Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib

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Background: EGFR tyrosine kinase inhibitors (TKI) have significantly improved the response rate (RR) and survival in patients with tumors harboring EGFR-sensitizing mutations. An invariable consequence of treatment with EGFR-TKIs is the development of acquired resistance. The most common mechanism o...

Background: EGFR tyrosine kinase inhibitors (TKI) have significantly improved the response rate (RR) and survival in patients with tumors harboring EGFR-sensitizing mutations. An invariable consequence of treatment with EGFR-TKIs is the development of acquired resistance. 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. Despite these developments, it is almost certain that selection pressure will lead to the emergence of newer clones that are resistant to treatment with osimertinib. In fact, a newly identified EGFR mutation (C797S) that results in acquired resistance to osimertinib has been reported recently. The use of local ablative therapies for patients who develop limited metastatic disease oligoprogressive disease) on EGFR-TKI therapy is promising. We hypothesize that following local ablative therapy to treat oligoprogressive disease after emergence of resistance to AZD9291, osimertinib can be resumed safely and reinitiation of osimertinib results in additional progression-free survival benefits. 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). If biopsy for EGFR mutation status confirmation is not clinically feasible, EGFR mutations may be confirmed by ctDNA analysis using a CLIA certified assay. Presence of measurable disease per RECIST version 1.1 ECOG performance status 0-2 Adequate end organ function If patients are not eligible for LAT, they will be referred for standard of care chemotherapy as per treating physicians discretion. These patients may also be considered for other clinical trials. Design: This is a single-institution, open-label phase II trial of osimertinib. Eligible patients not previously treated with osimertinib will be treated with osimertinib daily until disease progression. At the time of progression, patients with oligoprogressive disease (no more than 5 sites of progressive disease) will be assessed for LAT. If patients are eligible for LAT, osimertinib will be resumed after LAT and they will be followed for second progression on osimertinib (PFS2). If patients progress at the same site where LAT has been performed before, the progression will be considered to be a result of inadequate ablation and they will be considered for repeat LAT and again re-challenged with osimertinib if clinically feasible. Tumor samples will be obtained at baseline by a mandatory biopsy. At the time of first progression on osimertinib if a patient is eligible for surgery as a form of LAT, then a tissue sample will be obtained for genomic and proteomic studies to identify mechanisms of acquired resistance. For patients who are not eligible for LAT or a form of LAT that is not surgery (radiation, radiofrequency ablation, cryoablation), then a mandatory biopsy will be performed, if clinically safe, to obtain tissue for above studies. Re-treatment will be allowed for a small number of subjects.

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