CHIH-HSIN YANGLu, ShunShunLuHayashi, HidetoshiHidetoshiHayashiFelip, EnriquetaEnriquetaFelipSpira, Alexander IAlexander ISpiraGirard, NicolasNicolasGirardKim, Yu JungYu JungKimLee, Se-HoonSe-HoonLeeOstapenko, YuriiYuriiOstapenkoDanchaivijitr, PongwutPongwutDanchaivijitrLiu, BaogangBaogangLiuAlip, AdlindaAdlindaAlipKorbenfeld, ErnestoErnestoKorbenfeldMourão Dias, JosianeJosianeMourão DiasBesse, BenjaminBenjaminBessePassaro, AntonioAntonioPassaroLee, Ki-HyeongKi-HyeongLeeXiong, HailinHailinXiongHow, Soon-HinSoon-HinHowCheng, YingYingChengChang, Gee-ChenGee-ChenChangYoshioka, HiroshigeHiroshigeYoshiokaThomas, MichaelMichaelThomasNguyen, DannyDannyNguyenOu, Sai-Hong IgnatiusSai-Hong IgnatiusOuMukhedkar, SanjaySanjayMukhedkarPrabhash, KumarKumarPrabhashD'Arcangelo, ManoloManoloD'ArcangeloAlatorre-Alexander, JorgeJorgeAlatorre-AlexanderVázquez Limón, Juan CarlosJuan CarlosVázquez LimónAlves, SaraSaraAlvesStroyakovskiy, DaniilDaniilStroyakovskiyPeregudova, MarinaMarinaPeregudovaŞendur, Mehmet Ali NahitMehmet Ali NahitŞendurYazici, OzanOzanYaziciCalifano, RaffaeleRaffaeleCalifanoGutiérrez Calderón, VanesaVanesaGutiérrez Calderónde Marinis, FilippoFilippode MarinisKim, Sang-WeSang-WeKimGadgeel, Shirish MShirish MGadgeelOwen, ScottScottOwenXie, JohnJohnXieSun, TaoTaoSunMehta, JaydeepJaydeepMehtaVenkatasubramanian, RajaRajaVenkatasubramanianEnnis, MariahMariahEnnisFennema, ElizabethElizabethFennemaDaksh, MaheshMaheshDakshRoshak, AmyAmyRoshakMan, JulieJulieManKnoblauch, Roland ERoland EKnoblauchBauml, Joshua MJoshua MBaumlBaig, MahadiMahadiBaigShah, SujaySujayShahSethi, SeemaSeemaSethiCho, Byoung ChulByoung ChulCho2026-01-092026-01-092025-10-30https://scholars.lib.ntu.edu.tw/handle/123456789/735212Previous results from this phase 3 trial showed that progression-free survival among participants with previously untreated (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC) was significantly improved with amivantamab-lazertinib as compared with osimertinib. Results of the protocol-specified final overall survival analysis in this trial have not been reported.We randomly assigned, in a 2:2:1 ratio, participants with previously untreated -mutated (exon 19 deletion or L858R substitution), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib, osimertinib, or lazertinib. Overall survival (assessed in an analysis of the time from randomization to death from any cause) in the amivantamab-lazertinib group as compared with the osimertinib group was a key secondary end point. Additional end points included safety.A total of 429 participants each were assigned to receive amivantamab-lazertinib or osimertinib. Over a median follow-up of 37.8 months, amivantamab-lazertinib led to significantly longer overall survival than osimertinib (hazard ratio for death, 0.75; 95% confidence interval, 0.61 to 0.92; P = 0.005); 3-year overall survival was 60% and 51%, respectively. At the clinical cutoff date, 38% of participants in the amivantamab-lazertinib group and 28% in the osimertinib group were still receiving the assigned treatment. Adverse events of grade 3 or higher were more common with amivantamab-lazertinib (in 80% of participants) than with osimertinib (in 52%), particularly skin-related events, venous thromboembolism, and infusion-related events; these findings were consistent with the established safety profile of each treatment. No new safety signals were observed with additional follow-up.Amivantamab-lazertinib led to significantly longer overall survival among participants with previously untreated -mutated advanced NSCLC than osimertinib but was associated with an increased risk of adverse events of grade 3 or higher. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).en[SDGs]SDG2[SDGs]SDG3journal article10.1056/NEJMoa250300140923797