Lazertinib Versus Osimertinib in Previously Untreated EGFR-Mutant Advanced NSCLC: A Randomized, Double-Blind, Exploratory Analysis From MARIPOSA
- PMID: 40617394
- DOI: 10.1016/j.jtho.2025.06.030
Lazertinib Versus Osimertinib in Previously Untreated EGFR-Mutant Advanced NSCLC: A Randomized, Double-Blind, Exploratory Analysis From MARIPOSA
Abstract
Introduction: Lazertinib is a central nervous system-penetrant, third-generation EGFR tyrosine kinase inhibitor (TKI) that was selected for combination with amivantamab due to its relatively low rates of wild-type EGFR toxicities. In the phase 3 MARIPOSA study, amivantamab plus lazertinib (amivantamab-lazertinib) significantly improved progression-free survival (PFS; p < 0.001) versus osimertinib in participants with treatment-naive EGFR-mutant advanced NSCLC. A lazertinib monotherapy arm was included to assess the contribution of components in the combination. This is the first randomized, double-blind comparison of two third-generation EGFR TKIs, lazertinib and osimertinib.
Methods: In MARIPOSA, 1074 participants were randomized 2:2:1 to receive amivantamab-lazertinib (n = 429), osimertinib monotherapy (n = 429), or lazertinib monotherapy (n = 216). This exploratory analysis compared the efficacy and safety of lazertinib and osimertinib.
Results: At a median follow-up of 22.0 months, median PFS was 18.5 months for lazertinib versus 16.6 months for osimertinib (hazard ratio = 0.98, 95% confidence interval: 0.79-1.22; p = 0.86). PFS results were comparable between arms among predefined subgroups. Among participants with measurable disease at baseline, objective response rate was 83% for lazertinib versus 85% for osimertinib, with a median duration of response among confirmed responders of 16.6 months versus 16.8 months, respectively. Median overall survival was not reached for both arms (hazard ratio = 1.00, 95% confidence interval: 0.73-1.38) at the interim analysis. Adverse events for both arms were mostly grades 1 to 2 and frequently related to EGFR inhibition. Lazertinib was associated with lower rates of QT interval prolongation versus osimertinib.
Conclusions: Lazertinib demonstrated comparable efficacy and safety to osimertinib, including in predefined subgroups.
Keywords: EGFR-mutant NSCLC; First-line treatment; Lazertinib; Osimertinib; Tyrosine kinase inhibitor.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Disclosure Dr. Lee reports serving in a consulting or advisory role for Abion, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, IMBdx, ImmuneOncia, Janssen, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; receiving honoraria from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and Yuhan Corporation; and receiving research funding from AstraZeneca, Lunit, and Merck Sharp & Dohme, outside of the current work. Dr. Lu reports serving in a consulting or advisory role for AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison, Bristol Myers Squibb, Simcere Pharmaceutical Group, Zai Lab, GenomiCare, Yuhan Corporation, Roche, and Innovent Biologics; participating in a speakers bureau for AstraZeneca, Roche, Hansoh, and Hengrui Therapeutics; and receiving research funding from AstraZeneca, Hutchison MediPharma, Bristol Myers Squibb, Hengrui Therapeutics, BeiGene, Roche, Hansoh, and Lilly Suzhou Pharmaceutical, outside of the current work. Dr. Hayashi reports serving in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, and Janssen; having patents, royalties, or other intellectual property with Sysmex; receiving honoraria from Ono Pharmaceutical, Bristol Myers Squibb Japan, Eli Lilly, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, Merck Sharp & Dohme, Novartis, Merck Serono, Amgen, Daiichi Sankyo/UCB Japan, Guardant Health, and Takeda; and receiving research funding from Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca, AbbVie, AC Medical, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly Japan, EPS Associates, GlaxoSmithKline, Japan Clinical Research Operations, Kyowa Kirin, Merck Serono, Novartis, Otsuka, Parexel, Pfizer, PPD-SNBL, Quintiles, Taiho Pharmaceutical, Takeda, Yakult Honsha, Chugai Pharma, and Sysmex, outside of the current work. Dr. Felip reports serving in a consulting or advisory role for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, Takeda, and Peptomyc; receiving speakers bureau fees from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Roche, Takeda, and CME Outfitters; having other relationships with Grifols; and receiving research funding (institution) from Merck and Merck KGaA, outside of the current work. Dr. Spira reports serving in a leadership role at NEXT Oncology Virginia; holding stock in Eli Lilly; receiving honoraria from CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Bayer; serving in a consulting or advisory role for Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone bio, Daiichi Sankyo/AstraZeneca, Regeneron, Array BioPharma, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, and Blueprint Medicines; and receiving research funding from LAM Therapeutics, Regeneron, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, NewLink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, MacroGenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone bio, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Alkermes, and Revolution Medicines, outside of the