Comparative Efficacy and Safety of Osimertinib Versus First-Generation EGFR-TKIS as First-Line Treatment in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Abstract

Objective of this study was to compare the efficacy and safety of Osimertinib versus first-generation EGFR-TKIs (gefitinib, erlotinib) as first-line treatment in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) through a systematic review and meta-analysis. A systematic review was conducted following PRISMA 2020 guidelines (PROSPERO: CRD420251163356). PubMed, Embase, and Scopus were searched from inception through September 2025. Eligible studies were randomized controlled trials (RCTs) and comparative cohort studies. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Hazard ratios (HRs) and risk ratios (RRs) were pooled. Risk of bias was assessed using RoB-2 and ROBINS-I. Evidence certainty was graded using GRADE. Eight studies (3 RCTs, 5 cohort studies; N=2824) met inclusion criteria; seven studies contributed to quantitative synthesis. Osimertinib significantly improved PFS (HR=0.46; 95% CI: 0.37–0.57; p<0.001) and OS (HR=0.80; 95% CI: 0.71–0.90; p<0.001). ORR (RR=1.04; 95% CI: 0.99–1.10; p=0.12) and DCR (RR=1.03; 95% CI: 0.99–1.07; p=0.18) were comparable. Grade ≥3 AEs were significantly lower with Osimertinib (RR=0.68; 95% CI: 0.56–0.83; p<0.001). Any-grade AEs were also reduced (RR=0.92; 95% CI: 0.87–0.98; p=0.008). GRADE certainty was high for PFS, OS, Grade ≥3 AEs, and any-grade AEs, and moderate for ORR and DCR. In conclusion, Osimertinib demonstrates significant improvements in PFS and OS with a favorable safety profile compared with first-generation EGFR-TKIs, supporting guideline recommendations as the preferred first-line targeted therapy in EGFR-mutated advanced NSCLC.