Primary Outcomes

Measure: Change of tumor burden (in centimeters) for participants during protocol therapy

Time: Change from Baseline Tumor burden, measured every 8 weeks, up to approximately 4 years

Secondary Outcomes

Description: Safety of BIBW 2992 will be evaluated as indicated by intensity and incidence of adverse events, graded according to US National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0. Safety endpoints include: events leading to dose reduction events leading to permanent treatment discontinuation the overall incidence and CTC criteria grade of adverse events, as well as relatedness of adverse events to treatment causes of death

Measure: Number of participants with adverse events.

Time: up to approximately 36 months

Description: CTC number changes from cycle 1, day 1 to cycle 2/3, day 1 will be correlated with response rate, progression-free survival as well as skin toxicity.

Measure: Total number of circulating tumor cell (CTC) numbers.

Time: up to approximately 36 months

Measure: Clinical benefit in progression free survival.

Time: every 3 months up to approximately 4 years

Measure: Clinical benefit in overall survival.

Time: every 3 months up to approximately 4 years

Description: Diagnostic tumor specimens will be retrieved for all subjects participating in the protocol. These specimens will be used for confirmation of ErbB2 status as well as correlative analyses of clinical response.

Measure: ErbB2 levels benefit during therapy.

Time: up to approximately 4 years

91 A Prospective Study of Plasma Genotyping as a Noninvasive Biomarker for Genotype-directed Cancer Care

Tumor genotyping has become an essential biomarker for the care of advanced lung cancer and melanoma, and is currently used to identify patients for treatment with targeted kinase inhibitors like erlotinib and vemurafenib. However, tumor genotyping can be slow and cumbersome, and is limited by availability of tumor biopsy tissue for testing. The aim of this study is to prospectively evaluate a blood-based genotyping tool that can quantify the presence of oncogenic mutations (EGFR, KRAS, BRAF) in patients with lung cancer and melanoma. This assay is being studied both as a diagnostic tool for classifying patient genotype, and a serial measurement tool for quantification of response and progression on therapy.

NCT02279004 NSCLC Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.. Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- L858R ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M --- --- L858R ---

Primary Outcomes

Description: We will determine the accuracy of a droplet digital PCR (ddPCR)-based plasma genotyping assay in performing noninvasive tumor genotyping.

Measure: Accuracy of Plasma Genotyping Assay

Time: 2 years

Secondary Outcomes

Description: The amount of time required to perform this noninvasive genotyping assay.

Measure: Turnaround Time of Plasma Genotyping Assay

Time: 2 years

Description: The ability of serial quantitative ddPCR-based plasma genotyping to predict early treatment failure in patients initiating a new line of therapy.

Measure: Early Treatment Failure

Time: 2 years

Description: We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.

Measure: Accuracy of Plasma NGS

Time: 2 years

92 Blood Detection of EGFR Mutation For Iressa Treatment

This study was proposed to validate the efficacy of gefitinib as first-line therapy in advanced lung adenocarcinoma with EGFR mutation determined by plasma cf-DNA.

NCT02282267 Lung Adenocarcinoma Drug: Gefitinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

- EGFR sensitive mutation (including exon 19 del and/or exon 21 L858R) in plasma cf-DNA by ddPCR. --- L858R ---

Primary Outcomes

Measure: objective response rate of gefitinib

Time: up to 6 months

93 Retrospective Multicenter Observational Study in NSCLC Patients With Epidermal Growth Factor Receptor (EGFR) Activating Mutation Treated First Line by Tyrosine Kinase Inhibitor (TKI)

The purpose of our retrospective study is to describe which circumstances EGFR TKI is continued despite progression according to the usual Response Evaluation CrIteria in Solid Tumours (RECIST) in patients with EGFR activating mutations and acquired resistance to EGFR TKI .We will collect their social and demographic data (age, sex), first Progression Free Survival ( PFS) - from start of EGFR TKI to 1st progression PFS 1- and - from first progression according to RECIST to second progression : PFS2- , Overall Survival (OS) - from diagnosis OS 1 and from first progression OS 2 -, mutational status. We will analyze more closely the mode of progression (site), the therapeutic approach at disease progression. We will define two subgroups: those for whom EGFR TKI was continued at least three months despite progression defined according to RECIST criteria, and those for whom a second-line treatment (chemotherapy without EGFR TKI) was chosen at disease progression. It will be individualized the subgroup of patients in whom it was continued TKI after progression.

NCT02293733 NSCLC Non Small Cells Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Variables as : age, gender, PS, histology, brain metastasis, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued or TKI stopped at progression, metastasis number and site, will be considered for adjustment.. Univariate and multivariate analysis of OS. • Univariate and multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. --- L858R ---

Following variables will be considered for adjustment: age, gender, PS, histology, brain metastases, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued to progression or TKI stopped at progression, metastasis number and site. --- L858R ---

Primary Outcomes

Description: • Primary outcome: the therapeutic management of secondary resistance to EGFR TKI (erlotinib or gefitinib) in patients with advanced NSCLC with EGFR activating mutation. Comparison of demographic, clinical, biological features and outcome of patients continuing EGFR TKI at progression versus interrupting TKI at progression. Composite measures will be performed : demographic and clinical data, Progression Free Survival (PFS), Overall Survival (OS), mutational status, mode of progression, therapeutic approach at progressive disease in patients with EGFR mutation treated in first line by EGFR TKI (all population and subgroups : patients receiving EGFR-TKI at progressive disease - Group 1 -, patients discontinuing EGFR TKI at progressive disease - Group 2- ).

Measure: Proportion of patients continuing TKI at 1st progression and proportion of patients discontinuing EGFR TKI at 1st progression. Analysis of the therapeutic management in the 2 groups. This outcome consists in multiple measures.

Time: Patients are followed up to 48 Months maximum

Secondary Outcomes

Description: A comparison of clinical data and outcome of patients receiving EGFR-TKI beyond progressive disease (group 1) versus discontinuing EGFR-TKI at progressive disease (group 2) will be made.

Measure: Comparison of clinical data and outcome of patients

Time: Patients are followed up to 48 Months maximum

Description: • Median Progression Free Survival (PFS) (months) in group 1 and 2 - from start of EGFR TKI to first progression : PFS 1- and - from first progression to second progression : PFS2 -.

Measure: Median Progression Free Survival (PFS)

Time: Patients are followed up to 48 Months maximum

Description: • Univariate an multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. Variables as : age, gender, PS, histology, brain metastasis, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued or TKI stopped at progression, metastasis number and site, will be considered for adjustment.

Measure: Univariate and multivariate analysis of Median over survival (OS)

Time: Patients are followed up to 48 Months maximum

Description: • Univariate and multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. Following variables will be considered for adjustment: age, gender, PS, histology, brain metastases, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued to progression or TKI stopped at progression, metastasis number and site

Measure: Univariate and multivariate analysis of OS

Time: Patients are followed up to 48 Months maximum

94 A Phase III, Double-blind, Randomised Study to Assess the Safety and Efficacy of AZD9291 Versus a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor as First Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non Small Cell Lung Cancer.

To assess the efficacy and safety of AZD9291 versus a standard of care epidermal growth factor receptor tyrosine kinase inhibitor in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

NCT02296125 Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer Drug: AZD9291 80 mg/40 mg + placebo Drug: Placebo Erlotinib 150/100mg Drug: Placebo Gefitinib 250 mg Drug: Erlotinib 150/100 mg Drug: Gefitinib 250 mg Drug: Placebo AZD9291 80 mg/ 40 mg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The three domains of interest were separately analysed using an ANCOVA stratified by race (Asian versus Non-Asian) and mutation type (Ex19del versus L858R). --- L858R ---

4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). 5. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status. --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS. The primary endpoint of PFS was based on Investigator assessment.

Measure: Median Progression Free Survival (PFS) (Months)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS.

Measure: Percentage of Participants in Progression Free Survival at 6, 12, and 18 Months

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression

Secondary Outcomes

Description: ORR was defined as the number (%) of participants with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy. ORR was based on Investigator assessment.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression

Description: Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy.

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression

Description: The DCR was defined as the percentage of participants who had a best overall response (BOR) of Complete response (CR), Partial response (PR) or Stable disease (SD) ≥6 weeks prior to any Progressive disease (PD) event and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy.

Measure: Disease Control Rate (DCR)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression

Description: The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy

Measure: Depth of Response

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression

Description: Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy

Measure: Overall Survival (OS)- Number of Participants With an Event

Time: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)

Description: To characterise the pharmacokinetics (PK) of osimertinib

Measure: Plasma Concentrations of AZD9291

Time: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)

Description: To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ5104.

Measure: Plasma Concentrations of Metabolites AZ5104

Time: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)

Description: To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ7550.

Measure: Plasma Concentrations of Metabolite AZ7550

Time: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)

Description: The CTSQ-16 was a 16-item questionnaire measuring 3 domains related to participant's satisfaction with cancer therapy: Expectations of therapy, Feelings about side effects, and Satisfaction with therapy. Scores ranged from 0 to 100 for each domain, with a higher score associated with the best outcome on each domain. The three domains of interest were separately analysed using an ANCOVA stratified by race (Asian versus Non-Asian) and mutation type (Ex19del versus L858R). The results of the analyses were presented in terms of mean together with standard deviation.

Measure: Participants Reported Outcome by Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 Questionnaire)

Time: Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months)

Description: The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)

Time: Questionnaires completed at baseline, first 9 months, and at week 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 and 36

Description: The EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, combined to produce 5 functional scales, 3 symptom scales, 6 individual items, and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30)

Time: Questionnaires completed at baseline, first 9 months, and at week 6, 12, 18, 24, 30, and 36.

95 Phase 1/2 Open Label Study Of Pf 06459988 (Epidermal Growth Factor Receptor T790m Inhibitor) In Patients With Advanced Epidermal Growth Factor Receptor Mutant (Del 19 Or L858r + - T790m) Non Small Cell Lung Cancer

Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). The resulting PF-06459988 dose selected from the phase 1 portion will undergo a series of sub-studies to fully characterize the impact of food, antacid and CYP3A4 inhibitors/inducers. The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M.

NCT02297425 Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC Drug: PF-06459988
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

A Study For Patients With EGFRm (Epidermal Growth Factor Receptor Mutant) Lung Cancer Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). --- L858R ---

The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M. --- L858R ---

Progression-Free Survival (PFS) - Phase 2. The period from study entry until disease progression, death or date of last contact.. Inclusion Criteria: - Evidence of histological or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del19 or L858R) NSCLC that is resistant to standard therapy. --- L858R ---

Inclusion Criteria: - Evidence of histological or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del19 or L858R) NSCLC that is resistant to standard therapy. --- L858R ---

Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC Lung Neoplasms null --- L858R ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Number of participants with Dose-limiting toxicities (DLT) (phase 1)

Time: up to 21 days

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response (phase 2)

Time: Time from first dose of study drug to objective response of CR or PR up to 24 months

Secondary Outcomes

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response for those patients with measurable disease (phase 1)

Time: time from first dose of study drug until objective response of CR or PR up to 24 months

Description: The period from study entry until disease progression, death or date of last contact.

Measure: Progression-Free Survival (PFS) - Phase 2

Time: time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

96 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Rosuvastatin (a Sensitive BCRP Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of rosuvastatin, following multiple oral dosing of AZD9291 in the fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily as a single agent until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02317016 Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling - AZD9291 Drug: AZD9291 tablet dosing Drug: Rosuvastatin Procedure: Pharmacokinetic sampling - rosuvastatin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 [Period 1] and Day 32 [Period 3], respectively).

Measure: Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC0-t. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration at Time "t" (AUC0-t) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of CL/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance (CL/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of Vz/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Volume of Distribution (Vz/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of t1/2(lambda_z). Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Terminal Elimination Half-life (t1/2[lambda_z]) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of AUCtau. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUCtau) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Maximum Plasma Concentration at Steady State (Css,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of tss,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,min over the dosing interval. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Minimum Plasma Concentration at Steady State (Css,Min) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291 by assessment of CLss/F after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance at Steady State (CLss/F) for AZD9291 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRCss,max for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of Css,Max (MRCss,Max) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRAUCtau for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of AUCtau (MRAUCtau) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

97 A Phase 2, Multicenter, Randomized, Double-blind Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib in Subjects Who Have Previously Untreated Metastatic, EGFR-mutated Non-small Cell Lung Cancer (NSCLC) and BDX004 Positive Label

Phase 2 multicenter, controlled, randomized, double-blind study to evaluate the efficacy and safety of ficlatuzumab versus placebo when administered with erlotinib in subjects with previously untreated metastatic EGFR-mutated NSCLC and BDX004 Positive Label.

