Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems

BackgroundImmune checkpoint inhibitors-induced myocarditis presents unique clinical challenges. Here, we assessed post-marketing safety of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors by mining the real-world data reported in two international pharmacovigilance databases.MethodsWe analyzed immune checkpoint inhibitors (ICIs)-associated fatal adverse drug events (ADEs) reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) collected from July 1, 2014 to December 31, 2019 and data from EudraVigilance (EV) database accessed on February 29, 2020. Three different data mining approaches were used to detect the signal of fatal myocarditis caused by ICIs.ResultsBased on 7613 ICIs-related ADEs reported to the EV database and 5786 ICIs-associated ADEs submitted to the FAERS database, the most frequently reported ADE was ipilimumab-related colitis. For myocarditis, nivolumab-associated myocarditis was the most common. Among the five fatal toxic effects associated with ICIs, the lethality rate of myocarditis was the highest. Therefore, we further analyzed ICI-associated myocarditis and found that elderly patients and male patients were more likely to develop ICIs-related myocarditis. The results of signal detection showed that the risk signal of avelumab-related myocarditis detected by reporting odds ratio (ROR) method and proportional reporting ratios (PRR) method was the highest, whereas the signal strength of ipilimumab-related myocarditis detected by Bayesian confidence propagation neural networks (BCPNN) method was the strongest.ConclusionThe findings of this study indicated the potential safety issues of developing myocarditis when using ICIs, which were consistent with the results of previous clinical trials and could provide a reference for clinical workers when using ICIs.

Automated summary

This study assessed the post-marketing safety of immune checkpoint inhibitors (ICIs) by analyzing real-world data from two international pharmacovigilance databases. It found that myocarditis was the most common fatal adverse event associated with ICIs, especially in elderly and male patients. Signals for avelumab-related myocarditis were the highest using reporting odds ratio and proportional reporting ratios methods, while ipilimumab-related myocarditis showed the strongest signal using Bayesian confidence propagation neural networks method.