Background: Some non-small-cell lung cancers (NSCLC) have a mutation in a gene that makes a protein called EGFR. This particular cancer can be treated with certain drugs such as Erlotinib (Tarceva), Gefitinib (Iressa) and Osimertinib (Tagrisso). But many tumors become resistant to these drugs because of a second mutation. Researchers want to test if adding local ablative therapy (LAT) extends the benefits of the drug, Osimertinib. LAT can include techniques such as surgery, radiofrequency ablation, cryotherapy or radiation therapy. Objective: To test if re-taking osimertinib after LAT is safe, tolerable, and effective for people whose NSCLC has progressed after initial treatment with osimertinib. Eligibility: Adults ages 18 and older with certain types of NSCLC. Participants will be divided into various groups as described below. Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Tumor scans Eye exam Review of tumor sample. Participants will take the study drug by mouth once a day. They will continue until they can no longer tolerate it or their disease worsens. They will keep a dosage diary. All participants will start each 21-day course with physical exam; blood, urine, and saliva tests; and electrocardiogram. They will have scans every 6 weeks and echocardiogram every 3 months. Groups 1 and 2 will: Start osimertinib right away. Have LAT if their disease gets worse and is suitable for LAT. If LAT cannot be performed or LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Re-start osimertinib after LAT, or other treatments if not suitable for LAT. Group 3 will: Have LAT. If LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Start osimertinib after LAT. After participants stop taking the drugs, they will have a final visit. This will include: Medical history Physical exam Heart and blood tests Participants will be called every year for follow-up.
Name: osimertinib
Description: Single daily dose of osimertinib until progression. The starting dose of osimertinib will be 80 mg per day for patients without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline.Type: DrugArm 1 Arm 2
Name: LAT
Description: local ablative therapy. Subjects may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, radiofrequency ablationType: OtherArm 1 Arm 2
Description: progression-free survival (PFS)
Measure: determine PFS in patients with oligoprogressive disease after treatment with LAT followed by osimertinib Time: progression of diseaseDescription: time to second progression (PFS2)
Measure: Patients who progress on their initial treatment with osimertinib and receive LAT therapy (surgery, radiation therapy, or RFA) followed by osimertinib will be evaluated for their time to second progression (PFS2) Time: progression of diseaseDescription: response rate
Measure: response rate Time: end of treatmentDescription: overall survival
Measure: overall survival Time: deathDescription: EGFR mutation status using liquid biopsies
Measure: feasibility of evaluating EGFR mutation status using liquid biopsies Time: end of treatmentAllocation: Non-Randomized
Parallel Assignment
There are 2 SNPs
In fact, a newly identified EGFR mutation (C797S) that results in acquired resistance to osimertinib has been reported recently. --- C797S ---
- Patients with histologically confirmed, by the NCI Laboratory of Pathology or by CLIA-certified Next Generation Sequencing or cobas EGFR Mutation Test v1/2 at an outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation (detected histologically or via ctDNA analysis using a CLIA assay) with: - No prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1) OR -- Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2) OR - Progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3) - Presence of measurable disease per RECIST version 1.1. --- T790M ---
- Patients with histologically confirmed, by the NCI Laboratory of Pathology or by CLIA-certified Next Generation Sequencing or cobas EGFR Mutation Test v1/2 at an outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation (detected histologically or via ctDNA analysis using a CLIA assay) with: - No prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1) OR -- Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2) OR - Progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3) - Presence of measurable disease per RECIST version 1.1. --- T790M --- --- T790M ---
The most common mechanism of resistance observed in approximately 50% of all cases is the emergence of a secondary mutation (T790M) in exon 20. - Osimertinib is a third-generation EGFR-TKI designed to target the T790M mutation, which has shown impressive responses in both first- and second-line settings. --- T790M ---
The most common mechanism of resistance observed in approximately 50% of all cases is the emergence of a secondary mutation (T790M) in exon 20. - Osimertinib is a third-generation EGFR-TKI designed to target the T790M mutation, which has shown impressive responses in both first- and second-line settings. --- T790M --- --- T790M ---
Objectives: - Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive disease after treatment with osimertinib - Assess mechanisms of acquired resistance to osimertinib Eligibility: - Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). --- T790M ---
Objectives: - Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive disease after treatment with osimertinib - Assess mechanisms of acquired resistance to osimertinib Eligibility: - Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). --- T790M --- --- T790M ---