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.

Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

MEDLINE and the Cochrane Library were searched through 15 May 2025.

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.

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 (I² statistic). GRADE assessed the certainty of the evidence.

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) I²=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) I²=0%. The certainty of the evidence was graded as moderate.

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.

CRD420251006128.