NCT02318368 Non-small Cell Lung Cancer Drug: Ficlatuzumab Drug: Erlotinib Drug: placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- An EGFR exon 19 deletion and/or an exon 21 (L858R) substitution mutation. --- L858R ---

Primary Outcomes

Measure: Progression Free Survival is defined as the time from the date of randomization to the date of the first objective documentation of radiographic disease progression or death due to any cause, whichever occurs first.

Time: Approximately 24 months

Secondary Outcomes

Measure: Overall Survival as measured from the date of randomization to the date of death.

Time: Approximately 48 months

Measure: Objective response rate is defined as a CR or PR according to RECIST v.1.1 recorded from randomization until disease progression or death due to any cause.

Time: Approximately 24 months

Measure: Disease control rate is defined as CR, PR, or SD at least 4 cycles (16 weeks) according to the RECIST v.1.1 recorded in the time period between randomization and disease progression or death to any cause.

Time: Approximately 24 months

Measure: Safety and tolerability, as defined by number of AEs.

Time: Approximately 24 months

Measure: PK parameters of ficlatuzumab and erlotinib will be calculated from serum and plasma levels in the blood over time.

Time: Cycle 1 day 1 & day 15, Cycle 2 day 1 & day 15, Cycle 3 day 1 & day 15, Cycle 4 day 1 & day 15, Cycle 5 day 1, Cycle 7 day 1, Cycle 9 day 1, Cycle 11 day 1

98 An epidemiOlogy Study to deteRmine the Prevalence of EGFR muTations in RUSsian Patients With Advanced NSCLC (ORTUS)

This is a multicentre, non-interventional, prospective study to be carried out in representative oncology departments / institutions in order to determine the prevalence of EGFR mutations in treatment-naive Russian patients with cytologically verified advanced NSCLC in Russia.

NCT02321046 Non-Small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment. --- L858R ---

Primary Outcomes

Measure: EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment

Time: up to 18 months

Secondary Outcomes

Measure: Patient characteristics: Gender. Age. Race, ethnicity. Smoking habits. Family history of NSCLC.

Time: up to 18 months

Description: Date of the cytological verification of the NSCLC diagnosis. Disease stage and TNM classification. Morphological classification. Extent of the disease. Performance Status ECOG, including at diagnosis

Measure: Disease information/diagnostic procedures

Time: up to 18 months

Measure: EGFR mutations profile in cytology and/or histology (depending on the availablility of samples) and plasma samples at the time of every progression or in 1.5 year follow up in case of no progression

Time: up to 18 months

Description: 1st line and subsequent lines of therapy treatment, therapy regimen, medicines used for therapy (drugs by INN), for EGFRm+ patients - number of cycles of antitumor therapy, onset date, end date of each line

Measure: Characteristics of the 1st line and subsequent lines of antitumor therapy

Time: up to 18 months

Description: Treatment response/ progression of disease on every line of antitumor therapy: progressive disease, partial response, stable disease and complete response according to RECIST 1.1 evaluation and/or any other clinical assessment. Death: Disease-related or for other reasons

Measure: Clinical outcome/Patient response (for EGFRm+ patients who entered observation phase)

Time: up to 18 months

99 A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.

The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

NCT02335944 Non Small Cell Lung Cancer Drug: INC280 Drug: EGF816
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion criteria: - Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC - Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. --- L858R ---

Primary Outcomes

Measure: Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D)

Time: First 28 days of treatment

Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1

Time: At least 24 weeks

Description: Frequency of treatment-emergent adverse events

Measure: Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity

Time: At least 24 weeks

Secondary Outcomes

Description: Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II)

Time: At least 24 weeks

Description: Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II)

Time: At least 24 weeks

Description: ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Overall Response Rate (Phase Ib and Phase II Group 4)

Time: At least 24 weeks

Description: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Disease Control Rate (Phase I/II)

Time: At least 24 weeks

Description: Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Progression Free Survival (Phase I/II)

Time: At least 24 weeks

Description: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Duration of Response (Phase I/II)

Time: At least 24 weeks

Description: OS is defined as the time from first dose of the study treatment to the date of death due to any cause.

Measure: Overall Survival (Phase I/II)

Time: At least 24 weeks

Measure: Plasma concentration versus time profiles

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Description: TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Time to Response (Phase I/II)

Time: At least 24 weeks

100 Gefitinib Alone or With Concomitant Whole Brain Radiotherapy for Patients Harboring an EGFR Mutation With Multiple Brain Metastases From Non-Small-cell Lung Cancer: a Phase II/III Randomized Controlled Trial

1. Compare the effect and safety of gefitinib alone with gefitinib plus concomitant WBRT(whole-brain radiotherapy ) in treatment of NSCLC patients harboring an EGFR mutation with multiple BM. 2. Verify the failure pattern of NSCLC patients harboring an EGFR mutation with multiple BM. 3. Explore the rescuable therapy after progression of disease.

NCT02338011 Non-Small Cell Lung Cancer Brain Metastases EGFR Gene Mutation Drug: Gefitinib Radiation: WBRT
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Brain Neoplasms
HPO:Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - years of age or older - ECOG score ≤ 2 - Recursive Partitioning Analysis(RPA) Class I-II; - The pathological diagnosis of primary non-small cell lung cancer and detection of pulmonary primary ARMs; - Sequencing EGFR mutation(primary lesion or metastases,exon 19 deletions or exon 21 L858R (EGFR mutation in exon 21, L858R point mutation) mutations; - Enhanced MRI showed brain metastases ≥ 4; - 1 or 2 line treatment revealed failure; - No use of EGFR-TKIs(Tyrosine kinase inhibitors) previously; - No treatment for BM previously,including WBRT, SRS, surgery or experimental therapy; - Expected survival period over 3 months; - Two weeks before randomization, organs function in patients with meet the following criteria: - bone marrow:HB(hemoglobin) ≥ 90g/L, neutrophil≥ 1.5 × 109/L and platelet ≥ 100 × 109/L; - liver function:total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal; - renal function:more than 1.5 times the upper limit of normal serum creatinine or creatinine clearance rate ≥ 60 ml/min; - Urine dipstick testing the proteinuria < 1+; if the urine dipstick test value, 1+, is 24 hours total urine protein must < 500mg; - blood glucose:normal range,DM(diabetes mellitus) patients are under treatment and have a stable state; - Can understand and consent Exclusion Criteria: - Patients have been treated with brain radiation or surgery of BM; - Prior of EGFR-TKIs; - Mixed with small cell lung cancer patients with components; - Wild-type of EGFR; - Unable to tolerate MRI scanning; - Post 2 line treated patients; - Brain meninges metastases or incorporate with brain meninges metastases; - 5 years before other cancers except NSCLC treatment in patients with the start of the study (except for simple operation resection and there are at least 5 consecutive years disease free survival, has been cured of cervical carcinoma in situ, has cured the base cell cancer and bladder epithelial tumor); - Before entering the group 4 weeks received any other investigational drugs; - Incorporate with local symptoms(hemiplegic paralysis, anepia, nystagmus, ataxia.et); --- L858R ---

Inclusion Criteria: - years of age or older - ECOG score ≤ 2 - Recursive Partitioning Analysis(RPA) Class I-II; - The pathological diagnosis of primary non-small cell lung cancer and detection of pulmonary primary ARMs; - Sequencing EGFR mutation(primary lesion or metastases,exon 19 deletions or exon 21 L858R (EGFR mutation in exon 21, L858R point mutation) mutations; - Enhanced MRI showed brain metastases ≥ 4; - 1 or 2 line treatment revealed failure; - No use of EGFR-TKIs(Tyrosine kinase inhibitors) previously; - No treatment for BM previously,including WBRT, SRS, surgery or experimental therapy; - Expected survival period over 3 months; - Two weeks before randomization, organs function in patients with meet the following criteria: - bone marrow:HB(hemoglobin) ≥ 90g/L, neutrophil≥ 1.5 × 109/L and platelet ≥ 100 × 109/L; - liver function:total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal; - renal function:more than 1.5 times the upper limit of normal serum creatinine or creatinine clearance rate ≥ 60 ml/min; - Urine dipstick testing the proteinuria < 1+; if the urine dipstick test value, 1+, is 24 hours total urine protein must < 500mg; - blood glucose:normal range,DM(diabetes mellitus) patients are under treatment and have a stable state; - Can understand and consent Exclusion Criteria: - Patients have been treated with brain radiation or surgery of BM; - Prior of EGFR-TKIs; - Mixed with small cell lung cancer patients with components; - Wild-type of EGFR; - Unable to tolerate MRI scanning; - Post 2 line treated patients; - Brain meninges metastases or incorporate with brain meninges metastases; - 5 years before other cancers except NSCLC treatment in patients with the start of the study (except for simple operation resection and there are at least 5 consecutive years disease free survival, has been cured of cervical carcinoma in situ, has cured the base cell cancer and bladder epithelial tumor); - Before entering the group 4 weeks received any other investigational drugs; - Incorporate with local symptoms(hemiplegic paralysis, anepia, nystagmus, ataxia.et); --- L858R --- --- L858R ---

Primary Outcomes

Description: Compare the progression free survival(PFS) and safety in two arms,including intracranial PFS、extracranial PFS and overall PFS.

Measure: Time to progression

Time: 12-14 months

Secondary Outcomes

Measure: Overall survival

Time: 3 years

Description: intracranial or extracranial site

Measure: Disease Progression Classification

Time: 3 years

Description: measured by ECGO(Eastern Cooperative Oncology Group) PS (Performance Status)

Measure: Health-related quality of life

Time: 3 years

Description: measured by scale of MMSE( Mini Mental Status Examination)

Measure: Mental Status

Time: 3 years

101 PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER

This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

NCT02349633 Non-Small Cell Lung Cancer Drug: PF-06747775 Drug: Palbociclib Drug: Avelumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER. --- T790M --- --- L858R ---

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. --- L858R ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M --- --- T790M --- --- L858R ---

Partial Inclusion criteria: Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC: 1. --- L858R ---

In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm (del 19 or L858R) with any T790M status are eligible to enroll. --- L858R ---

Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. --- T790M --- --- L858R ---

Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. --- T790M --- --- L858R ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Partial Inclusion criteria: Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC: 1. --- L858R ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. --- L858R ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Phase 1 Primary Endpoint - Number of patients with dose limiting toxicities during Phase 1

Time: 21 days

Description: Cohort 1 is an evaluation of PF 06747775 single agent at RP2D Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either palbociclib or avelumab, respectively, based on safety and tolerability. Determination of the RP2D will be performed using the mTPI design. For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib combination, a randomized evaluation of the combination vs PF-06747775 single agent (2:1 ratio) will be initiated (Cohort 2B). For Cohort 3, after determination of the RP2D for the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an overall total of approximately 20 patients to further explore the safety, PK, and antitumor activity of the combination.

Measure: Phase 1b/2 - Cohort 1 = confirmed OR per RECIST; Cohort 2A = Cycle 2 DLT; Cohort 2B = PFS and Cohort 3 = Cycle 1 DLT

Time: Cohorts 1, 2A and 2B = 21 day cycles and Cohort 3 = 28 day cycles

Secondary Outcomes

Description: Number of patients with OR based assessment of confirmed CR or PR according to RECIST. CR are those that persist on repeat imaging at least 4 weeks after the initial documentation of response. PR are those that are greater or equal to a 30% decrease ( per RECIST) under the baseline of the sum of diameters of all target measurable disease

Measure: Phase 1: Secondary Endpoint - Number of patients with Objective Response (OR)

Time: Time from first dose of study drug until OR of CR or PR up to 24 months

Description: PFS (cohort 1, 2A and 3) ORR (cohort 2A, 2B and 3) DOR (All cohorts)

Measure: Phase 1b/2

Time: Time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

102 A Randomized, Double-blind Phase 2 Study of Itacitinib in Combination With Erlotinib Versus Erlotinib Alone in Subjects With Stage IIIB/ IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Activating Mutations

The purpose of this study is to determine if Itacitinib in combination with erlotinib is safe and effective in the treatment of nonsquamous non-small cell lung cancer (NSCLC) that is Stage IIIB/Stage IV or recurrent whose tumors have EGFR activating mutations.

