First‐Line Third‐Generation EGFR Tyrosine Kinase Inhibitor Monotherapy for Advanced EGFR‐Mutated Non‐Small Cell Lung Cancer: A Systematic Review and Network Meta‐Analysis

Third-generation (third-gen) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the management of advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, a head-to-head comparison of efficacy and safety among third-gen EGFR TKIs is lacking. Seven randomized controlled trials with 3012 patients were included. All third-gen TKIs significantly prolonged progression-free survival (PFS) compared to first-generation (first-gen) TKIs, with no significant differences in PFS or objective response rate among the third-gen TKIs. Furmonertinib ranked highest for PFS (HR, 0.82; 95% credible intervals [CrI], 0.72-0.94). Aumolertinib demonstrated the best intracranial control (HR, 0.74; 95% CrI, 0.63-0.89). Osimertinib (HR, 0.90; 95% CrI, 0.83-0.99) and lazertinib (HR, 0.89; 95% CrI, 0.79-1.00) showed overall survival benefits over first-gen TKIs. Furmonertinib, aumolertinib, and osimertinib had lower rates of severe treatment-related adverse events (TRAEs), while befotertinib exhibited the highest risk of grade ≥3 TRAEs (RR, 3.96; 95% CrI, 2.35-7.17). This study is the first head-to-head comparison of third-gen EGFR-TKIs using a Bayesian network meta-analysis, offering critical insights into efficacy and safety. Our results support personalized selection of third-gen EGFR TKIs for patients with advanced EGFR-mutated NSCLC, particularly for subpopulations with CNS metastases or different mutation subtypes.