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

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.

This prospective phase 2 trial enrolled EGFR-mutated NSCLC patients in three cohorts: tyrosine kinase inhibitor (TKI)-naive (cohort 1), previously treated with TKI and developed acquired T790M resistance mutation (cohort 2), or previously treated with osimertinib and developed resistance (cohort 3). Patients in cohorts 1 and 2 received upfront osimertinib followed by LAT on oligoprogression, followed by osimertinib rechallenge. Cohort 3 patients underwent LAT on enrollment, followed by osimertinib rechallenge. The primary end points were safety, tolerability, and PFS2 among the patients who underwent LAT across all three cohorts combined. Secondary end points were PFS1 and overall response rates.

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.

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.