NCT02355431 Solid Tumors and Hematologic Malignancy NSCLC (Non-small Cell Lung Carcinoma) Drug: Itacitinib Drug: erlotinib Drug: placebo
MeSH:Carcinoma, Non-Small-Cell Lung Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of nonsquamous NSCLC that is Stage IIIB, Stage IV, or recurrent (including Stage II). - Documented evidence of an activating mutation in EGFR in tumor samples (exon 19 deletions or point mutation L858R in exon 21 or point mutations at codon 719). --- L858R ---

Primary Outcomes

Description: Subjects will take erlotinib daily and begin dosing with itacitinib once daily (QD) on Cycle 1, Day 1. The safety and tolerability of the regimen will be assessed during the first 21 days of therapy

Measure: Part 1: Determination of the dose of itacitinib that is safe and tolerable in combination with erlotinib as measured by the number of dose-limiting toxicities (DLTs) observed in the evaluation cohort.

Time: Baseline through Day 21

Measure: Part 2: Overall Survival (OS)

Time: Randomization until death. Approximately 31 months.

Description: PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner.

Measure: Part 2: Progression-free survival (PFS)

Time: Randomization to disease progression, or death due to any cause if sooner. Approximately 23 months.

Secondary Outcomes

Description: Objective response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment

Measure: Part 2: Objective Response

Time: Baseline through end of study. Approximately 31 months.

Description: Duration of response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Measure: Part 2: Duration of Response

Time: Baseline through end of study. Approximately 31 months.

Measure: Part 2: Safety and tolerability of the treatment regimens assessed by a summary of adverse events and clinical laboratory assessments.

Time: Baseline through approximately 30 days post treatment discontinuation. Assessed after approximately 31 months.

103 A Phase I/Ib Trial of MK-3475 (Pembrolizumab) and Afatinib in EGFR-Mutant Non-small Cell Lung Cancer With Resistance to Erlotinib

This phase I/Ib trial studies the side effects and best dose of pembrolizumab when given together with afatinib dimaleate in treating patients with non-small cell lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or has come back and does not respond to erlotinib hydrochloride. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and afatinib dimaleate together may be an effective treatment for non-small cell lung cancer.

NCT02364609 Recurrent Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer Drug: Afatinib Dimaleate Biological: Pembrolizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.. Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R ---

Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) - Subjects that require treatment with a strong inhibitor of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) will be excluded; they may be included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and they are willing to switch prior to enrollment; if a subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug administration - Receiving drugs known to be strong inducers or inhibitors of permeability (P)-glycoprotein that are known to interact with afatinib including, but not limited to: ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the subject must stop the strong inducer or inhibitor of P-glycoprotein 7 days before or 5 half lives before study drug administration (whichever timepoint is longer) - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study - Hormonal treatment within 2 weeks prior to start of study treatment - Radiotherapy within 4 weeks prior to enrollment, except as follows: - Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to enrollment, and - Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor-investigator prior to enrolling - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of study Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R ---

Primary Outcomes

Description: Descriptive summaries will be provided for number and proportion with specific type and grade of toxicities.

Measure: Maximum tolerated dose (MTD) recommended dose of pembrolizumab in combination with lead in pembrolizumab and afatinib dimaleate

Time: Day 21

Description: Will be determined by the overall assessment of the MTD and toxicities observed in the dose de-escalation portion of this study.

Measure: Recommended phase II dose

Time: Day 21

Secondary Outcomes

Description: Descriptive summaries will be provided for numbers and proportion of patients responding.

Measure: Overall response rate per RECIST 1.1

Time: Up to 3 years

Description: Kaplan-Meier plot and life-table summary will be used.

Measure: Progression free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years

Other Outcomes

Description: Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in plasma EGFR-mutant DNA levels

Time: Baseline to up to 3 years

Description: Descriptive associations with response rate and PFS will be performed. Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in PDL1 expression by immunohistochemistry

Time: Baseline to up to 3 years

104 A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY OF PF- 06439535 PLUS PACLITAXEL-CARBOPLATIN AND BEVACIZUMAB PLUS PACLITAXEL -CARBOPLATIN FOR THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER.

This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.

NCT02364999 Non-Small Cell Lung Cancer Drug: Bevacizumab-Pfizer Drug: Bevacizumab-EU Drug: Paclitaxel Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Known sensitizing EGFR mutations (for example, deletion 19 or L858R) or EML4-ALK translocation positive mutations. --- L858R ---

Primary Outcomes

Description: ORR refers to percentage of participants who achieved complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits.

Measure: Objective Response Rate (ORR) by Week 19

Time: 25 weeks

Secondary Outcomes

Description: AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Measure: Number of Participants With Treatment-Emergent Adverse Events

Time: 55 weeks

Description: Laboratory evaluation included hematology (hemoglobin, white blood cells, platelets and absolute neutrophil count), blood chemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, magnesium, blood urea nitrogen or urea, and albumin ), coagulation (international normalized ratio for prothrombin time and activated partial thromboplastin time) and urinalysis (dipstick followed by a quantitative urine protein analysis for results of 2+ or greater).

Measure: Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)

Time: 55 weeks

Description: DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause in the absence of documented PD. DOR was based on the Brookmeyer and Crowley method.

Measure: Duration of Response (DOR)

Time: 55 weeks

Description: This outcome measure refers to the possibility of being progression free at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Measure: Progression Free Survival Rate at 55 Weeks

Time: 55 weeks

Description: This outcome measure refers to the possibility of being alive at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Measure: Survival Rate at 55 Weeks

Time: 55 weeks

Measure: Serum Concentration of Bevacizumab up to 1 Year

Time: Pre-dose from Cycle 1 to Cycle 17, 2.5 hours post-dose in Cycle 1, and 1.5 hours post-dose in Cycle 5

Description: ADA assay was performed using a sensitive, specific, and semi-quantitative electrochemiluminescent (ECL) method, which used biotinylated- and ruthenium-labeled PF-06439535 as reagents. Samples with ADA titer greater than or equal to (>=) 2.29 were considered positive.

Measure: Number of Participants With Anti-Drug Antibody (ADA)

Time: 55 weeks

Description: Only samples that were confirmed positive for ADA were further tested for NAb. The NAb analysis was conducted using a single validated quasi-quantitative enzyme-linked immunosorbent assay (ELISA) that utilized PF-06439535 as a reagent. Samples with NAb titer >=1.70 were considered positive.

Measure: Number of Participants With Neutralizing Antibody (NAb)

Time: 55 weeks

105 T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry

The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin).

NCT02368990 Non Small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation prior to enrolment into the study that the tumour harbours the following EGFR mutations known to be associated with EGFR-targeted TKI sensitivity: Ex19Del, L858R, L861Q, and G719X. --- L858R ---

There are Epidermal Growth Factor Receptor (EGFR) mutations known to be associated with EGFR-targeted TKI sensitivity ( Ex19Del, L858R, L861Q, and G719X). --- L858R ---

Primary Outcomes

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause or censoring (at end of 24 months).To assess efficacy of permetrexed + cisplatinum/carboplatin as the 2nd line of treatment of NSCLC.

Measure: Overall Survival

Time: 24 months from last subject in

Secondary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visits

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the date of complete or partial response until the first date of recurrence or progression. To assess the efficacy of 2nd line treatment and beyond.

Measure: Duration of Response as defined by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause. This will be done to assess efficacy of pemetrexed + cisplatin/carboplatin as the 2nd line treatment of NSCLC.

Measure: Progression Free Survival

Time: 24 months from last subject in

106 A Phase Ib, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumour Activity of Volitinib in Combination With Gefitinib in Patients With Epidermal Growth Factor Receptor-mutated Non-small Cell Lung Cancer Who Have Progressed on Epidermal Growth Factor Receptor Inhibitor Treatment

This is a Phase 1b, open-label, multicentre study of AZD6094 in combination with gefitinib in patients with epidermal growth factor receptor (EGFR) mutation positive (m+) and progressed on EGFR Tyrosine kinase inhibitor (TKI) treatment.

NCT02374645 Non-Small Cell Lung Cancer Drug: Volitinib Drug: gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed locally advanced or metastatic NSCLC patients who are harbouring an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X). --- L858R ---

Primary Outcomes

Description: the grade of AE event according to CTC AE 4.0

Measure: Number of adverse events and serious adverse events

Time: From ICF signed to within 28 days after the last dose

Secondary Outcomes

Description: Peak Plasma Concentration (Cmax)

Measure: The Pharmacokinetics (PK) profiles of AZD6094

Time: Cycle 1 Day1 and Day 15

Description: Area under the plasma concentration versus time curve (AUC)

Measure: The Pharmacokinetics (PK) profiles of AZD6094

Time: Cycle 1 Day1 and Day 15

Description: 6-months PFS, 12 months PFS and 24 month PFS

Measure: Progression-free survival (PFS)

Time: from enrolled until progression or death due to any cause, assessed up to 2 year

Description: CR+PR+SD

Measure: Disease control rate(DCR)

Time: 12 weeks and 24 weeks

107 A Study to Evaluate the Efficacy of Rh-Endostatin (Endostar®) in Combination With Icotinib for Advanced Non-Small Cell Lung Cancer With EGFR Mutations

This single-arm pilot study tries to invesitgate how well giving icotinib with rh-endostatin (Endostar®) works in treating patients with advanced stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. Icotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Anti-angiogeneiss drug, such as rh-endostatin, can block tumor growth by inhibiting the ability of tumors to grow new blood vessels and spread. It is not yet known whether icotinib is more effective when given with rh-endostatin in NSCLC patients with EGFR activating mutations.

NCT02375022 Lung Cancer Drug: Endostar and icotinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - Histologic documentation of non small cell lung cancer, with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

- Other active malignancy Inclusion Criteria: - Histologic documentation of non small cell lung cancer, with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

EGFR mutation status: activating mutation (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

Primary Outcomes

Measure: Objective response rate

Time: 6 months

Secondary Outcomes

Measure: Progression free survival

Time: 12 months

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety: Number of Participants with Adverse Events

Time: 12 months

108 SHERLOC: A Phase 2 Study of MM-121 in Combination With Docetaxel Versus Docetaxel Alone in Patients With Heregulin Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Merrimack Pharmaceuticals Inc.)

The purpose of this study is to determine whether the combination of MM-121 plus docetaxel is more effective than docetaxel alone in regards to PFS in patients with heregulin-positive NSCLC.

NCT02387216 Non-Small Cell Lung Cancer NSCLC Adenocarcinoma Heregulin Drug: MM-121 Drug: Docetaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Serum levels of MM-121 will be measured at a central lab using an enzyme-linked immunosorbent assay.. Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Non-Small Cell Lung Cancer NSCLC Adenocarcinoma Heregulin Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma This study is a randomized, open-label, international, multi-center, phase 2 study in patients with Heregulin-positive NSCLC histologically classified as adenocarcinoma that have progressed following no more than two systemic therapies for locally advanced or metastatic disease, one of which must have been a platinum containing regimen. --- L858R ---

Serum levels of MM-121 will be measured at a central lab using an enzyme-linked immunosorbent assay.. Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Non-Small Cell Lung Cancer NSCLC Adenocarcinoma Heregulin Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma This study is a randomized, open-label, international, multi-center, phase 2 study in patients with Heregulin-positive NSCLC histologically classified as adenocarcinoma that have progressed following no more than two systemic therapies for locally advanced or metastatic disease, one of which must have been a platinum containing regimen. --- L858R --- --- L858R ---

Primary Outcomes

Description: Disease status will be assessed according to RECIST v 1.1

Measure: Progression Free Survival

Time: Time from randomization to progression

Secondary Outcomes

Description: Time from randomization to death

Measure: Overall survival

Time: Approximately 3 years

Description: Based on RECIST v1.1

Measure: Objective Response Rate

Time: approximately 3 years

Description: Time from randomization to progression

Measure: Time to Progression

Time: approximately 3 years

Description: Adverse events analysis

Measure: Rate of adverse events reported with the combination of MM-121 with docetaxel

Time: approximately 3 years

Description: Pharmacokinetic (PK) profile of MM-121 when given in combination with docetaxel, and of docetaxel when given in combination with MM-121. PK evaluation will be performed on samples obtained at Week 1 pre-dose and post-dose and at pre-dose at Cycle 2 and beyond to assess pre-treatment trough concentrations of MM-121. The maximum observed concentration (Cmax) will be presented and calculated using non-compartmental analysis. Serum levels of MM-121 will be measured at a central lab using an enzyme-linked immunosorbent assay.

Measure: Pharmacokinetic (PK) parameters of MM-121 in combination with docetaxel and docetaxel when given in combination with MM-121.

Time: approximately 3 years

109 Phase I/Ib Trial of Single Agent PBF-509 and in Combination With PDR001 for Patients With Advanced NSCLC

The purpose of this study is to determine the safety, tolerability, feasibility and preliminary efficacy of the administration of PBF-509 (Adenosine A2a receptor antagonist) as single agent or in combination with PDR001 (programmed cell death 1 receptor antibody (PD-1 Ab)) to NSCLC patients.

