Umbrella Systematic Review of the Efficacy and Safety of PD-1 Inhibitors Combined with CTLA-4 Inhibitors in the Treatment of Melanoma

The objective is to assess the effectiveness and safety of combining PD-1 inhibitors with CTLA-4 inhibitors for melanoma treatment, drawing on current meta-analysis findings and evaluating the supporting evidence. We used medical subject words and free text words (such as “PD-1 inhibitor”, “CTLA-4 inhibitor”, “melanoma”) as search keywords to search the literature in six literature databases from the establishment of the database to 11 April 2025. Using the PICO (Participant, Intervention, Control, and Outcome) framework, we identified 27 unique associations between combination treatment efficacy outcomes and 70 unique associations between adverse event outcomes, which were re-evaluated using a random effects model. A total of 10 meta-analysis were included, including 36 randomized controlled trials and two retrospective studies. According to the evaluation meta-analysis of AMSTAR 2 (A MeaSurement Tool to Assess Systematic Reviews, version 2), all 10 meta-analysis were of very low quality. The association of outcome indicators was re-analyzed based on the random effects model, of which 26 associations showed high efficacy of combination therapy and 66 associations showed poor safety of combination therapy. In conclusion, a PD-1 inhibitor combined with a CTLA-4 inhibitor is a very effective method for the treatment of melanoma, but the incidence of various types of adverse reactions is high, and the evidence is not reliable. Therefore, future studies need higher quality evidence.