Adverse Events Associated With Immune Checkpoint Inhibitors For Solid Tumor:A Systematic Review And Meta-analysis

Background:Immune checkpoint inhibitors(ICIs)are now a mainstay of cancer treatment.Given the increasing use of ICIs,its associated adverse events have drawn attention.With different types of manifestations from traditional radiotherapy and chemotherapy,the adverse events following the use of ICIs are widely distributed,and there are several reports of fatal adverse reactions(Fatal Adverse Events,FAEs).Hence,evidence in large sample size is needed to guide the clinical application of ICIs drugs.Purpose:1.To evaluate the risk of fatal adverse events associated with ICIs for solid tumor.2.To investigate the incidence and distribution of adverse events associated with ICIs for solid tumor.Methods:1.A PubMed search through April 15,2018,using the following subject words was performed: “ipilimumab,” “nivolumab,” “pembrolizumab,” “atezolizumab.” A meta analysis was conducted on the basis of Review Manager 5.3 software after literature screening.2.A Embase,PubMed and Cochrane Library search through February 28,2019,using the following subject words was performed: “ipilimumab,” “nivolumab,”“pembrolizumab,” “atezolizumab,” “durvalumab,” “avelumab.” A meta analysis was conducted on the basis of R software 3.5.0 after literature screening.Results:1.A total of 12 articles were included,including 6390 patients.Compared with placebo,the OR value of FAE in ICIs was 2.01(95% CI: 1.17,3.44;P=0.01),and the OR value of FAEs in CTLA-4 inhibitor was 2.47(95% CI: 1.31,4.66).(P=0.005),the OR value of FAEs in PD-1 inhibitor was 1.06(95% CI: 0.37,3.05;P=0.92).Subgroup analysis in different doses of CTLA-4 inhibitors showed that the incidence of FAEs between two groups was significantly different(P=0.05).Specific FAEs is listed in proportional order:gastrointestinal toxicity 25%,pulmonary toxicity 20%,cardiotoxicity 10% and hepatotoxicity 10%.2.A total of 67 articles were included,including 18133 patients.By the combination,the incidence and distribution characteristics of various immune-related adverse reactions in solid tumors were clarified.Conclusion:1.CTLA-4 inhibitors significantly increase the risk of developing FAEs in patients.2.The fatal toxicity of Ipilimumab is dose dependent.3.The incidence of various immune-related adverse events and their 95% confidence intervals were obtained.4.The most common cause of FAEs in the therapy of PD-1/PD-L1 inhibitors or combined immunotherapy are lung toxicity,and the most common cause of FAEs in the therapy of CTLA-4 inhibitors are gastrointestinal toxicity.