NCT02403193 Non-small Cell Lung Cancer (NSCLC) Drug: PBF-509_80 mg Drug: PBF-509_160 mg Drug: PBF-509_320 mg Drug: PBF-509_640 mg Drug: Combo PBF-509 (160 mg) + PDR001 Drug: Combo PBF-509 (320 mg) + PDR001 Drug: Combo PBF-509 (640 mg) + PDR001 Drug: RP2D (PBF-509+PDR001)_immuno naïve Drug: Experimental: RP2D (PBF-509+PDR001)_immuno treated
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Patients must previously have received at least one prior line of therapy for their disease 3. EGFR mutation with exon 19 deletion or L858R mutation (Exon 21) or ALK rearrangement positive must have failed prior TKI therapy 4. Able, willing to give written consent for available archival tumor samples (not mandatory) and tumor biopsies before and during protocol therapy (mandatory). --- L858R ---

Primary Outcomes

Description: The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.

Measure: Maximum Tolerated Dose (MTD) of PBF-509 as single agent

Time: 28 days

Description: The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PDR001 and PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.

Measure: Maximum Tolerated Dose (MTD) of the combination (PBF-509+PDR001) treatment

Time: 56 days

Secondary Outcomes

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients after oral administration of PBF-509.

Measure: Time to PBF-509 peak concentration in plasma "Tmax"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients during a dosing interval at steady state.

Measure: Time to PBF-509 peak concentration in plasma at steady state "Tmax,ss"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed after administration.

Measure: PBF-509 peak concentration in plasma "Cmax"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed during a dosing interval at steady state.

Measure: PBF-509 peak concentration in plasma at steady state"Cmax,ss"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase. "AUC(0-inf)" will be given in Amount·time/ volume units

Measure: The area under PBF-509 plasma concentration-time curve to infinite time "AUC(0-inf)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to a definite time t. "AUC(0-t)" will be given in Amount·time/ volume units.

Measure: The area under PBF-509 plasma concentration-time curve up to time 't' "AUC(0-t)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve over the dosing interval. "AUC(0-τ)" will be given in Amount·time/ volume units.

Measure: The area under PBF-509 plasma concentration-time curve over the dosing interval "AUC(0-τ)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the terminal half-life of PBF-509 in plasma. "t½" will be given in hours (h)

Measure: PBF-509 half-life in plasma " t½"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent volume of distribution during terminal phase after oral / extravascular administration. "Vd/F" will be given in Volume or volume/kg units.

Measure: PBF-509 apparent volume of distribution following extravascular administration"Vd/F"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent total plasma or serum clearance of drug after oral administration. "Cl/F" will be given in the Volume/ time or volume/ time/ kg units.

Measure: PBF-509 total body clearance following extravascular administration "Cl/F"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the accumulation ratio calculated from Cmax,ss at steady state and Cmax after single dosing.

Measure: The PBF 509 accumulation index "Rac"

Time: 8 days

Description: ORR: Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). ORR is defined as confirmed complete response (CR) or partial response (PR) based on modified RECIST v1.1.

Measure: Efficacy as measured by Objective response rate (ORR)

Time: 3 years

Description: The disease control rate (DCR) will be estimated considering the following variables: Complete response (CR), Partial response (PR) and stable disease (SD) as described by Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). These variables will be assessed based on Imaging-based evaluation methods as chest x-ray, conventional computed tomography (CT) and magnetic resonance imaging (MRI) that will be performed every 2 cycles of 28 days administration

Measure: Efficacy as measured by Disease control rate (DCR)

Time: 3 years

Description: Duration of response (DoR) is defined as the duration from the first documentation of OR to the first documented disease progression or death due to any cause, whichever occurs first.

Measure: Efficacy as measured by duration of response (DoR)

Time: 3 years

Description: Progression-free survival (PFS) will be measured from the start of treatment until the documentation of disease progression or death due to any cause, whichever occurs first. For subjects who are alive and progression-free at the time of data cut-off for analysis, PFS will be censored at the last tumor assessment date.

Measure: Efficacy as measured by progression-free survival (PFS)

Time: 3 years

Description: Overall survival (OS) will be determined as the time from the start of treatment until death due to any cause.

Measure: Efficacy as measured by overall survival (OS)

Time: 3 years

110 Open Label Multicenter Phase I/II Study of the Safety and Efficacy of PDR001 Administered to Patients With Advanced Malignancies

The purpose of this "first-in-human" study of PDR001 is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 administered i.v. as a single agent to adult patients with solid tumors. By blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, PDR001 inhibits the PD-1 immune checkpoint, resulting in activation of an antitumor immune response by activating effector T-cells and inhibiting regulatory T-cells. This study has been designed as a phase I/II, multi-center, open-label study starting with a phase I dose escalation part followed by a phase II part. PDR001 will be administered every 2 weeks until patient experiences unacceptable toxicity, progressive disease per immune related Response Criteria (irRC) and/or treatment is discontinued at the discretion of the investigator or the patient.

NCT02404441 Me Melanoma NSCLC Triple Negative Breast Cancer Anaplastic Thyroid Cancer Other Solid Tumors Biological: PDR001
MeSH:Thyroid Neoplasms Triple Negative Breast Neoplasms Thyroid Carcinoma, Anaplastic
HPO:Anaplastic thyroid carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Only patients with EGFR mutation-negative tumor are eligible (defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a minimum; however, if more extensive EGFR mutation testing has been performed, the tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to be considered EGFR mutation-negative). --- L858R ---

Primary Outcomes

Description: To estimate the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) for PDR001

Measure: Part l: The exposure (AUC(0-336h)) after first dose of treatment

Time: 8 months

Description: To estimate the RP2D and/or the MTD for PDR001

Measure: Part l: Incidence of dose limiting toxicities (DLTs)

Time: 8 months

Description: As per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 - to estimte the anti-tumor activity of PDR001. Each cycle = 28 days

Measure: Part ll: Overall response Rate (ORR)

Time: 61 months

Secondary Outcomes

Description: To assess emergence of anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of PDR001. Each cycle = 28 days; End of treatment = expected to be in average 1 year after the start of study treatment

Measure: Presence and/or concentration of anti-PDR001

Time: 42 months

Description: Preliminary antitumor activity of PDR001

Measure: Overall Response Rate (ORR) - Phase l only

Time: 27 months

Description: Preliminary antitumor activity of PDR001

Measure: Progression Free Survival (PFS) - Phase l/ll

Time: 61 months

Description: Preliminary antitumor activity of PDR001

Measure: Duration of Response (DOR) - Phase l/ll

Time: 61 months

Description: Preliminary antitumor activity of PDR001

Measure: Disease Control Rate (DCR) - Phase l/ll

Time: 61 months

Description: Preliminary antitumor activity of PDR001

Measure: Overall Response Rate (ORR) per immune related Response Criteria - Phase ll only

Time: 61 months

Description: Characterize the pharmacokinetic (PK) profile of PDR001

Measure: Serum pharmacokinetic (PK) parameter AUCs

Time: 37 months

Description: Characterize the pharmacokinetic (PK) profile of PDR001

Measure: Serum Pharmacokinetic (PK) parameter Cmax

Time: 37 months

Description: Characterize the pharmacokinetic (PK) profile of PDR001

Measure: Serum Pharmacokinetic (PK) parameter Tmax

Time: 37 months

111 A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer

The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC.

NCT02411448 Metastatic Non-Small Cell Lung Cancer Drug: Ramucirumab Drug: Placebo Drug: Erlotinib Drug: Gefitinib Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Study of Ramucirumab (LY3009806) in Combination With Erlotinib in Previously Untreated Participants With EGFR Mutation-Positive Metastatic NSCLC (RELAY) The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). --- L858R ---

- Eligible for first-line treatment with erlotinib based on documented evidence of tumor harboring an activating EGFR mutation [exon 19 deletion or exon 21 (L858R) substitution mutation]. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the date of radiographically documented progressive disease (PD) based on investigator assessment, or the date of death due to any cause, whichever is first assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Progression Free Survival (PFS)

Time: Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months)

Description: A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section.

Measure: Number of Participants With Treatment-Emergent Adverse Events

Time: Cycle 1 Day 1 through End of Study (Up To 3 Years)

Secondary Outcomes

Description: OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who was not known to have died as of the data-inclusion cutoff date for a particular analysis,OS was censored for that analysis at the date of last contact prior to the data-inclusion cutoff date (contacts considered in the determination of last contact date include adverse event (AE) date, lesion assessment date, visit date, and last known alive date).

Measure: Part B: Overall Survival (OS)

Time: Randomization to Date of Death from Any Cause (Up To 37 Months)

Description: ORR was defined as the percentage of randomized participants achieving a best overall response of partial response (PR) or complete response (CR) assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DCR was defined as the percentage of randomized participants achieving a best overall response of CR,PR, or stable disease(SD) assessed via Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1. CR was defined as the disappearance of all lesions,pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions.PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease(PD) was at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DoR was defined as the date of first documented CR or PR (responder) to the date of progressive disease or the date of death due to any cause, whichever was earlier. If a responder was not known to have died or have progressive disease, then the participant was censored at the date of last evaluable tumor assessment.CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 37 Months)

Description: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Measure: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Time: Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1

Description: Part B: Number of Participants With Anti-Ramucirumab Antibodies.

Measure: Part B: Number of Participants With Anti-Ramucirumab Antibodies

Time: Cycle 1 Predose through Follow-up (Up To 37 Months)

Description: The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-millimeter (mm) lines. A higher score for any item represented a higher level of symptoms/problems. The LCSS total score was defined as the mean of all 9 items. Average symptom burden index (ASBI) was calculated as the mean of the six symptom-specific questions from the LCSS. Potential scores range from 0 (for best outcome) to 100 (for worst outcome).

Measure: Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS)

Time: Baseline, End of Study (Up To 37 Months)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 10 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 28 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 40 (each cycle is 2 weeks)

112 Randomized Double-blinded Comparative Trial to Study the Add-on Activity of Combination Treatment of Nicotinamide on Progression Free Survival for EGFR Mutated Lung Cancer Terminal Stage Patients Being Treated With Gefitinib or Erlotinib

Nicotinamide is an inhibitor of human sirtuins (HDAC III), and is found to re-activate epigenetically silenced tumor suppressors, RUNX3 (runt-related gene 3) and others, in cancer cells. Nicotinamide was found to be effective in several animal cancer models including lung, bladder, liver, etc. The purpose of this study is to determine whether nicotinamide is also effective in the treatment of human lung cancer.

NCT02416739 Non-Small-Cell Lung Carcinoma Drug: Nicotinamide
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Non-Small-Cell Lung Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung The standard therapy to the EGFR (epidermal growth factor receptor) mutation positive non-small-cell lung cancer patients who are not eligible to operation is to administer EGFR-TKIs (tyrosine kinase inhibitors, gefitinib or erlotinib). --- L858R ---

Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Non-Small-Cell Lung Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung The standard therapy to the EGFR (epidermal growth factor receptor) mutation positive non-small-cell lung cancer patients who are not eligible to operation is to administer EGFR-TKIs (tyrosine kinase inhibitors, gefitinib or erlotinib). --- L858R --- --- L858R ---

Primary Outcomes

Description: Cox regression analysis

Measure: Hazard ratio (PFS) of the nicotinamide arm to the placebo arm

Time: two year

Secondary Outcomes

Description: chi-square test of complete response and partial response (RECIST 1.1)

Measure: Response rate

Time: two year

Description: measured by the cancer-related QOL questionaire response (questioned at each visit)

Measure: Difference in quality of life between the nicotinamide arm and the placebo arm

Time: two year

Description: Cox regression analysis

Measure: Overall survival

Time: two year

113 Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study

The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure.

NCT02418234 Non-small Cell Lung Cancer Stage III Non-Small-Cell Lung Cancer Metastatic Other: mutation detection Other: ARMS and ddPCR Genetic: ctDNA analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Investigator confirmed progression according RECIST 1.1 during EGFR-TKI treatment within 28 days of the enrollment - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Patient must be able to comply with the protocol Exclusion Criteria: - Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined disease progression for more than 28 days while on previous EGFR-TKI treatment. --- G719A --- --- L858R ---

Primary Outcomes

Description: The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).

Measure: Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay

Time: up to 2 years

Description: The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.

