The efficacy and safety of combined ipilimumab and nivolumab versus ipilimumab in patients with Stage III/IV unresectable melanoma: A systematic review and meta-analysis

Background: In this meta-analysis, we compared the clinical efficacy and safety of ipilimumab/nivolumab combination therapy with those of ipilimumab monotherapy for stage III/IV unresectable melanoma. Materials and Methods: A search for randomized controlled trials (RCTs) reported by relevant studies conducted up to May 2021 was performed in the PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP databases. Literature screening, data extraction, and quality evaluation were conducted independently by two researchers. The target parameters were complete response (CR), partial response (PR), objective response rate (ORR), time to progression (TTP), overall survival (OS), adverse events (AEs), and AEs in each organ system. Results: Ten articles reporting the results of three RCTs, including 790 subjects, were evaluated. In the pooled results, the CR (risk ratio [RR] = 4.48, 95% confidence interval [CI] [2.73, 7.33]), PR (RR = 2.82, 95% CI [2.09, 3.81]), and ORR (RR=3.31, 95%CI[2.60, 4.20]) were statistically different between the two treatment groups. The CR, PR, and ORR in the combination therapy group were 22.00% (90/409), 36.43% (149/409), and 58.44% (239/409), respectively, versus 4.97% (18/362), 12.98% (47/362), and 17.96% (65/362), respectively, in the monotherapy group. There were significant differences in TTP and OS between the two groups (TTP: hazard ratio [HR] = 0.41, 95% CI [0.35, 0.49]; OS: HR = 0.55, 95% CI [0.45, 0.67]). PFS and OS were longer in the combination therapy group than in the monotherapy group. The incidence of treatment-related AEs (TRAEs) and AEs leading to death (RR = 1.00, 95% CI [0.97, 1.02]; RR = 2.28, 95% CI [0.54, 9.55], respectively) was not significantly different, but the incidence of Grade 3-4 AEs and AEs leading to discontinuation was higher in the combination therapy group than in the monotherapy group (RR = 1.81, 95% CI [1.15, 2.86]); RR = 2.66, 95% CI [2.02, 3.52], respectively). Conclusions: Ipilimumab/nivolumab combination therapy was more effective than ipilimumab monotherapy for patients with stage III/IV unresectable melanoma. Although the incidence of TRAEs did not differ between the two groups, the severity of cases (Grade 3-4 AEs and AEs leading to discontinuation) was lower in the monotherapy group than in the combination therapy group. Additional high-quality studies are needed to verify the efficacy and safety of this drug combination, determine the optimal dosage, and explore additional potential drug