Introduction: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who received ≤ 3 prior lines of systemic therapy. Herein, we report phase 2 efficacy and safety of first-line nazartinib., Methods: This single-arm, open-label, global study enrolled treatment-naive adult patients with stage IIIB/IV NSCLC harboring EGFR-activating mutations (eg, L858R and/or ex19del). Patients with neurologically stable and controlled brain metastases were also eligible. Patients received oral nazartinib 150 mg once daily. The primary endpoint was Blinded Independent Review Committee (BIRC)-assessed overall response rate (ORR) per RECIST v1.1., Results: Forty-five patients received ≥ 1 dose of nazartinib. The median follow-up time from enrollment to data cutoff (November 1, 2019) was 30 months (range: 25-34). The BIRC-assessed ORR was 69% (95% CI, 53-82). The median progression-free survival (PFS) was 18 months (95% CI, 15-not estimable [NE]). The median overall survival was NE. In patients with baseline brain metastases (n = 18), the ORR and median PFS (95% CIs) were 67% (41-87) and 17 months (11-21). Seventeen of 18 patients had brain metastases as non-target lesions; the CNS lesions were absent/normalized in 9 of 17 (53%). Only 2 of 27 patients without baseline brain metastases developed new brain metastases postbaseline. Most frequent adverse events (≥ 25%, any grade, all-causality) were diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough, and stomatitis (27% each)., Conclusions: First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC., Trial Registration: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02108964., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Dr. Tan reports consulting or advisory role for Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer, Amgen, and Janssen; travel, accommodation, and expenses from Pfizer, Boehringer Ingelheim, and Roche; honoraria from Bristol-Myers Squibb, Takeda, Novartis, Roche, and Pfizer; and research funding (institution) from Novartis, GlaxoSmithKline, Amgen, and AstraZeneca. Dr. S–W Kim reports advisory role for AstraZeneca, Amgen, Boehringer Ingelheim, Eli Lilly, and Novartis; research funding from AstraZeneca and Novartis; and honoraria from Boehringer Ingelheim. Dr. PonceAix reports consulting or advisory role for Bristol-Myers Squibb, Merck, and Roche; speakers' bureau for Bristol-Myers Squibb, Merck, and Roche; and travel, accommodations, expenses from AstraZeneca, Merck, and Roche. Dr. Sequist reports consulting or advisory role for AstraZeneca, Genentech/Roche, Janssen Oncology, and Takeda; and research funding (institution) from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Genentech, Guardant Health, Johnson & Johnson, Loxo, Merck, Merrimack, Novartis, and Pfizer. Dr. Smit reports consulting or advisory role (institution) for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, MSD Oncology, Novartis, Roche/Genentech, Seattle Genetics, and Takeda; and research funding (institution) from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Roche/Genentech. Dr. Yang reports personal fees (advisory board) from AstraZeneca, Boehringer Ingelheim, Roche, Novartis, Bristol-Myers Squibb, Ono Pharmaceuticals, Takeda, Eli Lilly, Pfizer, MSD, Merck, Amgen, Yuhan, and Daiichi Sankyo; grants to conduct investigator initiated study from AstraZeneca; and institutional fees (advisory board) from Amgen, Boehringer Ingelheim, Takeda, Eli Lilly, Pfizer, MSD, Merck, Bayer, Yuhan, Daiichi Sankyo, Janssen, and GlaxoSmithKline. Dr. Hida reports honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Clovis Oncology, Kissei Pharmaceutical, Eli Lilly, MSD, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; and research funding (institution) from Abbvie, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Clovis Oncology, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Ignyta, Janssen, Kissei Pharmaceutical, Kyowa Hakko Kirin, Eli Lilly, Merck Serono, MSD, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Pfizer, Servier, Taiho Pharmaceutical, and Takeda. Dr. Toyozawa reports honoraria from Chugai Pharma, Kyowa Hakko Kirin, Lilly Japan, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Taiho Pharmaceutical, Bristol-Myers Squibb, and MSD; and research funding (institution) from Abbvie, Amgen, Daiichi Sankyo, Lilly Japan, Novartis, Pfizer, and Takeda. Dr. Felip reports consulting or advisory role for Abbvie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Genzyme, GlaxoSmithKline, Janssen, Eli Lilly, Merck Serono, MSD Oncology, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi, and Takeda; speakers' bureau for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CME outfitters, Eli Lilly, Medscape, MSD, Novartis, PeerVoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, and touchIME; research funding (institution) from EMD Serono and Merck; and other relationship from GRÍFOLS. Dr. Wolf reports consulting or advisory role for Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Ignyta, Janssen, Eli Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, and Takeda; research funding (institution) from Bristol-Myers Squibb, Janssen, Novartis, and Pfizer; and travel, accommodations, expenses from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Ignyta, Janssen, Eli Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, and Takeda. Dr. Grohé reports honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD Oncology, Novartis, Roche, and Takeda; consulting or advisory role for AstraZeneca, Boehringer Ingelheim, and MSD Oncology; research funding (institution) from AstraZeneca; and travel, accommodations, expenses from Boehringer Ingelheim, Bristol-Myers Squibb, and Roche. Dr. Leighl reports honoraria from Boehringer Ingelheim; consulting or advisory role for Xcovery; research funding (institution) from EMD Serono, Guardant Health, Eli Lilly, MSD, Novartis, and Roche Canada; and travel, accommodations, expenses from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, MSD, Nektar, and Roche. Dr. Riely reports research funding (institution) from GlaxoSmithKline, Infinity Pharmaceuticals, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche/Genentech, and Takeda; patents, royalties, other intellectual property (institution): patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases; travel, accommodations, expenses from MSD; and other relationship from Pfizer, Roche/Genentech, and Takeda. Dr. Cui and Dr. Belli report employment at Novartis and own Novartis stock. Dr. Zou is a former employee at Novartis and owns Novartis stock. Dr. Ghebremariam reports employment at Novartis, owns Novartis stock, and reports travel, accommodation, and expenses from Novartis. Leslie O'Sullivan-Djentuh and Dr. Giovannini report employment at Novartis. Dr. D-W Kim reports research funding (institution) from Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan; and travel, accommodations, expenses from Amgen and Daiichi Sankyo., (Copyright © 2022. Published by Elsevier Ltd.)