Measure: Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient

Time: up to 2 years

Secondary Outcomes

Description: The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure

Time: up to 2 years

Description: The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure

Time: up to 2 years

114 Correlation Between Epithelial Growth Factor Receptor(EGFR) Mutation Using cfDNA and CTCs in Patients With Non-Small Cell Lung Cancer

Correlation of epithelial growth factor receptor mutation in blood of lung cancer patient and clinical outcome.

NCT02422628 Lung Cancer
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

3. Tumor harboring EGFR mutation including activating mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861 4. Treatment naive 5. Patients will receive EGFR-TKI as first line treatment. --- L858R ---

3. Tumor with no EGFR mutation detected (mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861) 4. EGFR TKI treatment naïve and without any EGFR TKI treatment in the following process ------- Exclusion criteria For exclusion in the study of NSCLC patients and control subjects should fulfill the following criteria: 1. Subjects should not enter the study if any of the following exclusion criteria are fulfilled: Involvement in the planning and/or conduct of the study (applies to staff at the study site) 2. Previous enrolment in the present study 3. --- L858R ---

Primary Outcomes

Measure: Progressive disease measured by RECIST criteria after receiving 1st line EGFR-TKI

Time: 3 years

115 A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

NCT02438722 Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Drug: Afatinib Dimaleate Biological: Cetuximab Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R ---

Crohn's disease, malabsorption, etc) - Patients must be able to swallow medication by oral route - Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50% - Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed - Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive - Patients must not have any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug - Patients must not be planning to receive any other investigational agents during the course of protocol treatment - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab - Prestudy history and physical must be obtained with 28 days prior to registration - Patients must have Zubrod performance status of 0 - 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R ---

Primary Outcomes

Measure: OS (phase III)

Time: From date of registration to date of death due to any cause, assessed up to 3 years

Measure: PFS (phase II)

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Secondary Outcomes

Measure: PFS

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Description: Compared between arms using a chi-squared test of independence at the 1-sided 5% level.

Measure: Response rates

Time: Up to 3 years

Measure: Time to treatment discontinuation

Time: From date of registration to date of discontinuation of treatment or death due to any cause, assessed up to 3 years

Measure: Time to treatment failure

Time: From date of registration to date of first documentation of progression or symptomatic deterioration, early discontinuation of treatment, or death due to any cause, assessed up to 3 years

Description: Assessed using a chi-squared or Fisher's exact test (as appropriate) at the 1-sided 5% level.

Measure: Toxicity rates assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 3 years

Other Outcomes

Description: For each of these markers, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the absolute difference between the copy number after progression and the copy number in the pre-treatment specimen (or an appropriate transformation of the difference, determined after exploratory data analysis) is not equal to zero.

Measure: Change in copy number alterations in MET, EGFR, and HER2, analyzed using fluorescence in situ hybridization

Time: Baseline up to 3 years (after disease progression)

Description: To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.

Measure: Change in the ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Baseline up to 3 years (at progression)

Description: To evaluate the hypothesis that H-score positive status at baseline is associated with absolute difference in PFS (and OS) among patients randomized to receive afatinib dimaleate monotherapy a test of interaction will be performed at the 1-sided 20% level.

Measure: EGFR immunohistochemistry H-score

Time: Baseline

Description: Tumor marker levels over time will be evaluated using a linear mixed model for continuous markers and using generalized estimating equations for binary markers. A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.

Measure: Levels of circulating tumor markers

Time: Up to 3 years

Description: To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test..

Measure: Presence of de novo EGFR T790M mutation or other molecular alterations

Time: Baseline

Description: To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). Cox regression will be used to assess the predictive association of the ratio in the afatinib dimaleate monotherapy arm with both OS and PFS

Measure: Ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Up to 3 years

116 A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02442349 Non-Small Cell Lung Cancer Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in Asia Pacific patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) sensitising mutation positive (ie, G719X, exon 19 deletion, L858R, L861Q) and T790M mutation positive (hereafter referred to as EGFRm+ and T790M+) un-resectable, locally advanced or metastatic NSCLC (Stage IIIB-IV), who have progressed on an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(EGFR-TKI), either as first line treatment or following one line of EGFR-TKI and one line of platinum containing doublet chemotherapy. --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time of first dose until objective disease progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time first dose until date of progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

117 Pilot Study of Local Therapies for Oligometastatic Non-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations

This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.

NCT02450591 Oligometastatic Lung Adenocarcinoma Drug: Erlotinib Other: Local Therapies
MeSH:Adenocarcinoma Adenocarcinoma of Lung

At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.. Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

Primary Outcomes

Description: At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.

Measure: Feasibility as Measured by at Least Five Patients Will Need to Complete Local Therapy.

Time: 2 years

118 A Phase Ib/II, Open-label, Multicenter Trial With Oral cMET Inhibitor INC280 Alone and in Combination With Erlotinib Versus Platinum With Pemetrexed in Adult Patients With EGFR Mutated, cMET-amplified, Locally Advanced/Metastatic Non-small Cell Lung Cancer (NSCLC) With Acquired Resistance to Prior EGFR Tyrosine Kinase Inhibitor (EGFR TKI)

The purpose of this study was to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of INC280 in combination with erlotinib in the Phase Ib of this study, and to assess the anti-tumor activity and safety of INC280 alone, and in combination with erlotinib, versus platinum with pemetrexed in the Phase II of this study, in adult patients with EGFR mutated, cMET amplified, advanced/metastatic non-small cell lung cancer with acquired resistance to prior EGFR TKI.

NCT02468661 Non-Small Cell Lung Cancer Drug: INC280 single agent Drug: erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Composite pharmacokinetics of erlotinib in the presence of INC280.. Inclusion Criteria: - Locally advanced or metastatic NSCLC - EGFR mutation (L858R and /or ex19del) - cMET amplification by FISH (GCN ≥ 6), - Acquired resistance to EGFR TKI (1st or 2nd generation) - ECOG performance status (PS) ≤ 1. Exclusion Criteria: - Prior treatment with 3rd generation TKI - PhaseII : Prior treatment with any of the following agents: - Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor. --- L858R ---

- Platinum-based chemotherapy as first line treatment Inclusion Criteria: - Locally advanced or metastatic NSCLC - EGFR mutation (L858R and /or ex19del) - cMET amplification by FISH (GCN ≥ 6), - Acquired resistance to EGFR TKI (1st or 2nd generation) - ECOG performance status (PS) ≤ 1. Exclusion Criteria: - Prior treatment with 3rd generation TKI - PhaseII : Prior treatment with any of the following agents: - Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor. --- L858R ---

Primary Outcomes

Description: To determine MTD and/or RP2D of INC280 in combination with erlotinib

Measure: Phase Ib: Frequency and characteristics of Dose Limiting Toxicity (DLTs) to the INC280 and erlotinib combination

Time: First 28 days of dosing

Secondary Outcomes

Description: ORR, proportion of patients with a best overall response of complete response or partial Response (CR+PR)

Measure: Phase Ib: Overall response rate (ORR)

Time: Every 3 weeks, up to 5 years

Description: DCR, proportion of patients with best overall response of CR, PR or SD

Measure: Phase Ib: Disease Control Rate (DCR)

Time: Every 6 weeks, up to 2 years

Description: DOR, defined as time from the first documented CR or PR to first documented progression or death due to any cause

Measure: Phase Ib: Duration of Response (DOR)

Time: Every 6 weeks, up to 2 years

Description: PFS, defined as time from the first dose of study treatment to disease progression or death due to any cause

Measure: Phase Ib: Progression-free Survival (PFS)

Time: Every 6 weeks, up to 2 years

Description: Safety and tolerability of INC280 in combination with erlotinib assessed by change in vital signs, laboratory results and electrocardiogram (ECG).

Measure: Phase Ib: Number of patients with adverse events (AEs) as a measure of safety and tolerability

Time: Every 3 weeks, up to 2 years

Description: Composite pharmacokinetics of INC280 in the presence of erlotinib.

Measure: Phase Ib: Plasma concentration-time profiles of INC280 and pharmacokinetic parameters

Time: 6 weeks

Description: Composite pharmacokinetics of erlotinib in the presence of INC280.

Measure: Phase Ib: Plasma concentration-time profiles of erlotinib in the presence of INC280

Time: 6 weeks

119 A Single Arm, Open-label, Phase 2 Study Evaluating the Efficacy, Safety and PK of HM61713 in Patients With T790M-positive NSCLC After Treatment With an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor

The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT02485652 Non Small Cell Lung Cancer Drug: HM61713
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R ---

Primary Outcomes

Description: To assess the anti-tumor efficacy of HM61713 as measured by objective response rate (ORR).

Measure: Objective response rate (ORR)

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Secondary Outcomes

Description: To assess clinical efficacy of HM61713 regarding disease control rate (DCR).

Measure: Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Duration of overall tumor response (DR).

Measure: Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Progression-free survival (PFS).

Measure: Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Overall survival (OS).

Measure: Overall survival (OS), defined as the time from first administration of study drug until death from any cause

Time: From first dose to end of study or date of death from any cause whichever came first, assessed up to 48 months

Description: To assess clinical efficacy of HM61713 regarding Time to progression (TTP).

Measure: Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding tumor shrinkage.

Measure: Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST tumor response

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Peak concentration (Cmax) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Trough plasma concentration (Ctrough) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Area under the plasma concentration time curve over the 24-hour dosing interval (AUC) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status.

Measure: Patient reported outcomes (PROs)

Time: At baseline and every 6 weeks from time of discontinuation, assessed up to 24 months

Description: To evaluate the effect of HM61713 on the QT interval.

Measure: ECG/QTc (absolute values and change from baseline)

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: Incidence of reported AEs and abnormal laboratory tests (AEs will be assessed using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4).

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: QTc interval as assessed by digital ECG with central reading. The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.

Time: Adverse events will be collected from baseline until 28 days after the last dose

120 Genomic Landscape of EGFR Mutant NSCLC Prior to Afatinib and at the Time of Disease Progression Following Afatinib

The investigators propose to conduct a pilot feasibility study of single agent afatinib in patients with previously untreated metastatic EGFR (epidermal growth factor receptor) mutant adenocarcinoma of the lung (NSCLC = non-small cell lung cancer) with the sole purpose of characterizing the genomic landscape before afatinib and at the time of disease progression.

NCT02491775 Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R ---

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Description: The investigators will compare tumor sequencing prior to afatinib treatment to the time of disease progression to see if the genetic sequencing changed between pre-treatment and progression. The investigators plan to conduct exome and transcriptome sequencing of tumor before therapy with afatinib and at the time of relapse. In addition, exome sequencing of peripheral blood DNA will be done (for germline). Given the complexities of genomic analyses of paired samples in the face of limited data, the investigators will not be able to do any formal power calculations in this feasibility study. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Measure: Genetic changes associated with disease progression following treatment with afatinib

Time: Estimated to be 1 year

Secondary Outcomes

Description: Investigators will look at tumor tissue associated with a therapeutic response and compare with tumor tissue associated with disease progression and see if there are any mutation differences. Therapeutic Response Complete response is disappearance of all target lesions and non-target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Types of mutations in signaling kinases associated with therapeutic response

Time: Estimated to be 1 year

Description: A variant is considered to have mutant biased expression if the variant is expressed and the variant allele frequency is greater than 20% higher in the RNA-seq data compared to the exome sequencing data. A variant is considered to have wild type biased expression if the gene is expressed, the region of the variant is covered at 5X or greater depth, and the VAF is at least 20% lower in the RNA-seq data compared to the exome sequencing data. Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

Measure: Allelic ratio of wild type to mutant EGFR (roughly corrected for intrinsic differences in tumor cellularity) with duration of response

Time: Estimated to be 1 year

121 A Phase 1b/2 Study of ASP2215 in Combination With Erlotinib in Subjects With EGFR Activating Mutation-Positive (EGFRm+) Advanced NSCLC Who Have Acquired Resistance to an EGFR Tyrosine Kinase Inhibitor (TKI)

The purpose of the Phase 1b part of the study was to evaluate the safety and tolerability of ASP2215 in combination with erlotinib and determine the recommended phase 2 dose (RP2D) of ASP2215. The purpose of the Phase 2 part of the study was to evaluate the objective response rate (ORR) of the RP2D of ASP2215 in combination with erlotinib.

NCT02495233 Non-Small-Cell Lung Cancer Drug: Gilteritinib Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Participant had a documented exon 19 deletion or exon 21 L858R EGFR activating mutation. --- L858R ---

Primary Outcomes

Measure: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: Cycle 1 and Cycle ≥2 (up to 141 days)

Description: Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) that started after administration of the study drugs and occurred within 30 days of the last dose of the study drugs. If a participant experienced an event both during the preinvestigational period and during the investigational period, the event was considered a TEAE only if it worsened in severity.

