Long-Term Impact of First-Line Amivantamab Plus Lazertinib Versus Osimertinib on Mechanisms of Acquired Resistance in MARIPOSA: A Brief Report
Abstract
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.
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BibTeX
@article{hayashi2026longterm,
title = {{Long-Term Impact of First-Line Amivantamab Plus Lazertinib Versus Osimertinib on Mechanisms of Acquired Resistance in MARIPOSA: A Brief Report}},
author = {Hidetoshi Hayashi and Byoung Chul Cho and David R. Spigel and Nicolas Girard and Se-Hoon Lee and Shun Lu and Sanjay Popat and James Chih-Hsin Yang and Antonio Passaro and Clarissa Baldotto and Maya Gottfried and Josiane Mourão Dias and Ana Caroline Zimmer Gelatti and Bo Wang and Julian Kam and Seema Sethi and Sujay Shah and Medha Kamat and Jiarui Zhang and Joshua C. Curtin and William N. William and Benjamin Besse},
journal = {Journal of Thoracic Oncology},
year = {2026},
month = nov,
doi = {10.1016/j.jtho.2026.103894},
url = {https://hal.science/hal-05851600v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Long-Term Impact of First-Line Amivantamab Plus Lazertinib Versus Osimertinib on Mechanisms of Acquired Resistance in MARIPOSA: A Brief Report
AU - Hidetoshi Hayashi
AU - Byoung Chul Cho
AU - David R. Spigel
AU - Nicolas Girard
AU - Se-Hoon Lee
AU - Shun Lu
AU - Sanjay Popat
AU - James Chih-Hsin Yang
AU - Antonio Passaro
AU - Clarissa Baldotto
AU - Maya Gottfried
AU - Josiane Mourão Dias
AU - Ana Caroline Zimmer Gelatti
AU - Bo Wang
AU - Julian Kam
AU - Seema Sethi
AU - Sujay Shah
AU - Medha Kamat
AU - Jiarui Zhang
AU - Joshua C. Curtin
AU - William N. William
AU - Benjamin Besse
PY - 2026
DA - 2026/11/04
JO - Journal of Thoracic Oncology
DO - 10.1016/j.jtho.2026.103894
UR - https://hal.science/hal-05851600v1
AB - 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.
SN - 1556-0864
SN - 1556-1380
ER -