Comparative efficacy of osimertinib with and without radiation therapy in EGFR-mutated nonsmall cell lung cancer with brain metastases.

Brain metastases are common in patients with EGFR-mutant nonsmall cell lung cancer (NSCLC), yet optimal management remains under investigation. Osimertinib has demonstrated central nervous system (CNS) activity, but the added benefit of combining it with upfront local therapy is unclear. This study evaluated the comparative efficacy of osimertinib alone versus in combination with radiation therapy (RT) or stereotactic radiosurgery (SRS) in patients with EGFR-mutant NSCLC and brain metastases. We conducted a retrospective cohort study using the TriNetX Research Network, identifying adult patients diagnosed between 2010 and 2024 with EGFR-mutant NSCLC and brain metastases who received osimertinib. Patients were grouped into those who received RT or SRS within 6 months of starting osimertinib (cohort 1) and those who received osimertinib alone (cohort 2). Propensity score matching (1:1) was used to balance baseline characteristics. The primary outcome was 3-year survival; secondary outcomes included CNS complications, healthcare utilization, and second-line therapy initiation. Among 743 eligible patients, 217 in each cohort were matched. Three-year survival was significantly higher in cohort 1 (43% v 29%; HR 0.67, P = .003). Median survival was 25 months v 16 months, respectively. CNS complication rates were not significantly different overall, though sensitivity analysis excluding prior CNS history showed increased complications with osimertinib alone (HR 2.0, P = .007). SRS was independently associated with reduced mortality (HR 0.49, P = .003). Upfront local therapy with osimertinib may improve survival in EGFR-mutant NSCLC with brain metastases, though careful patient selection is warranted.