Measure: Number of Participants With Adverse Events

Time: From first dose of study drug up to 30 days after the last dose of study (maximum study drug exposure 114 days)

Secondary Outcomes

Measure: Area Under the Concentration-time Curve at 24 Hours (AUC24) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Maximum Concentration (Cmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Time After Dosing When Cmax Occurs (Tmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Description: All participants in Gilteritinib 120 mg + Erlotinib 150 mg group discontinued before cycle 3.

Measure: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) of Gilteritinib

Time: Predose on Day 1, 3, 8, 15, 22, 28 of cycle 1, Day 1 of cycle 3 and Day 1 of cycle 4

Measure: AUC24 of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Cmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Tmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Ctrough of Erlotinib

Time: Day 8, 15, 22, 28 of cycle 1

Description: ORR was defined as Objective Response Rate (ORR) was the proportion of patients whose best overall response was complete response (CR) or partial response (PR) per RECIST version 1.1. Only patients with measurable disease at baseline were to be included in the analysis of ORR.

Measure: Objective Response Rate (ORR) in Phase 1b

Time: End of treatment (approximately 4 months)

122 A Phase I Trial of AZD9291 and Necitumumab in EGFR-Mutant Non-Small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be a better treatment for EGFR-mutant non-small cell lung cancer.

NCT02496663 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Biological: Necitumumab Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 5.0. The recommended phase II dose (RP2D) will be the MTD, pending review of other safety/tolerability considerations. The RP2D will be determined based upon the MTD in the dose escalation portion as well as other considerations such as toxicities at additional courses. After completing the 4 expansion cohorts, the dose level will be re-reviewed to confirm that the RP2D is in fact well tolerated.

Measure: Maximum tolerated dose (MTD) of necitumumab combined with osimertinib

Time: 21 days

Description: Will be graded according to NCI CTCAE version 5.0. Grade and attribution will be summarized by dose level, cycle, organ system and type.

Measure: Incidence of toxicity

Time: Up to 1 year

Secondary Outcomes

Description: Will be graded according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR). Point estimates and associated 90% confidence intervals will be calculated.

Measure: Objective response rate (ORR) in patients treated at the recommended phase II dose

Time: Up to 1 year

Description: Kaplan-Meier plots will be used to summarize the progression-free survival. Medians and associated 95% confidence intervals will be calculated.

Measure: Progression-free survival (PFS)

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

Description: DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease. Point estimates and associated 90% confidence intervals will be calculated.

Measure: Disease control rate (DCR) with combination osimertinib and necitumumab

Time: Up to 1 year

Other Outcomes

Description: The PK analyses will be descriptive and will permit comparison of the plasma levels of osimertinib and its metabolites in the presence of necitumumab (in this trial) with levels in other studies where osimertinib is given alone or combined with other drugs. We will estimate mean PK parameters as well as the between-patient variability. Results will be listed and plotted, by dose as well as by objective response, qualitative patterns will be described, and means and standard deviations will be calculated for use in planning follow-up studies.

Measure: Pharmacokinetic (PK) parameters of osimertinib in combination with necitumumab

Time: Prior to dosing on day 1 of course 2, 1, 2, 4, 6, 8, and 24 hours after dosing in course 2 (dose escalation and cohort A); prior to treatment on day 1 of course 2 for up to 4 courses (cohorts B, C, and D)

Description: Will study biopsied tumor tissue as well as serial plasma deoxyribonucleic acid specimens. For each cohort alone, Fisher's exact test, and in a stratified analysis including all cohorts, an exact logistic regression model, will be used to examine the association with objective response and a Cox proportional hazards model will be used to examine the association with PFS. Odds ratio's and hazard ratio's will be estimated and associated 90% two-sided confidence intervals will be constructed. Testing will be one-sided, at the 0.05-level.

Measure: Presence of biomarkers of response and resistance to previous EGFR-tyrosine kinase inhibitors

Time: Up to 1 year

123 Phase II Study of ASP8273 — An Open-Label, Study of the Oral Administration of ASP8273 in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-NaïvePatients With Non-Small Cell Lung Cancer Harboring EGFR Mutations

The purpose of this study is to determine the safety, the antitumor activity and the pharmacokinetics of ASP8273 in EGFR tyrosine kinase inhibitor (EGFR-TKI)-naïve patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations.

NCT02500927 EGFR-TKI-naïve Patients With NSCLC Harboring EGFR Activating Mutations Drug: ASP8273 Capsules Drug: ASP8273 Capsules A
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the deletion of exon 19 (del ex19), L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R ---

Primary Outcomes

Measure: Safety assessed by AEs

Time: Up to 18 months

Measure: Safety assessed by Laboratory tests

Time: Up to 18 months

Measure: Safety assessed by Vital signs

Time: Up to 18 months

Measure: Safety assessed by Percutaneous oxygen saturation (SpO2)

Time: Up to 18 months

Measure: Safety assessed by Body weight

Time: Up to 18 months

Description: ECG: Electrocardiogram

Measure: Safety assessed by 12-lead ECG

Time: Up to 18 months

Measure: Safety assessed by Ophthalmologic examination

Time: Up to 18 months

Measure: Safety assessed by Chest X-ray examination

Time: Up to 18 months

Measure: Safety assessed by Chest computed tomography (CT) examination

Time: Up to 18 months

Measure: Safety assessed by ECOG Performance Status

Time: Up to 18 months

Secondary Outcomes

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR) or Partial Response (PR)among all analyzed subjects

Measure: Overall response rate

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR), Partial Response (PR), or Stable disease (SD) among all analyzed subjects

Measure: Disease control rate

Time: Up to 18 months

Measure: Plasma concentrations of unchanged ASP8273

Time: Up to Day1 of Cycle 3

124 A Phase 1 Trial of MLN0128 (TAK-228) in Combination With Osimertinib (AZD9291) in Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02503722 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage III Lung Non-Small Cell Cancer AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Stage IIIB Lung Non-Small Cell Cancer AJCC v7 Stage IV Lung Non-Small Cell Cancer AJCC v7 Other: Laboratory Biomarker Analysis Drug: Osimertinib Other: Pharmacological Study Drug: Sapanisertib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion) - Progressive disease on osimertinib (AZD9291) given first line - For the dose expansion portion ONLY, patient must: 1) have progression of disease with first line osimertinib administered for advanced or metastatic disease as the last previous systemic treatment, 2) be treatment naïve for other 3rd generation EGFR-TKI (CO-1686) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - For the dose expansion, no other systemic therapies for advanced/metastatic disease is permissible after first line osimertinib - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated; patients with small brain metastases for which radiation or surgery is not indicated, may be eligible on discussion with the study chair. --- L858R ---

medically significant (symptomatic) bradycardia, complete left bundle branch block, third degree heart block and second-degree heart block or history of arrhythmia requiring an implantable cardiac defibrillator; or within the last 6 months before administration of the first dose of drug: - Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) - Placement of a pacemaker for control of rhythm - Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures - Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures - New York Heart Association (NYHA) class III or IV heart failure - Symptomatic pulmonary embolism or asymptomatic pulmonary emboli within the last 3 months - Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTcF >= 470 msec (mean value) obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value, or history of congenital long QT syndrome, or torsades de pointes); any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Left ventricular ejection fraction (LVEF) by either multigated acquisition (MUGA) or echocardiography (ECHO) less than lower limit of normal - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Concurrent anti-cancer therapy - History of hypersensitivity attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) or osimertinib (AZD9291) - Pregnant women or women who are breast feeding are not eligible for the study; the effects of MLN0128 (TAK-228) and osimertinib (AZD9291) on the developing human fetus are unknown - Women of non-child bearing potential must be: - Women more than 50 years must be post-menopausal for at least 12 months following the end of all exogenous hormonal treatments OR - Women under 50 years must be postmenopausal for at least 12 months following the end of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution OR - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation - Women of child bearing potential must have a negative serum or urine pregnancy test within 7 days of registration and must agree to: - Practice 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 120 days (or longer, as mandated by local labeling [e.g., United Surgical Partners International (USPI), Summary of Product Characteristics (SmPC), etc.;]) after the last dose of study drug, OR - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to: - Practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR - Practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug - Inability to discontinue drugs that are strong cytochrome P450 3A4 (CYP3A4) or P450 3A5 (CYP3A5), cytochrome P450 2C19 (CYP2C19), and cytochrome P450 2C9 (CYP 2C9) inhibitors and/or inducers; and substrates of CYP 3A4/5 or CYP1A2 that are sensitive or have a narrow therapeutic window at least three weeks prior to study registration - Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug - Consumption of grapefruit or grapefruit juice is not permitted during the study; patients should not consume food or beverages containing the fruit or juice of grapefruits or Seville oranges within 7 days before the first dose of study drug and throughout the study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with MLN0128 (TAK-228) and osimertinib (AZD9291) - No concomitant use of proton pump inhibitors (PPI) is allowed; any prior PPI must be discontinued at least one week before receiving MLN0128 (TAK-228) Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion) - Progressive disease on osimertinib (AZD9291) given first line - For the dose expansion portion ONLY, patient must: 1) have progression of disease with first line osimertinib administered for advanced or metastatic disease as the last previous systemic treatment, 2) be treatment naïve for other 3rd generation EGFR-TKI (CO-1686) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - For the dose expansion, no other systemic therapies for advanced/metastatic disease is permissible after first line osimertinib - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated; patients with small brain metastases for which radiation or surgery is not indicated, may be eligible on discussion with the study chair. --- L858R ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC)

Time: 28 days

Description: Toxicities will be graded according to the NCI CTCAE v4. CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Dose-limiting toxicity (DLT) of sapanisertib in combination with osimertinib in patients with EGFRm NSCLC

Time: 28 days

Secondary Outcomes

Description: Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Non-DLTs associated with the administration of sapanisertib and osimertinib

Time: Up to 30 days after completion of study treatment

Description: PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.

Measure: Pharmacokinetic (PK) profiles of sapanisertib in combination with osimertinib

Time: Baseline, and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib administration, before administration and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib on day 26 of course 1; and day 1 of course 2

Description: Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

Description: Will be assessed using RECIST 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival of patients with T790M- NSCLC in an expansion cohort

Time: At 6 months

Description: Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates analyzed in tumor and blood. Descriptive statistics and plotting of data will also be used to better understand potential relationships.

Measure: Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid specimens

Time: Up to 2 years

125 Randomized Blinded Phase III Assessment of Second or Third-Line Chemotherapy With Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced Non-Small Cell Lung Cancer and With at Least One Measurable Lung Lesion

To compare the overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. Secondary purposes of the study are: - To compare the neutropenia (incidence of Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 × 10^9/L]) on Day 8 (+/- 1 day) of Cycle 1), DoR, neutrophil count on Day 8 (+/- 1 day) of Cycle 1, incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1, QoL (EORTC QLQ-C30 [item 30, average overall quality of life over all observable weeks]), ORR, and PFS in patients with NSCLC treated in the DP Arm to patients treated in the D Arm as 2nd- or 3rd-line therapy for advanced or metastatic disease. - To compare the safety and adverse events profile of the DP Arm to D Arm. - To compare dose intensity of docetaxel (percent dose administered compared to dose assigned) between the 2 treatment arms. - To evaluate population pharmacokinetics in patients enrolled in China and rest of world (RoW).

NCT02504489 Non-Small Cell Lung Cancer Drug: Docetaxel + Plinabulin (DP) Drug: Docetaxel (D)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Radiographic tumor assessment is to be performed within 28 days prior to randomization. 5. patients with nonsquamous NSCLC must have been tested for EGFR exon 19 deletion and Exon 21 L858R substitution mutation. --- L858R ---

Primary Outcomes

Description: Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy

Measure: Overall Survival

Time: Approximately 2 years after study initiation

Secondary Outcomes

Description: Incidence of Grade 4 neutropenia on Day 8 of Cycle 1

Measure: Grade 4 neutropenia

Time: During 1st 21-day cycle

Description: Neutrophil count on Day 8 of Cycle 1

Measure: Neutrophil count

Time: During 1st 21-day cycle

Description: incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1

Measure: docetaxel dose reduction and/or docetaxel dose withheld

Time: During 2nd 21-day cycle

Description: Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)

Measure: Quality of Life (EORTC QLQ-C30)

Time: Approximately 2 years after study initiation.

Description: Overall response rate

Measure: ORR

Time: Approximately 2 years after study initiation.

Description: Progress-free survival

Measure: PFS

Time: Approximately 2 years after study initiation.

