Outcomes after SRS and ipilimumab plus nivolumab for melanoma brain metastases following prior immune checkpoint inhibitor or targeted therapy

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 to 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 = 0.007) and iPFS (15.1 vs. 5.9 months) than those with prior ICI. On multivariable analysis, prior ICI (HR 2.23, 95% confidence interval [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.