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

ABSTRACT 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.