A multicenter pilot study of afatinib re-challenge in patients with <i>EGFR</i> -mutated non-squamous non–small cell lung cancer previously treated with osimertinib.

e20748 Background: Osimertinib (+ chemotherapy) is the standard first-line treatment for EGFR -mutated non-squamous non-small cell lung cancer (NSqNSCLC). However, evidence regarding the efficacy of EGFR-TKI re-challenge after progression on osimertinib remains insufficient. This study evaluated the efficacy and safety of afatinib as a subsequent therapy following progression on osimertinib and conventional chemotherapy. Methods: This multicenter, single-arm, phase II study enrolled patients (pts) with advanced/recurrent EGFR -mutated (del19 or L858R) NSqNSCLC and an ECOG PS 0–1. All pts underwent NGS-based comprehensive genomic profiling (CGP) after progressing on osimertinib. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Between Oct 2022 and Dec 2024, 19 pts were enrolled. Due to slow accrual, the study was terminated before reaching the planned sample size. Of 17 evaluable pts, the ORR was 11.8% (95% CI: 1.5-36.4), mPFS was 4.5 mos. (95% CI: 2.9-9.2), and mOS was 20.8 mos. (95% CI: 9.0-NA). CGP identified several biomarkers potentially involved in osimertinib resistance, including EGFR C797S (n = 1), ERBB2 mutation (n = 1), PIK3CA mutation (n = 1), RET mutation (n = 1), and METex14 skipping (n = 1); however, no clear correlation between these markers and afatinib efficacy was observed. Any-grade adverse events (AEs) occurred in 88.2% of pts, with Grade 3 AEs in 29.4% (5/17), primarily diarrhea, which were manageable with dose interruptions or reductions. Conclusions: Afatinib re-challenge showed limited efficacy in pts with EGFR -mutated NSqNSCLC pretreated with osimertinib and chemotherapy. While the safety profile was consistent with previous reports, these findings suggest that alternative therapeutic strategies should be prioritized in this clinical setting. (UMIN000049225). Clinical trial information: UMIN000049225 .