Immune-related adverse events from combination immunotherapy in cancer patients: A comprehensive meta-analysis of randomized controlled trials

Although available evidence from clinical trials has shown that immune checkpoint inhibitors (ICIs) combination therapy can lead to a series of immune-related adverse events (irAEs), the overall risk of irAEs on combination therapy has yet not been systematically reported. Therefore, we performed a meta-analysis to comprehensively explore the overall risks for irAEs on combination immunotherapy.PubMed, Embase, and Google Scholar were systematically searched for relevant randomized controlled trials (RCTs) comparing combination immunotherapy to monotherapy. The meta-analysis was conducted by using Review Manager 5.3.A total of 11 RCTs involving 5307 patients were eligible for this meta-analysis. The risk ratio for all-grade diarrhea and all-grade colitis for combination therapy was 1.95 (95% CI 1.54, 2.46; P < 0.00001) and 4.45 (95% CI 3.04, 6.51; P < 0.00001), respectively. The risk ratio for all-grade hyperthyroidism and all-grade hypothyroidism for combination therapy was 2.84 (95% CI 1.71, 4.72; P < 0.0001) and 1.71 (95% CI 1.38, 2.13; P < 0.00001), respectively. The risk ratio for all-grade increased AST and all-grade increased ALT was 3.87 (95% CI 2.74, 5.47; P < 0.00001) and 4.29 (95% CI 3.05, 6.04; P < 0.00001), respectively. The risk ratio for all-grade hypophysitis and all-grade pneumonitis was 4.24 (95% CI 2.26, 7.98; P < 0.00001) and 2.92 (95% CI 1.60, 5.33; P = 0.0005), respectively.Patients receiving combination immunotherapy are at increased risk of selected all-grade irAEs. Although fatal high-grade irAEs is rare, AEs caused by combination immunotherapy should be recognized promptly in order to avoid more serious complications.