Safety and efficacy of dual immune checkpoint inhibition for melanoma brain metastases and its comparison to ICI monotherapy: A systematic review and meta-analysis

Melanoma brain metastases remain a major cause of morbidity and death despite advances in systemic therapy. Dual immune checkpoint inhibition has shown promising intracranial activity, but the overall evidence is heterogeneous and its benefit relative to monotherapy remains clinically important to define. We performed a PRISMA-based systematic review and meta-analysis of prospective and retrospective studies evaluating dual immune checkpoint inhibition in adults with cutaneous or mucosal melanoma brain metastases. PubMed, Scopus, and Embase were searched from inception to November 5, 2025. Random-effects models were used to pool intracranial progression-free survival, overall survival, intracranial response outcomes, and adverse events. Comparative analyses versus monotherapy were performed when data were available. Twenty-four studies involving 3518 patients were included. In the overall dual ICI cohort, pooled intracranial progression-free survival was 51.9% at 6 months, 44.1% at 12 months, 40.5% at 2 years, and 38.8% at 3 years. Pooled intracranial objective response rate was 42.5%, increasing to 48% in first-line dual ICI recipients. Outcomes were more favorable in asymptomatic patients than in symptomatic patients, with pooled overall survival at 3 years of 52.3% versus 31.5%. Comparative analyses favored dual ICI over monotherapy for overall survival at 6 months, 12 months, and 2 years, while no significant difference was seen at 3 years. Elevated LDH was associated with worse survival, whereas BRAF mutation was not significantly associated with outcome. All-grade treatment-related adverse events occurred in 78% of patients, grade 3 or higher events in 48.2%, and all-grade immune-related adverse events in 65.5%. Across studies reporting adverse events for patients receiving dual and mono ICI, dual ICI therapy was consistently associated with higher rates of treatment-related and immune-related toxicities, which is consistent with the established safety profile of nivolumab plus ipilimumab and highlights the need for close monitoring, and early management of immune-related complications. Dual immune checkpoint inhibition provides meaningful and durable intracranial benefit in melanoma brain metastases, particularly in asymptomatic patients and when used early. Comparative analyses favored dual ICI over monotherapy at 6 months, 12 months, and 2 years. However, the 3-year survival advantage remains uncertain because of limited data and substantial heterogeneity. Symptomatic disease remains a major unmet need, and the potential survival benefit must be balanced against substantial toxicity.