Outcomes after SRS and Ipilimumab plus Nivolumab for Melanoma Brain Metastases Following Prior Immune Checkpoint Inhibitor or Targeted Therapy

Abstract Background Melanoma brain metastases (BM) carry high morbidity and mortality despite advances in systemic therapy. Combined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab (ipi/nivo) demonstrates intracranial activity, but the influence of prior systemic therapy exposure is poorly defined. This is the first real-world study evaluating outcomes of melanoma BM treated with stereotactic radiosurgery (SRS) and concurrent ipi/nivo, focusing on the impact of prior ICI or targeted therapy. Patients and Methods We retrospectively analyzed 68 patients with 413 melanoma BM treated with concurrent SRS and ipi/nivo from 2015–2025. Primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). Secondary endpoints included local and distant control, radionecrosis, and leptomeningeal disease. Univariable and multivariable Cox models identified predictors of outcome. Results Median OS was 24.0 months (12- and 24-month OS: 64% and 50%). ICI-naive patients had longer OS (50.5 vs 17.6 months; P = .007) and iPFS (15.1 vs 5.9 months) than those with prior ICI. On multivariable analysis, prior ICI (HR 2.23, 95% CI 1.13–4.41), prior BRAF/MEKi (HR 2.26, 95% CI 1.01–5.04), and ≥11 SRS-treated lesions (HR 3.22, 95% CI 1.43–7.21) predicted worse outcomes, while higher Graded Prognostic Assessment (GPA) favored OS (HR 0.46, 95% CI 0.29–0.75). At 24 months, local progression was 11%, distant 49%, radionecrosis 7%, and leptomeningeal disease 4%. Conclusion Concurrent SRS with ipi/nivo provides durable intracranial control with low toxicity. Patients with prior ICI or targeted therapy represent a high-risk subgroup with poorer outcomes, supporting exploration of intensified or novel strategies.