Abstract
OBJECTIVE: Dual immune checkpoint inhibitor (ICI) therapy might improve the outcome of adult patients with untreated metastatic BRAF-mutant melanoma. We synthesised the evidence of its effect on overall survival (OS) and adverse events. DESIGN: Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. DATA SOURCES: MEDLINE and the Cochrane Library were searched through 15 May 2025. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included randomised controlled trials (RCTs) assessing the effects of first-line dual ICI therapy compared with first-line dual targeted therapy (TT) on adult patients with metastatic BRAF-mutant melanoma. We considered articles in English or German language. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias. Time-to-event data were pooled using the generic inverse-variance method and expressed as HRs with 95% CIs. Dichotomous data were pooled using the Mantel-Haenszel method and expressed as risk ratios (RRs). Heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic). GRADE assessed the certainty of the evidence. RESULTS: We identified two RCTs (305 participants) with parallel assignment and intention-to-treat analyses. The primary beneficial outcome was overall survival (OS), and OS favoured the first-line ICI group: HR 0.66 (95% CI 0.49 to 0.90) I(2)=0%. In contrast, the primary adverse outcome was treatment-related adverse events of grade 3 or higher (TRAEs), and TRAE favoured the first-line TT group: RR 1.18 (95% CI 1.01 to 1.39) I(2)=0%. The certainty of the evidence was graded as moderate. CONCLUSIONS: The evidence base is compatible with a favourable effect of first-line nivolumab plus ipilimumab for adults with untreated metastatic BRAF-mutant melanoma on survival and an unfavourable effect on toxicity when compared with first-line TT. Future RCTs could provide more data on therapy failure and quality of life. PROSPERO REGISTRATION NUMBER: CRD420251006128.