Endocrine Adverse Events Of Immune Checkpoint Inhibitors:A Network Meta-analysis

Objective: To conduct a systematic review and quantify the types and incidence of immune-related endocrine adverse events(ir AEs)associated with immune checkpoint inhibitors(ICIs)and their combination therapies.This study aims to provide comprehensive and systematic evidence-based medicine on ICIs-related endocrine toxicity,and to provide references for toxicity management of ICIs and evidence for their safe clinical use.Methods: This study used a systematic search method,searching databases including Pub Med,Web of Science,EMBase,Cochrane Library,and limited the types of randomized controlled trials included to those containing ICIs and their combination therapies.The Cochrane risk of bias assessment tool was used to evaluate potential biases in these randomized controlled trials,and a funnel plot was drawn to qualitatively evaluate publication bias.To quantitatively compare the endocrine toxicity of each ICI,this study used the STATA software’s mvmeta command to implement network meta-analysis in a frequentist framework,and calculated the surface under the cumulative ranking curve(SUCRA).Results: A total of 55 clinical trials were included in this study,comprising 32,522 patients receiving ICIs or their combination therapies.Overall,the included clinical trials were well-designed,with complete results reporting and low bias.The results of network meta-analysis showed that the use of pembrolizumab was associated with a significantly higher incidence of hypothyroidism compared to ipilimumab.The use of nivolumab and pembrolizumab was associated with a significantly higher incidence of hyperthyroidism compared to ipilimumab.Conversely,the use of ipilimumab was associated with a significantly higher incidence of hypophysitis compared to nivolumab and pembrolizumab.There were no significant differences observed in the incidence of adrenal insufficiency and thyroiditis between different ICI drugs with different mechanisms.Conclusion: The risk of endocrine adverse reactions caused by conventional treatments is lower than that of ICIs and combination therapies.The overall risk of endocrine adverse reactions with ICIs monotherapy is lower than that of two ICI drugs or two ICI drugs combined with traditional treatments.Patients treated with CTLA-4 inhibitors are at higher risk of hypophysitis.Patients treated with PD-1 inhibitors are at higher risk of hypothyroidism and hyperthyroidism adverse reactions.