Long-Term Impact of First-Line Amivantamab Plus Lazertinib Versus Osimertinib on Mechanisms of Acquired Resistance in MARIPOSA: A Brief Report.
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Start Page
Article number 103894
ISSN
1556-1380
Date Issued
2026-04-28
Author(s)
Hayashi, Hidetoshi
Cho, Byoung Chul
Spigel, David R
Girard, Nicolas
Lee, Se-Hoon
Lu, Shun
Popat, Sanjay
Passaro, Antonio
Baldotto, Clarissa
Gottfried, Maya
Dias, Josiane Mourão
Zimmer Gelatti, Ana Caroline
Wang, Bo
Kam, Julian
Sethi, Seema
Shah, Sujay
Kamat, Medha
Zhang, Jiarui
Curtin, Joshua C
William, William N
Besse, Benjamin
Abstract
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.
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.
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).
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.
Subjects
Acquired resistance
Amivantamab
EGFR-mutant NSCLC
Lazertinib
Second-line progression-free survival
Type
journal article