Abstract
Advanced unresectable melanoma carries a poor prognosis, with minimal benefit from chemotherapy and limited responsiveness to radiotherapy. The emergence of immune checkpoint inhibitors (ICIs) targeting PD-1, CTLA-4, and LAG-3 has transformed treatment outcomes; however, their comparative efficacy and safety remain unclear. This systematic review and meta-analysis evaluated and compared the efficacy and safety of PD-1 and CTLA-4 monotherapies against traditional systemic therapies, as well as the dual regimens PD-1 + CTLA-4 and PD-1 + LAG-3 against their respective monotherapies, in patients with advanced unresectable melanoma. A comprehensive search of PubMed and the Cochrane CENTRAL database was conducted on March 18, 2025, for randomized controlled trials comparing ICIs against conventional therapies or other ICI regimens. Primary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ≥ 3 adverse events (AEs). A random-effects meta-analysis was performed, and risk of bias was assessed using the Cochrane RoB 2.0 tool. Eleven randomized controlled trials (n = 4,111) met the inclusion criteria. The PD-1 + CTLA-4 combination demonstrated the greatest clinical benefit, significantly improving OS (HR = 0.59), PFS (HR = 0.45), and ORR (RR = 3.11) compared with monotherapy, but was associated with a higher incidence of grade ≥ 3 AEs (RR = 2.14). The PD-1 + LAG-3 regimen showed a moderate yet statistically significant advantage in efficacy over PD-1 monotherapy (OS HR = 0.80) while maintaining better tolerability. PD-1 monotherapy demonstrated greater efficacy and a more favorable safety profile than CTLA-4 monotherapy when each was compared with traditional therapy. In conclusion, PD-1 + CTLA-4 offers the most substantial therapeutic improvement but with considerable toxicity, whereas PD-1 + LAG-3 provides a more balanced efficacy-safety profile. PD-1 monotherapy remains the safest option, though less effective than combination strategies. These findings highlight the evolving role of combination immunotherapies and the potential clinical value of LAG-3 as a novel checkpoint target in melanoma management. See also the graphical abstract(Fig. 1).