Comparative efficacy and safety of first, second, and third-generation EGFR tyrosine kinase inhibitors in treatment-naïve EGFR-mutant advanced non-small cell lung cancer: a systematic review and network meta-analysis of randomized controlled trials.

The optimal first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains uncertain due to the availability of multiple generations of TKIs and limited head-to-head comparisons. A systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) was conducted comparing first, second, and third-generation EGFR-TKIs in treatment-naïve EGFR-mutant NSCLC. Databases including PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials were searched. Outcomes included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 adverse events (AEs). Hazard ratios (HRs) and odds ratios (ORs) were pooled using a frequentist random-effects NMA. Treatments were ranked using P-scores. Nine RCTs were included for PFS and eight for OS and AEs. For OS, dacomitinib (HR 0.75, 95% CI 0.59-0.95) and osimertinib (HR 0.80, 95% CI 0.67-0.96) showed significant benefit versus first-generation TKIs. For PFS, all evaluated second- and third-generation TKIs significantly improved PFS, with furmonertinib (HR 0.44, 95% CI 0.34-0.57) having the highest P-score. In safety analysis, no EGFR-TKI showed a statistically significant difference in grade ≥ 3 adverse events compared with first-generation TKIs. Although befotertinib and dacomitinib had numerically higher odds, all confidence intervals were wide and crossed the null value. While several EGFR-TKIs improved efficacy over first-generation agents, no single treatment was clearly superior across all efficacy and safety outcomes. Osimertinib showed consistent efficacy, while its safety advantage became evident in the sensitivity analysis excluding FLAURA China.