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

Background: 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. Methods: 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. Results: 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 105, 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. Conclusions: 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.