Osimertinib Versus First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Metastatic EGFR-Mutant Non-Small Cell Lung Cancer: A Target Trial Emulation Study of Real-World Survival and Safety Outcomes.

Abstract

Although clinical trials support osimertinib's efficacy over standard epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in metastatic EGFR-mutant non-small cell lung cancer (NSCLC), large real-world comparisons against first-generation TKIs are limited. We compared the real-world effectiveness and safety of first-line osimertinib versus first-generation TKIs (erlotinib, gefitinib) using a target trial emulation approach. This retrospective cohort study used the TriNetX Research Network global database. We identified adults with newly diagnosed metastatic EGFR-mutant NSCLC initiating first-line EGFR-TKI therapy (January 2014-March 2025). After 1:1 propensity score matching (PSM), overall survival (OS; primary outcome) and safety were compared between treatment arms. Following PSM, a total of 3,168 patients (1,584 per arm) were analyzed. The median OS was significantly longer with osimertinib compared with first-generation TKIs (1,505 <i>v</i> 901 days; hazard ratio [HR], 0.612 [95% CI, 0.549 to 0.683]; <i>P</i> < .001). Survival benefits were consistent across subgroups, particularly pronounced in Asian patients (HR, 0.439). First-generation TKIs had higher rates of dermatologic toxicities, severe infections, and hospitalizations. Osimertinib showed higher rates of abnormal ECG findings and thrombocytopenia. Sensitivity analyses confirmed the robustness of the primary findings. In this large real-world comparative effectiveness study using target trial emulation, first-line osimertinib was associated with substantially prolonged OS and a favorable safety profile, including lower rates of severe infections and hospitalizations, compared with first-generation EGFR-TKIs in patients with metastatic EGFR-mutant NSCLC.