current work. Dr. Girard reports serving in a consulting or advisory role for Roche, Eli Lilly, AstraZeneca, Novartis, Pfizer, Bristol Myers Squibb, Merck Sharp & Dohme, Takeda, Janssen, Sanofi, Amgen, Gilead Sciences, BeiGene, AbbVie, Daiichi Sankyo/AstraZeneca, LEO Pharma, and Ipsen; having a family member employed by AstraZeneca; having travel, accommodations, or expenses paid by Roche; and receiving research funding from Roche, AstraZeneca, Bristol Myers Squibb, and MSD Avenir, outside of the current work. Dr. Danchaivijitr reports receiving honoraria from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Janssen, and Astellas Pharma; serving in a consulting or advisory role for Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Janssen, Astellas Pharma, and Eisai; participating in a speakers bureau for Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Janssen, Astellas, Amgen, BioPharma, and Eisai; and receiving research funding from Merck Sharp & Dohme, Roche, and Janssen, outside of the current work. Dr. Alip reports serving in a consulting or advisory role for Boehringer Ingelheim, Cipla Malaysia, Eisai Malaysia, Ipsen, and Merck Sharp & Dohme; participating in a speakers bureau for Bristol Myers Squibb, AstraZeneca, and Ipsen; and receiving research funding from Janssen, Merck Sharp & Dohme, Novartis, and AstraZeneca, outside of the current work. Dr. Mourão Dias reports serving in a consulting or advisory role for AstraZeneca and Merck Sharp & Dohme; participating in a speakers bureau for Amgen, AstraZeneca, Roche, Sanofi, Takeda, and Janssen; receiving research funding from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Debiopharm Group, GlaxoSmithKline, Incyte, Ipsen, Janssen, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and Xcovery; and having travel, accommodations, or expenses paid by Amgen, Boehringer Ingelheim, Janssen, and Sanofi, outside of the current work. Dr. Lee reports receiving grants or contracts from Merck Serono; and receiving consulting fees from Merck Sharp & Dohme, Pfizer, Eli Lilly, Yuhan Corporation, AstraZeneca, and Bristol Myers Squibb, outside of the current work. Dr. How reports having travel, accommodations, or expenses paid by Merck Sharp & Dohme; receiving honoraria from Roche, Merck Sharp & Dohme, and AstraZeneca; and receiving research funding from AstraZeneca, Merck Sharp & Dohme Oncology, Novartis, and Janssen Oncology, outside of the current work. Dr. Chang reports receiving honoraria from F. Hoffmann-La Roche, Lilly Oncology, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp & Dohme, outside of the current work. Dr. Yang reports receiving honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda; serving in a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Clovis Oncology, Daiichi Sankyo, G1 Therapeutics, GlaxoSmithKline, Hansoh, Incyte, Janssen, Eli Lilly, Merck Serono, MSD Oncology, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Yuhan Corporation; and having travel, accommodations, or expenses paid by Pfizer, outside of the current work. Dr. Besse reports participating in advisory board meetings (institution) with AbbVie, BioNTech SE, Beijing Avistone Biotechnology, Bristol Myers Squibb, CureVac AG, PharmaMar, Regeneron, and Sanofi-Aventis; serving in a consulting or advisory role for AbbVie, Bristol Myers Squibb, CureVac AG, Eli Lilly, Ellipses Pharma, F. Hoffman-La Roche, Foghorn Therapeutics, Genmab, Immunocore, Owkin, and Sanofi-Aventis; participating in a steering committee meeting (institution) with AstraZeneca, Amgen, BeiGene, CureVac AG, Genmab A/S, Janssen, Merck Sharp & Dohme, Ose Immunotherapeutics, PharmaMar, Sanofi, and Takeda; and participating as a speaker (institution) for AbbVie, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Ose Immunotherapeutics, Sanofi-Aventis, and Servier, outside of the current work. Dr. Thomas reports receiving grants or contracts from AstraZeneca, Bristol Myers Squibb, Merck, Roche, and Takeda; receiving consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda; receiving payment or honoraria from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda; and receiving support for attending meetings and/or travel from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda, outside of the current work. Dr. Shah, Dr. Baig, Dr. Curtin, Dr. Zhang, Dr. Xie, Dr. Sun, Dr. Sethi, Dr. Wang, Elizabeth Fennema, Dr. Daksh, Mariah Ennis, and Dr. Bauml report employment by and may hold stock in Johnson & Johnson. Dr. Cho reports serving in a consulting or advisory role for AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cyrus Therapeutics, Guardant Health, Janssen, J INTS BIO, Kanaph Therapeutics, Eli Lilly, MedPacto, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, Takeda, and Yuhan Corporation; serving in a leadership role for Interpark Bio and J INTS BIO; holding patents, royalties, or other intellectual property at Champions Oncology; having other relationships with DAAN Biotherapeutics; holding stock in Theravance, Gencurix, BridgeBio, Kanaph Therapeutics, Cyrus Therapeutics, and Interpark Bio; and receiving research funding from Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, and Yuhan Corporation, outside of the current work. Dr. Kim, Dr. Ostapenko, Dr. Liu, Dr. Korbenfeld, Dr. Xiong, and Dr. Cheng report no disclosures.
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