This randomized, open label Phase IV trial will be performed in patients with a diagnosis of advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M Mutation negative, who have no previous chemotherapy for metastatic NSCLC. Neoadjuvant or adjuvant systemic treatments had to be finished at least (≥) 6 months before study inclusion. In conclusion, this study is investigating the important clinical question whether tumor growth and long term overall survival for a patient is better controlled in a specific treatment sequence of different EGFR-inhibitors. Patients will be treated with registered compounds according to their label in both treatment arms. Thus, all patients will get an effective treatment regimen and patients who progressed on afatinib, and who developed a T790M mutation will be treated subsequently with osimertinib. Those who progressed under osimertinib or under afatinib without T790M mutation will be treated according to the current treatment guidelines with Investigator´s choice of active therapy (ICT) including but not limited to platin doublet chemotherapy.
Name: Afatinib
Name: Osimertinib
Description: The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.
Measure: Time to EGFR-TKI failure within 24 months for afatinib followed by osimertinib in T790Mpositive group vs osimertinib Time: 24 monthsDescription: Time from randomization until ICT is indicated
Measure: Time to EGFR-TKI failure (afatinib versus osimertinib) Time: 24 monthsDescription: Time from randomization until disease progression according to RECIST or death
Measure: Progression-free survival (PFS: afatinib followed by osimertinib or ICT vs osimertinib followed by ICT) Time: 24 monthsDescription: Survival Status
Measure: Overall Survival (OS) Time: 24 monthsDescription: CR+PR according to RECIST
Measure: Response Rate (RR) Time: 12 monthsDescription: CR+PR according to RECIST
Measure: Response Rate (RR) Time: 24 monthsDescription: CR+PR+SD according to RECIST
Measure: Disease Control Rate (DCR) Time: 12 monthsDescription: CR+PR+SD according to RECIST
Measure: Disease Control Rate (DCR) Time: 24 monthsDescription: Adverse Events as assessed by intensity of the of the adverse events and the causal relation to trial medication Intensity/Severity: investigator will use the following definitions of severity in accordance with National Cancer Institute common terminology criteria for adverse events, CTCAE, version 5.0; assessment of the relationship of an adverse event to the administration of study drug is a clinical decision by the investigator Institute common terminology criteria for adverse events, CTCAE, version 5.0
Measure: Adverse Events Time: 24 monthsDescription: patient-reported quality of life assessed by European Quality of Life 5 Dimensions Questionnaire (EQ-5D)
Measure: Symptom control assessed by patient-reported quality of life (QoL): EQ-5D Time: 24 monthsDescription: patient-reported quality of life assessed by Questionnaire of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
Measure: Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-C30 Time: 24 monthsDescription: EORTC QLQ-LC29
Measure: Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-LC29 Time: 24 monthsAllocation: Randomized
Parallel Assignment
There is one SNP
AFAMOSI: Prospective, Randomized, Multicenter Phase IV Study to Evaluate the Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Non-squamous NSCLC in the First-line Setting. --- T790M ---
AFAMOSI: Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Nonsquamous NSCLC This randomized, open label Phase IV trial will be performed in patients with a diagnosis of advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M Mutation negative, who have no previous chemotherapy for metastatic NSCLC. --- T790M ---
AFAMOSI: Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Nonsquamous NSCLC This randomized, open label Phase IV trial will be performed in patients with a diagnosis of advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M Mutation negative, who have no previous chemotherapy for metastatic NSCLC. --- T790M --- --- T790M ---
Thus, all patients will get an effective treatment regimen and patients who progressed on afatinib, and who developed a T790M mutation will be treated subsequently with osimertinib. --- T790M ---
Those who progressed under osimertinib or under afatinib without T790M mutation will be treated according to the current treatment guidelines with Investigator´s choice of active therapy (ICT) including but not limited to platin doublet chemotherapy. --- T790M ---
The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.. Time to EGFR-TKI failure (afatinib versus osimertinib). --- T790M ---
Inclusion Criteria: - Histologically confirmed non-squamous NSCLC harboring EGFR mutation positive but T790M mutation negative by local testing - Unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease - TKI naïve for metastatic NSCLC, neoadjuvant or adjuvant chemotherapy allowed - At least one evaluable lesion according to RECIST v1.1 - Age ≥ 18 years - ECOG performance status 0 - 2 - Adequate organ function, defined as all of the following: 1. Absolute neutrophil count (ANC) ≥ 1500/mm3. --- T790M ---
Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ 3 times the upper limit of normal (ULN) (if related to liver metastases ≤ 5 times ULN) - Recovered from any previous therapy related toxicity to ≤ Grade 1 at before randomization (except for stable sensory neuropathy ≤ Grade 2 and alopecia) - Written informed consen Exclusion Criteria: - Any investigational drug within 30 days or hormonal anticancer treatment within 2 weeks prior to randomization (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted) - T790M mutation positive tumors (by local testing) - Radiotherapy within 2 weeks prior to randomization, except as follows: 1. Palliative radiation to target organs other than chest may be allowed up to 1 week prior to randomization 2. Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with coordinating investigator prior to enrolling - Major surgery within 2 weeks before starting study treatment or scheduled for surgery during the projected course of the study - Known hypersensitivity to afatinib or osimertinib or the excipients of any of the trial drugs - History or presence of clinically relevant cardiovascular abnormalities such as 1. uncontrolled hypertension 2. congestive heart failure NYHA classification of ≥ 3 3. unstable angina or poorly controlled arrhythmia as determined by the investigator 4. Myocardial infarction within 6 months prior to randomization 5. Clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. --- T790M ---
Other contraindications to study treatment (Investigators opinion) or legal incapacity or limited legal capacity Inclusion Criteria: - Histologically confirmed non-squamous NSCLC harboring EGFR mutation positive but T790M mutation negative by local testing - Unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease - TKI naïve for metastatic NSCLC, neoadjuvant or adjuvant chemotherapy allowed - At least one evaluable lesion according to RECIST v1.1 - Age ≥ 18 years - ECOG performance status 0 - 2 - Adequate organ function, defined as all of the following: 1. Absolute neutrophil count (ANC) ≥ 1500/mm3. --- T790M ---