When Brain Metastases Meet Immunotherapy: Real-World Outcomes With First-Line Pembrolizumab in PD-L1-High Metastatic NSCLC

Background: Although immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape for patients with non-small cell lung cancer (NSCLC), the impact on brain metastases (BM) remains uncertain, as these patients have often been excluded from or underrepresented in clinical trials. The aim of this study was to investigate the association between metastatic site and response to immunotherapy.Methods: This retrospective single-center study included 141 consecutive adults with advanced NSCLC, programmed death ligand 1 (PD-L1) tumor proportion score ≥50%, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and no activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement who received first-line pembrolizumab monotherapy between 2018 and 2022. Patients with BM received stereotactic radiosurgery or whole-brain radiotherapy before or in parallel with pembrolizumab according to multidisciplinary recommendations. Survival was analyzed using Kaplan-Meier estimates, log-rank testing, and Cox proportional hazards models. Because metastatic-site coding was available only for patients with documented distant metastases, the site-specific BM versus other metastatic site comparison was restricted to a 115-patient subset.Results: The full cohort comprised 141 analyzable patients. In the primary metastatic-site subset (n = 115), 28 patients had BM and 87 had other metastatic sites without BM. In this subset, progression-free survival (PFS) was longer in the BM group than in the non-BM metastatic-site group (hazard ratio [HR] 0.42, (95% CI 0.19–0.94; p = 0.035)). Median PFS was not reached in the BM group (95% CI 14.0 months to not reached) and was 26.0 months (95% CI 8.0 months to not reached) in the non-BM group. Overall survival (OS) did not differ significantly (HR 0.48, 95% CI 0.21–1.09; p = 0.080); the median OS was not reached in the BM group (95% CI 14.0 months to not reached) and was 30.0 months (95% CI 15.0–40.0 months) in the non-BM group.Conclusion: In this retrospective cohort, patients with BM who received pembrolizumab plus local CNS-directed radiotherapy had longer PFS than patients with other metastatic sites, but no statistically significant OS advantage. These findings should be interpreted cautiously because all BM patients received local radiotherapy and had lower extracranial metastatic burden; the observed PFS difference may reflect treatment-related confounding, selection bias, and baseline prognostic imbalance rather than intrinsic sensitivity of brain metastases to immunotherapy.