Local Ablative Therapy Followed by Osimertinib Rechallenge in Oligoprogressive, EGFR-Mutated NSCLC: A Phase 2 Study.

Introduction: Osimertinib has exhibited impressive efficacy in advanced EGFR-mutated NSCLC; however, resistance is inevitable. We hypothesized that local ablative therapy (LAT) for oligoprogressive disease (up to five sites), followed by osimertinib rechallenge, would be safe and provide additional second progression-free survival (PFS2) benefit. Methods: This prospective phase 2 trial enrolled Results: A total of 37 patients with EGFR-mutated NSCLC were enrolled; 25 in cohort 1, nine in cohort 2, and three in cohort 3. A total of 21 patients received LAT across all three cohorts combined, yielding a median PFS2 of 3.7 months (95% confidence interval: 1.9-4.6 mo) for this population. A subgroup with exceptionally long PFS2 was identified that achieved lower tumor burden and circulating tumor DNA-negative minimal residual disease of the EGFR clone with osimertinib before undergoing LAT. Most adverse events related to LAT were grades 1 and 2. Conclusions: This is the first prospective trial exploring local therapy and osimertinib rechallenge on oligoprogression on osimertinib. Interim analysis revealed that PFS2 in the intention-to-treat patients did not meet its primary goal when compared with historical data on continuation of first-generation EGFR TKIs after LAT. However, definite LAT can be carefully considered in patients using circulating tumor DNA-negative minimal residual disease status as a biomarker for predicting who will benefit from continuation of osimertinib post-LAT.