Efficacy and Safety of CTLA-4, PD-1, and LAG-3 Immune Checkpoint Inhibitors as Monotherapy and Combination Therapy in Advanced Melanoma: A Systematic Review and Meta-Analysis

BACKGROUND: Advanced unresectable melanoma has a poor prognosis, with limited benefit from chemotherapy and low responsiveness to radiotherapy. Immune checkpoint inhibitors (ICIs) targeting PD-1, CTLA-4, and LAG-3 have significantly improved outcomes, but comparative efficacy and safety remain uncertain. AIM: To systematically assess and compare the efficacy and safety of PD-1 and CTLA-4 monotherapies, and dual regimens including PD-1 + CTLA-4 and PD-1 + LAG-3, in patients with advanced unresectable melanoma. METHODS: A systematic search of PubMed and Cochrane CENTRAL was conducted on March 18, 2025. Eligible studies were randomized controlled trials comparing ICIs to conventional therapies or other ICI regimens. Primary outcomes 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. RESULTS: Eleven trials (n = 4,111) were included. The PD-1 + CTLA-4 combination showed the strongest improvements in OS (HR = 0.59), PFS (HR = 0.45), and ORR (RR = 3.11), but with the highest toxicity (RR = 2.14 for grade ≥3 AEs). PD-1 + LAG-3 showed a moderate but significant efficacy advantage over PD-1 monotherapy (OS HR = 0.80) with improved tolerability. PD-1 monotherapy outperformed CTLA-4 monotherapy across all endpoints and had the lowest toxicity. CONCLUSION: PD-1 + CTLA-4 provides the most substantial clinical benefit but with considerable toxicity. PD-1 + LAG-3 appears to offer a more balanced alternative. PD-1 monotherapy remains the safest option, though less effective than combination strategies.