Long-Term Impact of First-Line Amivantamab Plus Lazertinib Versus Osimertinib on Mechanisms of Acquired Resistance in MARIPOSA: A Brief Report.

INTRODUCTION: Amivantamab plus lazertinib is approved for first-line management of EGFR-mutated advanced non-small cell lung cancer (NSCLC). In MARIPOSA, amivantamab-lazertinib significantly improved overall survival versus osimertinib (HR, 0.75; P=0.005). We evaluated acquired resistance mechanisms and their impact on second-line progression-free survival (PFS) in MARIPOSA. METHODS: MARIPOSA (NCT04487080) assessed amivantamab-lazertinib versus osimertinib in previously untreated EGFR-mutated advanced NSCLC. Acquired resistance was assessed by Guardant360® next-generation sequencing of ctDNA from paired baseline and end-of-treatment (EOT) plasma samples. Known resistance mechanisms included EGFR/MET-dependent (e.g., C797S, MET amplification) and/or EGFR/MET-independent (e.g., PIK3CA, RAS/RAF, cell cycle, TP53/RB1 loss-of-function) resistance; absence of these detectable alterations constituted "unknown" resistance. Second-line PFS was defined as time from initiation of first subsequent therapy to investigator-assessed second progressive disease, or death. RESULTS: MET amplifications (3.4% vs 13.1%; nominal P=0.002) and secondary EGFR mutations (1.4% vs 7.6%; nominal P=0.01) were significantly reduced with amivantamab-lazertinib versus osimertinib, without significant increases in other known resistance pathways. Longer treatment with amivantamab was associated with fewer acquired MET and EGFR mutations. Median second-line PFS was substantially prolonged in the amivantamab-lazertinib versus osimertinib arm (8.4 vs 5.3 months; HR, 0.72; nominal P=0.02) among participants who started a first subsequent therapy. Participants harboring unknown resistance at EOT had longer median second-line PFS versus known resistance (7.4 vs 4.6 months; HR, 0.63; nominal P=0.01). CONCLUSIONS: Amivantamab-lazertinib reduces common resistance mechanisms (e.g., EGFR/MET) versus osimertinib, suggesting that this regimen is changing the underlying biology of EGFR-mutant disease, contributing to both first- and second-line long-term efficacy outcomes.