Background: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial., Patients and Methods: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion., Results: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy., Conclusions: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen., Competing Interests: Disclosure AP: consulting or advisory role for AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Lilly, GSK, Janssen, Merck Sharp & Dohme, Mundipharma, Novartis, and Roche; speakers bureaus for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, eCancer, Janssen, Merck Sharp & Dohme, Medscape, PeerVoice, and touchONCOLOGY; steering committee member for Janssen and ArriVent Biopharma. SHL: received honoraria from AstraZeneca/MedImmune, Roche, Merck, Lilly, and Amgen; consulting or advisory role for AstraZeneca, Roche, Merck, Pfizer, and Lilly; received research funding from Merck. BM: received speaking honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Pfizer, Roche, Sanofi, and Takeda; received support for attending meetings from Janssen, Pfizer, and Sanofi. JYS: participated in advisory boards for AstraZeneca, Roche, Boehringer Ingelheim, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharmaceutical Co, Ono Pharmaceutical, Takeda, CStone Pharmaceuticals, Janssen, and Bristol Myers Squibb; received speaking honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharmaceutical Co, Ono Pharmaceutical, and Bristol Myers Squibb; received grant from Roche. KA: received lecture fees for AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb, and Chugai Pharmaceutical Co. OJV: honoraria or advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, AstraZeneca, Pfizer, Lilly, Takeda, and Janssen; received travel, accommodations, and expenses from Takeda, AstraZeneca, Merck Sharp & Dohme, Pfizer, and Roche/Genentech. EF: consulting or advisory role for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, GSK, Janssen, Merck Serono, Novartis, Pfizer, Sanofi, Takeda, Peptomyc, Daiichi Sankyo Europe GmbH, F. Hoffman La-Roche, Merck Sharp & Dohme, BerGenBio, and Turning Point Therapeutics; speakers bureaus for AstraZeneca, Bristol Myers Squibb, Lilly, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Takeda, Amgen, F. Hoffman La-Roche, Janssen, Medical Trends, Merck Serono, Sanofi, and touchONCOLOGY; other relationships with GRIFOLS; received research funding from Merck and Merck KgaA. NG: invited speaker for Amgen, AstraZeneca, Bristol Myers Squibb, Mirati Therapeutics, MSD, Novartis, Pfizer, Roche, and Sanofi; advisory roles for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Grünenthal, Janssen, Lilly, MSD, Novartis, Owkin, Pfizer, Roche, Sanofi, and Takeda; received research funding for institution from Bristol Myers Squibb, Janssen, Roche, and Sivan; leadership role at ITMIG; family employment at AstraZeneca. ABC: invited speaker for Pfizer, Amgen, Takeda, Novartis, Roche, AstraZeneca, MSD, Janssen, Bristol Myers Squibb, and Sanofi; advisory roles for Novartis, AbbVie, Roche, Exeliom Biosciences, Pfizer, Janssen, Amgen, Takeda, AstraZeneca, and MSD; research funding of institution from Exeliom Biosciences; support for attending meetings from Roche, MSD, Novartis, Pfizer, AstraZeneca, Amgen, and Bristol Myers Squibb; participation on data monitoring safety board for InhaTarget Therapeutics and Merck. RC: invited speaker for Amgen, AstraZeneca, Lilly, GSK, Janssen, MSD, Pfizer, Roche, and Takeda; participated in advisory boards for Amgen, AstraZeneca, Bayer, Lilly, GSK, Janssen, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, and Takeda; speaker in educational activities for Medscape, PeerVoice, and TouchIME; holds stocks or shares in Supportive Care UK; has ownership interest in Christie Private Care; principal investigator for AbbVie, AstraZeneca, Bristol Myers Squibb, Clovis, Lilly, GSK, Janssen, MSD, Novartis, Pfizer, PharmaMar, Roche, and Takeda. FC: received consulting fees from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD; received honoraria for advisory role from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD; received support for attending meetings from OSE Immunotherapeutics; participated in advisory boards for Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD. SO: received advisory board consulting fees from Janssen, Bristol Myers Squibb, Novocure, and Roche. SP: participated in advisory boards for Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Janssen, Lilly, Medscape, MSD, Novartis, Pfizer, Sanofi, and Takeda; consulting fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; expert testimony for Merck Serono and Roche; invited speaker for VJOncology; received payment or honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda; principal investigator for