PD-1 and CTLA-4 inhibitors in combination vs. alone for the treatment of advanced melanoma: A systematic review and meta-analysis

Background: Metastatic melanoma treatment has drastically changed during the past decade with the advent of immunotherapy. We conducted a meta-analysis, to assess PD-1 and CTLA-4 inhibitors in combination vs. alone for the treatment of advanced melanoma. Methods: The EMBASE, Medline via PubMed, Scopus, Cochrane Central, and Web of Science databases were searched. The records retrieved were screened for eligibility. Odds ratio (OR) was applied to compare dichotomous variables. All the results were reported with 95% confidence intervals (CI). Mantel-Haenszel method was used to estimate pooled OR and 95% confidence intervals for dichotomous data. Results: We retrieved 3092 citations of which we included 3 randomized controlled trials and 2 retrospective, cohort studies. The pooled OR was 2.144 (95% CI: 1.650-2.786, I-2 = 80.38% P = .000) for overall response and 2.117 (95% CI: 1.578-2.841, I-2 = 70.17% P = .000) for the complete response (CR). Subgroup analysis in nivolumab category showed that the pooled OR was 1.766 (95% CI: 1.324-2.355, I-2 = 0.0% P = .000) for the overall response and was 1.284 (95% CI: 0.889-1.855, I-2 = 0.0% P = .182) for the CR and in the ipilimumab category the pooled OR was 5.440 (95% CI: 2.896-10.220, I-2 = 70.89% P = .001) for the overall response and was 5.169 (95% CI: 3.163-8.446, I-2 = 0.0% P = .000) for the CR. The incidence of any treatment-related adverse events was significantly higher in the combination group than that of the nivolumab monotherapy 4.044 (95% CI: 1.740-9.403, I-2 = 91.64% P = .001) or the ipilimumab monotherapy 2.465 (95% CI: 0.839-7.236, I-2 = 93.02 % P = .101). Conclusion: Combination therapy with ipilimumab plus nivolumab is a promising strategy in the treatment of patients with advanced melanoma with superior overall and complete responses over either monotherapies.