Lee S.H.Lu S.Hayashi H.Felip E.Spira A.I.Girard N.Kim Y.J.Ostapenko Y.Danchaivijitr P.Liu B.Alip A.Korbenfeld E.Dias J.M.Lee K.H.Xiong H.How S.H.Cheng Y.Chang G.C.Chih-Hsin Yang J.Besse B.Thomas M.Shah S.Baig M.Curtin J.C.Zhang J.Xie J.Sun T.Sethi S.Wang M.Fennema E.Daksh M.Ennis M.Bauml J.M.Cho B.C.Mahidol University2025-08-162025-08-162025-01-01Journal of Thoracic Oncology (2025)15560864https://repository.li.mahidol.ac.th/handle/123456789/111683Introduction: 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.MedicineArticleSCOPUS10.1016/j.jtho.2025.06.0302-s2.0-1050128567801556138040617394