The efficacy and safety of combination of PD-1 and CTLA-4 inhibitors: a meta-analysis

Background Recently, a series of clinical trials showed that combination of anti-programmed cell death-1 (alpha-PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (alpha-CTLA-4) could effectively eliminate tumor. However, in comparison with widely adopted mono-immune checkpoint inhibitors, chemotherapy, and targeted therapy, the advantage of combination therapy of alpha-PD-1 and alpha-CTLA-4 in response rate and prognosis is controversial especially considering probably increased treatment related adverse event. Thus, we conducted this meta-analysis to explore the efficacy and safety of combination treatment of alpha-PD-1 and alpha-CTLA-4. Methods This meta-analysis involved 8 clinical trials. In most trials, the primary endpoint was objective response rate (ORR). Thus we calculated risk ratio (RR) and 95% confidence interval (CI) to compare ORR of patients undergoing different treatment strategies. Moreover, the co-primary endpoints in few trials included progression-free survival and overall survival. Hazard ratio (HR) with 95% CI were employed to weigh the influence of different treatments on prognosis of patients. Subgroup analysis was conducted in patients with high and low expression of PD-L1. Lastly, the safety of combination therapy was evaluated by comparing treatment related adverse events among various treatment groups. Results Our results showed that ORR was significantly higher in patients receiving alpha-PD-1 plus alpha-CTLA-4 compared with alpha-PD-1 (RR 1.31, 95% CI 1.16-1.48) or alpha-CTLA-4 monotherapy (RR 2.11, 95% CI 1.84-2.43), chemotherapy and targeted therapy (RR 1.41, 95% CI 1.26-1.58). alpha-PD-1 plus alpha-CTLA-4 treated patients had a great advantage on monotherapy, chemotherapy and targeted therapy treated patients in PFS. Notably, no significant alteration in total adverse event rate was observed in alpha-PD-1 plus alpha-CTLA-4 treated patients. Results of subgroup analysis showed that combination therapy could enhance anti-tumor response in comparison with other treatments, especially for low PD-L1 expression patients undergoing nivolumab treatment (ORR: RR 1.35, 95% CI 1.11-1.65). Conclusion Combination treatment of alpha-PD-1 and alpha-CTLA-4 is a feasible strategy with enhanced efficacy and acceptable adverse event. Moreover, for some low PD-L1 expression patients, alpha-CTLA-4 might decrease the risk of resistance to alpha-PD-1 and demonstrate the synergistic anti-tumor effect.