Description: Duration of response

Measure: DoR

Time: Approximately 2 years after study initiation.

126 A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacy and Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA).

To assess the efficacy and safety of AZD9291 versus Placebo, in patients with Epidermal Growth Factor Receptor Mutation Positive stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy

NCT02511106 Stage IB-IIIA Non-small Cell Lung Carcinoma Drug: AZD9291 80 mg/40 mg Drug: Placebo AZD9291 80 mg/40 mg
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M. --- L858R ---

Stage IB-IIIA Non-small Cell Lung Carcinoma Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) with centrally confirmed, most common sensitising EGFR mutations (Ex19Del and L858R) either alone or in combination with other EGFR mutations as confirmed by a central test, who have had complete tumour resection, with or without postoperative adjuvant chemotherapy. --- L858R ---

Primary Outcomes

Description: Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence)

Measure: Disease free survival (DFS)

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Secondary Outcomes

Description: Defined as the proportion of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis

Measure: Disease free survival (DFS) rate at 2, 3 and 5 years

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Description: Defined as the time from the date of randomization until date of death due to any cause

Measure: Overall Survival (OS)

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Defined as the proportion of patients alive at 5 years, estimated from a Kaplan Meier plot of OS at the time of the primary analysis

Measure: Overall Survival rate at 5 years

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Measured by SF-36 Questionnaire consisting in 36 items that is an instrument for assessing a person's general health status over the past 28 days. The scores for each of the 8 health domain scores and for each of the physical and mental component summary measures from the SF-36 v2 will be summarized in terms of mean changes from baseline at each post-baseline assessment.

Measure: Patient health-related quality of life and symptoms (HRQoL) by SF-36v2 Health Survey

Time: From date of randomization until treatment completion or discontinuation (max. 36 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291

Measure: Plasma concentrations of AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZ5104 and AZ7550 metabolites

Measure: Plasma concentrations of AZ5104 and AZ7550 metabolites and ratio of metabolite to AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Other Outcomes

Description: AEs graded by CTCAE version 4.0

Measure: Incidence of Adverse Events (AEs)

Time: From date of randomization until 28 days after treatment completion (max. 37 months)

127 A Single Arm Phase IV Study of Afatinib in Elderly Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Exon 19 Deletions or Exon 21(L858R) Substitution Mutations

Continuous treatment until progression or occurence of intolerable Adverse Event (AE) or end of trial. The end of trial is one year after the last patient has entered the study.

NCT02514174 Carcinoma, Non-Small-Cell Lung ErbB Receptors Drug: Afatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Single Arm Phase IV Study of Afatinib in Elderly Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Exon 19 Deletions or Exon 21(L858R) Substitution Mutations. --- L858R ---

Staging is based on American Joint Committee on Cancer (AJCC) Staging for NSCLC 7th edition (R12-4710) - Evidence of common EGFR mutation (Del 19 and/or L858R) - Age >= 70 years - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (R01-0787) - Further inclusion criteria apply. --- L858R ---

Primary Outcomes

Description: On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants Reporting an Adverse Event (AE) Leading to Dose Reduction of Afatinib

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Secondary Outcomes

Description: Percentage of participants with adverse event being diarrhoea of CTCAE grade 3 or higher. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Diarrhoea of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Percentage of participants with adverse event = rash/acne (grouped term) of CTCAE grade 3 or higher. MedDRA preferred terms that described AEs of similar nature were grouped together as "grouped term" to ensure that important events would not be underestimated. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Rash/Acne (Grouped Term) of CTCAE Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Percentage of participants with adverse event = stomatitis (grouped term) of CTCAE grade 3 or higher. MedDRA preferred terms that described AEs of similar nature were grouped together as "grouped term" to ensure that important events would not be underestimated. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Stomatitis (Grouped Term) of CTCAE Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Percentage of participants with adverse event = paronychia (grouped term) of CTCAE grade 3 or higher. MedDRA preferred terms that described AEs of similar nature were grouped together as "grouped term" to ensure that important events would not be underestimated. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Paronychia (Grouped Term) of CTCAE Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Time to first dose reduction of afatinib caused by adverse events is defined as time from the date of the first administration of afatinib to the date of first dose reduction of afatinib caused by adverse events. Participants without AEs leading to dose reduction were censored at date of last intake of afatinib. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent from study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria). The cumulative probability of no dose reduction at the respective time point is given by the Kaplan-Meier estimate at the respective time point based on time to first dose reduction of afatinib caused by adverse events.

Measure: Time to First Dose Reduction of Afatinib Caused by Adverse Events

Time: On-treatment period, up to 1057 days

128 Pemetrexed Disodium and Cisplatin Chemotherapy Combined With Synchronous Gefitinib vs Chemotherapy Alone as Adjuvent Therapy in Patient With Stage II-IIIA, Epidermal Growth Factor Receptor Mutant Expressing Lung Adenocarcinoma

This randomized phase III trial is studying gefitinib and synchronous pemetrexed/cisplatin chenmotherapy to see how well it works compared to pemetrexed/cisplatin chenmotherapy alone in treating patients who have undergone surgery for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR activating mutation in Asian population.

NCT02518802 Lung Neoplasms Drug: Gefitinib Drug: Pemetrexed
MeSH:Adenocarcinoma Lung Neoplasms Adenocarcinoma of Lung
HPO:Neoplasm of the lung

- Target population is completely resected pathological stage II-IIIA(N1-N2) NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation. --- L858R ---

Primary Outcomes

Description: To evaluate the disease free survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for pathological stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: From date of randomization to the first documented disease progression or death, whichever occurs first, assessed up to 3 and 5 years.

Secondary Outcomes

Description: To evaluate the overall survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.

Measure: Overall survival

Time: From date of randomization to the first documented death, assessed up to 5 years.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

129 A Phase 1B Study of AZD9291 in Combination With Navitoclax in EGFR-Mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor

This phase Ib trial studies the side effects and best dose of osimertinib and navitoclax when given together and to see how well they work in treating patients with previously treated epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer that has spread to other places in the body (metastatic) or has not responded to previous treatment with initial EGFR kinase inhibitor. Osimertinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02520778 Advanced Lung Non-Squamous Non-Small Cell Carcinoma Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Stage III Lung Non-Small Cell Cancer AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Stage IIIB Lung Non-Small Cell Cancer AJCC v7 Stage IV Lung Non-Small Cell Cancer AJCC v7 Drug: Navitoclax Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R ---

Primary Outcomes

Description: Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Incidence of toxicity (dose escalation)

Time: Up to 2 years

Description: Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with > 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).

Measure: Feasibility of the combination therapy in T790M+ lung cancer (dose expansion)

Time: Up to 12 weeks (3 cycles of treatment)

Secondary Outcomes

Description: Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.

Measure: Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax

Time: Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2)

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.

Measure: Objective response rate

Time: Baseline up to 30 days after completion of study drug

Description: Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.

Measure: Change in plasma concentration of EGFR T790M and other EGFR mutations

Time: Baseline to up to 2 years

Description: Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.

Measure: Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue

Time: Baseline

130 The Postoperative Adjuvant Therapy of Gefitinib for High Risk Stage Ib NSCLC Patients With EGFR Sensitive Mutation, an Open, Paired, Non-interventional, Multi-center Clinical Study

Currently, whether adjuvant therapy should be applied to Stage Ib non-small cell lung cancer (NSCLC) patients who received radical resection remains controversial. There is still no clear evidence that the postoperative adjuvant chemotherapy or other treatments can improve the survival rate for patients with stage Ib NSCLC. Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib and Erlotinib are widely accepted as the first-line therapy for Epidermal growth factor receptor (EGFR) gene mutation late stage NSCLC patients. However the effect is largely uncertain for early stage patients who received surgery. The investigators aim to evaluate the effect of postoperative adjuvant use of Gefitinib for high risk stage Ib EGFR sensitive mutation NSCLC patients.

NCT02526537 NSCLC
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

2. Patients with pathology confirmed Ib stage NSCLC 3. Patients with deletion of exon 19 or mutation of L858R at exon 21 in EGFR gene 4. ECOG score of 0-1 5. Life expectancy over 12 weeks 6. --- L858R ---

Primary Outcomes

Measure: Relapse Free Survival in 2 years

Time: Treatment period: 2 years (24 months)

Secondary Outcomes

Measure: Relapse Free Survival in 3 years

Time: Follow-up: 3 years

Measure: 5 year Overall Survival

Time: Follow-up: 5 years

Measure: Relapse Free Survival in 5 years

Time: Follow-up: 5 years

131 Phase I, Open-Label, Two Parts Study in Chinese Patients With Advanced NSCLC Who Have Progressed Following Prior Therapy With an EGFR Tyrosine Kinase Inhibitor Agent

A Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291 administered orally once daily in Chinese patients with locally advanced or metastatic non small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent. 2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

NCT02529995 Carcinoma, Non-Small-Cell Lung With EGFR Mutation Positive Drug: AZD9291 40 mg Drug: AZD9291 80 mg
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

In addition other lines of therapy may have been given - Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6. World Health Organisation (WHO) performance status 0-1 7. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Rate and extent of absorption of single dose AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of apparent plasma clearance at steady state

Measure: CL(ss)/F of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: Treatment discontinuation plus 28 days or 12 months after last subject first dose (LSFD). Results are based on data cut off of 2 Nov 2016.

132 A Phase 1/2 Trial of Erlotinib and Onalespib Lactate in EGFR-Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02535338 Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Drug: Onalespib Lactate Other: Pharmacological Study
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R ---

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R ---

Primary Outcomes

Description: Will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Measure: Incidence of dose-limiting toxicities from onalespib lactate in combination with erlotinib hydrochloride (Phase I)

Time: Up to 28 days

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase II)

Time: Up to at least 1 year

Secondary Outcomes

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase I)

Time: Up to at least 1 year

Description: Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to at least 1 year

133 An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in First-line Treatment of Patients With Stage IIIB/IV Non-small Cell Lung Cancer Tumors With EGFR Activating Mutations

The purpose of the study was to evaluate the progression free survival (PFS), based on independent radiologic review (IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. This study also assessed Overall survival (OS); Overall response rate (ORR) as assessed by IRR; PFS as assessed by the investigator; Disease control rate (DCR) as assessed by IRR; Duration of Response (DOR) by IRR; Safety of ASP8273; and Quality of Life (QOL) and patient-reported outcome (PRO) parameters.

NCT02588261 Non-small Cell Lung Cancer (NSCLC) Drug: naquotinib mesilate Drug: Erlotinib Drug: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Neutrophil count > 1,000/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin > 8.0 g/dL - Serum creatinine ˂ 2.0 x upper limit of normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 mL/min as calculated by the Cockcroft Gault Method - Total bilirubin ˂1.5 x ULN (except for subjects with documented Gilbert's syndrome) - AST and ALT ˂ 3.0 x ULN or ≤ 5 x ULN if subject has documented liver metastases - Serum sodium level is ≥ 130 mmol/L - Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without T790M mutation, by local or central testing on examination of a NSCLC FFPE specimen (archival or fresh biopsy). --- L858R ---

Subjects harboring both exon 19 deletion and exon 21 L858R mutations are not eligible. --- L858R ---

Primary Outcomes

Description: PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by IRR. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.

Measure: Progression Free Survival (PFS) as Assessed by Independent Radiologic Review (IRR)

Time: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)

Secondary Outcomes

Description: All events of death after the first study drug administration were included.

Measure: Percentage of Deaths

Time: From date of randomization up to data cut-off date 21 Dec 2017 (approximately 22 months)

Description: Percentage of participants with OR was defined as the proportion of participants with best overall response as complete response (CR) or partial response (PR) without confirmation based on the RECIST v1.1 as assessed by the blinded IRR. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response (OR)

Time: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)

Description: PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on RECIST V1.1, as assessed by local investigator. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.

Measure: PFS as Assessed by the Investigator

Time: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)

Description: Percentage of participants with disease control was defined as the proportion of participants whose best overall response was rated as CR, PR or stable disease (SD) among all analyzed participants based on RECIST V1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug.

Measure: Percentage of Participants With Disease Control

Time: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)

Description: DOR was defined as the time from the date of the first response CR/PR (whichever was first recorded) as assessed by IRR to the date of radiographical progression or date of censoring. If a participant had not progressed, the participant was censored at the date of last radiological assessment or at the date of first CR/PR if no post-baseline radiological assessment was available. Results are based Kaplan-Meier estimate.

Measure: Duration of Response (DOR)

Time: From date of first response up to data cut-off date 09 May 2017 (approximately 15 months)

Description: Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization.