ARIAD Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Janssen, Lilly, Roche, Takeda, Trizel, and Turning Point Therapeutics; received support for attending meetings from Janssen and Roche; research grant from Guardant Health; other financial relationships with Amgen, Blueprint Medicines, Elsevier, and MSD. JLT: invited speaker for AstraZeneca, Lilly, MSD, Boehringer Ingelheim, Pfizer, and Takeda; participated in advisory boards for Amgen and AstraZeneca; received support for attending meetings from MSD. PT: received grants and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Roche, and Takeda. RDG: received grants from Alliance Foundation, Amgen, AstraZeneca, Big Ten Cancer Research Consortium, Bristol Myers Squibb, Chugai Pharmaceutical Co, Daiichi Sankyo, ECOG-ACRIN, Helsinn, Hoosier Cancer Research Network, Janssen, Jounce Therapeutics, Merck, National Cancer Institute, Pfizer, and Takeda; received payment or honoraria from Clinical Care Options, OncLive, Society for Immunotherapy of Cancer, and Targeted Oncology; received support for attending meetings from the International Association for the Study of Lung Cancer; participated in advisory boards for AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Oncocyte, Sanofi, and Takeda; leadership or other role in ASCO Scientific Review Committee and Meeting Abstracts, Hoosier Cancer Research Network, Journal of Clinical Oncology, National Cancer Institute Investigational Drug Steering Committee, and the Thoracic Clinical Trial Working Group. WNWJr: participated in advisory boards for AstraZeneca, Bayer, Merck, Novartis, Sanofi, and Takeda; invited speaker for Amgen, Bristol Myers Squibb, Lilly, Genentech/Roche, Janssen, Pfizer, and United Medical; expert testimony for Boehringer Ingelheim. KR: consultant for Amgen, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, EMD Serono, Genentech, GSK, Janssen, Lilly, Merck KGA, Mirati Therapeutics, Seattle Genetics, and Takeda; writing assistance from Blueprint Medicines, Genentech, Janssen, Merck, Mirati Therapeutics, Seattle Genetics, and Takeda; research funding of institution from Genentech, Blueprint Medicines, Calithera, Daiichi Sankyo, Elevation Oncology, and Janssen. TT: received honoraria from AstraZeneca K.K., Pfizer Japan Inc, Eli Lilly Japan, Chugai Pharmaceutical Co, MSD K.K., Pfizer Japan Inc, Takeda, Bristol Myers Squibb Japan, Amgen K.K., and Novartis; research funding of institution from Janssen Pharmaceutical K.K., AstraZeneca K.K., Pfizer Japan Inc, Eli Lilly Japan, Chugai Pharmaceutical Co, MSD K.K., Amgen K.K., Merck Biopharma Co., Ltd., and AnHeart Therapeutics Inc. SG: principal investigator for AstraZeneca, Novartis, and Janssen (fees to institution). DMK: participated in advisory boards for MSD, Merck, Roche, Bristol Myers Squibb, Takeda, Boehringer Ingelheim, Pfizer, Johnson & Johnson, Amgen, Sanofi-Aventis, and Novartis. AB: received consulting fees from Pfizer and Roche; honoraria from Novartis and Eli Lilly; participated in advisory boards for Pfizer, Roche, and Regeneron. MM: received consulting fees from Boehringer Ingelheim, Roche, Takeda, and AstraZeneca. PB, ABB, AG, JG, DM, MW, JX, TS, SS, BD, REK, JMB: employee of Janssen and may hold stock in Johnson & Johnson. RGC: invited speaker for AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Novartis, Pfizer, Roche, and Takeda; advisory roles for AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda; steering committee member for AstraZeneca and Janssen. BCC: consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Pfizer, Yuhan Corporation, Janssen, Takeda, Merck Sharp & Dohme, Ono Pharmaceutical, Lilly, MedPacto, Blueprint Medicines, Cyrus Therapeutics, Guardant Health, Novartis, CJ, ABION, BeiGene, CureLogen, Onegene Biotechnology, GI-Cell, HK inno.N, IMNEWRUN, Hanmi Pharmaceutical, Kanaph Therapeutics, BridgeBio, and Oscotec; leadership roles for Interpark Bio and J INTS BIO; patents, royalties, or other intellectual property for Champions Oncology, Crown Bioscience, and Imagen; other relationships with DAAN Biotherapeutics; owns stock or has other ownership interests with Theravance Biopharma, Gencurix, BridgeBio, Kanaph Therapeutics, Cyrus Therapeutics, Interpark Bio, and J INTS BIO; received research funding from Novartis, Bayer, AstraZeneca, MOGAM Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan Corporation, Ono Pharmaceutical, Dizal Pharma, Merck Sharp & Dohme, AbbVie, GI Innovation, Lilly, Blueprint Medicines, Interpark Bio, LG Chem, Oscotec, GI-Cell, ABION, Boehringer Ingelheim, CJ Bioscience, CJ Blossom Park, Cyrus Therapeutics, Genexine, Nuvalent Inc, Oncternal Therapeutics, Regeneron, BridgeBio, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS Bio, Hanmi Pharmaceutical, and CHA Bundang Medical Center. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)