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 NSCLC. In MARIPOSA, amivantamab-lazertinib significantly improved overall survival versus osimertinib (hazard ratio [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 circulating tumor DNA from paired baseline and end-of-treatment plasma samples. Known resistance mechanisms included EGFR- orMET-dependent (e.g., C797S, MET amplification) and EGFR- or MET-independent (e.g., PIK3CA, RASorRAF, cell cycle, TP53orRB1 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% versus 13.1%; nominal p = 0.002) and secondary EGFR mutations (1.4% versus 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 versus 5.3 mo; HR: 0.72; nominal p = 0.02) among participants who started a first subsequent therapy. Participants harboring unknown resistance at end of treatment had longer median second-line PFS versus known resistance (7.4 versus 4.6 mo; HR: 0.63; nominal p = 0.01). CONCLUSIONS: Amivantamab-lazertinib reduces common resistance mechanisms (e.g., EGFRorMET) 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.