Measure: Number of Participants With Adverse Events (AEs)

Time: From first dose of study drug up to 30 days after last dose of study drug taken up to data cut-off 09 May 2017

Description: ACT-EGFRI-18 is an 18-item Likert-scaled questionnaire, used to assess the effect of EGFR inhibitors on quality of life (QoL). The questionnaire is arranged in three HRQL dimensions: physical (seven items), social/emotional (six items), and functional well-being (five items). The response scores ranged from 0 to 4, and the response categories include "not at all", "a little bit", "somewhat", "quite a bit", and "very much." Negatively worded items (e.g., "My skin bleeds easily "or "My skin condition affects my mood") are reverse-scored, so that participants who experience a higher impact of symptom burden on HRQL receive a lower score (range 0-72).

Measure: Functional Assessment of Cancer Therapy - EGFR Inhibitors Subscale (FACT-EGFRI-18) Questionnaire

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: The EORTC-QLQ-LC13 is a validated module of the EORTC-QLQ-Core 30, which includes module items that evaluate symptoms such as cough, hemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling hands or feet, hair loss and pain. The total score for the questionnaire ranges from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems.

Measure: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC-QLQ-LC13)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: EORTC-QLQ-LC30 is a 30-item cancer-specific questionnaire with multitrait scaling was used to create five functional domain scales: Physical, Role, Emotional, Social and Cognitive; two items evaluate global QoL; in addition, three symptom scales assess Fatigue, Pain and Emesis; and six single items assess other symptoms. The total score ranges from 0 to 100, with a high score for a functional scale representing a high/healthy level of functioning and a high score for a symptom scale or item representing a high level of symptomatology or problems.

Measure: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: The EQ-5D is a generic preference-based measure that indirectly measures the utility for health that generates an index-based summary score based upon societal preference weights. The EQ-5D-5L consists of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale (VAS) for health status. Each item has 5 response levels ranging from level 1 (no problem or none) to level 5 (unable to perform activity). The VAS ranges from 0 (worst health status) and 100 (best health status).

Measure: EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

134 An Open-label, Multi-Centered, Dose Escalation Phase Ib Study (Expansion Stage) of Epitinib (HMPL-813) in Patients With Advanced Solid Tumors

Epitinib (HMPL-813) is a selective EGFR tyrosine kinase inhibitor. Epitinib has demonstrated strong inhibitory effects on multiple tumors with overexpressed EGFR or sensitive EGFR mutations in pre-clinical setting. This first-in-human study is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity(DLT), safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of Epitinib.

NCT02590952 Solid Tumor Drug: Epitinib
MeSH:Neoplasms
HPO:Neoplasm

On day 2/15/29/56, PK samples are collected predose in the morning.. Inclusion Criteria: - Histopathology confirmed solid tumors - Failed to standard treatment or no standard treatments for uncontrolled, recurrent and/or metastatic advance tumor (whatever previous surgery conditions) - Age 18-70 - ECOG 0-2, and no worse within 7days - Life expected > 12 weeks - written informed consent form voluntarily - For dose expansion cohort, subjects must be eligible for the following inclusion criteria: - EGFR sensitizing mutation in exon 19 deletion or exon 21(L858R). --- L858R ---

- Unrecovered from any previous therapy related toxicity to CTCAE 0 or 1or unrecovered from any previous surgery - Known dysphagia or drug malabsorption - Active infections such as acute pneumonia, hepatitis B immune-active periodphase - ocular surface diseases or dry eye syndrome - skin disease with obvious symptoms and signs - significant cardiovascular disease, including II-IV atrioventricular block, and acute myocardial infarction within 6 months, significant angina or Coronary artery bypass graft within 6 months - Female patients who are pregnant or feeding, or childbearing potential patient with pregnant testing positive - Any abnormal of clinical and laboratory so that patients unsuitable to attend the trial sine in the opinion of the investigator - Patients unable to comply with the protocol since significant psychological or psychogenic abnormal Inclusion Criteria: - Histopathology confirmed solid tumors - Failed to standard treatment or no standard treatments for uncontrolled, recurrent and/or metastatic advance tumor (whatever previous surgery conditions) - Age 18-70 - ECOG 0-2, and no worse within 7days - Life expected > 12 weeks - written informed consent form voluntarily - For dose expansion cohort, subjects must be eligible for the following inclusion criteria: - EGFR sensitizing mutation in exon 19 deletion or exon 21(L858R). --- L858R ---

Primary Outcomes

Description: for each patient, adverse events are collected from the date of consent until 30 days after trial discontinuation

Measure: incidence of all types/grades of adverse events

Time: from first patient in till 30 days after the last patient last visit. It is estimated that last patient last visit happens in Oct 2016.

Secondary Outcomes

Measure: Objective Response Rate

Time: An average of one year

Description: Based on single-dose PK result, multi-dose stage subjects take epitinib either once a day or twice a day. For twice a day epitinib uptake, on day 1/14/28, PK samples are collected predose, 1, 4, 8, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 2/3/7, PK samples are collected predose, 4, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 15/29/56, PK samples are collected predose in the morning. For once a day epitinib uptake, on day 1/14/28 PK samples are collected predose, 0.5, 1, 2, 4, 6, 8, 12 hours post-dose. On day 7, PK samples are collected predose and 4 hours post-dose. On day 2/15/29/56, PK samples are collected predose in the morning.

Measure: Area under the plasma concentration versus time curve (AUC)

Time: At single-dose stage (day 1-day 7): predose, 0.5,1, 2, 3, 4, 5, 6, 8,12,24, 36, 48, 72, 144 hours post-dose.

Description: Based on single-dose PK result, multi-dose stage subjects take epitinib either once a day or twice a day. For twice a day epitinib uptake, on day 1/14/28, PK samples are collected predose, 1, 4, 8, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 2/3/7, PK samples are collected predose, 4, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 15/29/56, PK samples are collected predose in the morning. For once a day epitinib uptake, on day 1/14/28 PK samples are collected predose, 0.5, 1, 2, 4, 6, 8, 12 hours post-dose. On day 7, PK samples are collected predose and 4 hours post-dose. On day 2/15/29/56, PK samples are collected predose in the morning.

Measure: Peak Plasma Concentration (Cmax)

Time: At single-dose stage (day 1-day 7): predose, 0.5,1, 2, 3, 4, 5, 6, 8,12,24, 36, 48, 72, 144 hours post-dose.

135 Adjuvant Nivolumab in Resected Lung Cancers (ANVIL) - A Randomized Phase III Study of Nivolumab After Surgical Resection and Adjuvant Chemotherapy in Non-Small Cell Lung Cancers

This phase III ALCHEMIST treatment trial studies how well nivolumab after surgery and chemotherapy work in treating patients with stage IB-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

NCT02595944 Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Biological: Nivolumab
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.. Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To evaluate whether adjuvant therapy with nivolumab will result in improved overall survival (OS) and/or disease-free survival (DFS) over standard observation in patients with stage IB >= 4 cm, II and IIIA, non-small cell lung cancer (NSCLC) following surgical resection and standard adjuvant therapy. --- L858R ---

Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.. Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To evaluate whether adjuvant therapy with nivolumab will result in improved overall survival (OS) and/or disease-free survival (DFS) over standard observation in patients with stage IB >= 4 cm, II and IIIA, non-small cell lung cancer (NSCLC) following surgical resection and standard adjuvant therapy. --- L858R --- --- L858R ---

Primary Outcomes

Description: DFS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparisons of DFS will use a logrank tests stratified on the randomization stratification factors with a one-sided type I error rate corresponding to the significance level associated with population being analyzed; that is, 1.5% for the overall population and 1% for the >= 50% population. The latter test will only be performed in the event that the primary test in all-comers is not statistically significant. Other comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Measure: Disease-free survival (DFS)

Time: Time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time, assessed up to 10 years

Description: OS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparisons of OS will use a logrank tests stratified on the randomization stratification factors with a one-sided type I error rate corresponding to the significance level associated with population being analyzed; that is, 1.5% for the overall population and 1% for the >= 50% population. The latter test will only be performed in the event that the primary test in all-comers is not statistically significant. Other comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Measure: Overall survival (OS)

Time: Time from randomization to death from any cause, assessed up to 10 years

Secondary Outcomes

Description: Toxicity rates will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Measure: Incidence of toxicity graded according to Common Terminology Criteria for Adverse Events version 5.0

Time: Up to 10 years

136 A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of JNJ-61186372, a Human Bispecific EGFR and cMet Antibody, in Subjects With Advanced Non-Small Cell Lung Cancer

The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of JNJ-61186372 as a monotherapy and in combination with lazertinib, and to determine the recommended Phase 2 dose (RP2D)(monotherapy) and recommended Phase 2 combination dose (RP2CD) (combination therapy) in participants with advanced non-small cell lung cancer (NSCLC).

NCT02609776 Non-Small-Cell Lung Cancer Drug: JNJ-61186372 Drug: JNJ-61186372 Drug: Lazertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

In cases where participants refuse currently available therapeutic options, this must be documented in the study records - For Part 1 Combination Dose Escalation only: Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation and (a) be treatment naïve for metastatic disease, without access to third generation TKI in the front-line setting, or (b) have progressed after front-line treatment with first (erlotinib or gefitinib) or second generation (afatinib) TKI and are ineligible for Cohort MET-1, or (c) have been treated with a third generation TKI (eg, osimertinib) in either the front line or second-line setting, and are not eligible for enrollment in either Cohort C or MET-1 For Part 2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2). --- L858R ---

In cases where participants refuse currently available therapeutic options, this must be documented in the study records - For Part 1 Combination Dose Escalation only: Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation and (a) be treatment naïve for metastatic disease, without access to third generation TKI in the front-line setting, or (b) have progressed after front-line treatment with first (erlotinib or gefitinib) or second generation (afatinib) TKI and are ineligible for Cohort MET-1, or (c) have been treated with a third generation TKI (eg, osimertinib) in either the front line or second-line setting, and are not eligible for enrollment in either Cohort C or MET-1 For Part 2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2). --- L858R --- --- L858R ---

Cohort E (combination JNJ-61186372 and lazertinib): Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation, and have progressed after first or second-line treatment with a third generation TKI (eg, osimertinib) - Participant must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Exclusion Criteria: - Participant has uncontrolled inter-current illness, including but not limited to poorly controlled hypertension, or diabetes, ongoing or active infection, (that is, has discontinued all antibiotics for at least one week prior to first dose of study drug), or psychiatric illness/social situation that would limit compliance with study requirements. --- L858R ---

Primary Outcomes

Description: The Dose Limiting Toxicity (DLT) is based on drug related adverse events and includes unacceptable hematologic toxicity, non-hematologic toxicity of Grade 3 or higher, or elevations in hepatic enzymes suggestive of drug-induced liver injury.

Measure: Part 1: Number of Participants With Dose Limiting Toxicity (DLT)

Time: Up to Day 28

Description: An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Measure: Part 2: Number of Participants With Adverse Events (AEs) and Serious AEs

Time: Screening up to follow-up (30 [+7] days after the last dose)

Description: Overall response rate (ORR) is defined as the percentage of participants who achieve either a CR or PR as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). CR: disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (< 10 mm short axis) and normalisation of tumour marker levels; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.

Measure: Part 2: Overall Response Rate (ORR)

Time: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)

Description: DOR will be calculated as time from initial response of CR (disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size ([<] 10 [mm] short axis) and normalisation of tumour marker levels) or PR (at least a 30 [%] decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits) to progressive disease (PD) or death due to underlying disease, whichever comes first, only for participants who achieve CR or PR.

Measure: Part 2: Duration of Response (DOR)

Time: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)

Description: Clinical benefit rate is defined as the percentage of participants achieving complete response (CR): disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (less than [<] 10 millimeter [mm] short axis) and normalisation of tumour marker levels or partial response (PR): at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.

Measure: Part 2: Percentage of Participants With Clinical Benefit

Time: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)

Secondary Outcomes

Description: The Cmax is the maximum observed serum concentration of JNJ-61186372.

Measure: Maximum Serum Concentration (Cmax) of JNJ-61186372

Time: Cycle 1 Day 1: predose through end of infusion (EOT) or Follow Up (approximately 16 months) (each cycle is of 28 days)

Description: The Tmax is defined as time to reach maximum observed serum concentration of JNJ-61186372.

Measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of JNJ-61186372

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: The AUC(t1-t2) is the area under the serum JNJ-61186372 concentration-time curve from time t1 to t2.

Measure: Area Under the Serum Concentration-Time Curve From t1 to t2 Time (AUC[t1-t2]) of JNJ-61186372

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: The AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau)

Measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau