Optimizing Lung‐molGPA‐Directed Therapy for EGFR/ALK/ROS1‐Wildtype Non‐Small Cell Lung Cancer Brain Metastases: Survival Outcomes Analysis

ABSTRACT Patients with non‐small cell lung cancer (NSCLC) and brain metastases whose tumors lack EGFR, ALK, or ROS1 alterations have heterogeneous outcomes and limited evidence to guide treatment intensity. We assessed whether Lung‐molGPA could stratify prognosis and inform treatment selection in this population. This retrospective two‐center cohort included 811 patients with EGFR/ALK/ROS1‐wild‐type NSCLC treated between September 2013 and August 2022. Overall survival (OS) was evaluated using Kaplan–Meier methods and center‐stratified multivariable Cox regression across three Lung‐molGPA strata and treatment modalities. Median OS was 6.9 months (95% confidence interval [CI], 6.4–7.4) overall and 4.81 (4.20–5.30), 7.65 (6.73–8.40), and 16.00 (13.40–22.90) months in the Lung‐molGPA 0–1.0, 1.5–2.0, and 2.5–3.0 groups, respectively ( p < 0.001). Compared with the 0–1.0 group, adjusted mortality was lower in the 1.5–2.0 (hazard ratio [HR], 0.68; 95% CI, 0.58–0.80) and 2.5–3.0 groups (HR, 0.39; 95% CI, 0.30–0.50). Chemotherapy, immunotherapy, antiangiogenic therapy, and brain‐ and chest‐directed local therapy were independently associated with lower mortality, although their associations varied across prognostic strata and treatment contexts. Lung‐molGPA provides clinically meaningful prognostic separation and may help tailor treatment intensity for EGFR/ALK/ROS1‐wild‐type NSCLC with brain metastases.