PURPOSE Lazertinib is a potent, central nervous system (CNS)–penetrant, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This global, phase 3 study (LASER301) compared lazertinib versus gefitinib in treatment-naïve patients with EGFR-mutated (exon 19 deletion [ex19del]/L858R) locally advanced or metastatic non-small cell lung cancer (NSCLC). METHODS Patients were ≥18 years with no prior systemic anti-cancer therapy. Neurologically stable patients with CNS metastases were allowed. Patients were randomized 1:1 to lazertinib 240 mg once daily (qd) orally (po) or gefitinib 250 mg qd po, stratified by mutation status and race. The primary endpoint was investigator-assessed progression-free survival (PFS) by RECIST v1.1. RESULTS Overall, 393 patients received double-blind study treatment across 96 sites in 13 countries. Median PFS was significantly longer with lazertinib than with gefitinib (20.6 vs 9.7 months; hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.34 to 0.58; P<0.001). The PFS benefit of lazertinib over gefitinib was consistent across all predefined subgroups. The objective response rate was 76% in both groups (odds ratio, 0.99; 95% CI, 0.62 to 1.59). Median duration of response was 19.4 months (95% CI, 16.6 to 24.9) with lazertinib versus 8.3 months (95% CI, 6.9 to 10.9) with gefitinib. Overall survival data were immature at the interim analysis (29% maturity). The 18-month survival rate was 80% with lazertinib and 72% with gefitinib (HR, 0.74; 95% CI, 0.51 to 1.08; P=0.116). Observed safety of both treatments was consistent with their previously reported safety profiles. CONCLUSION Lazertinib demonstrated significant efficacy improvement compared with gefitinib in the first-line treatment of EGFR-mutated advanced NSCLC, with a manageable safety profile.