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Eugene B. Cone, Lorine Häuser, Stephen W. Reese, Maya Marchese, David-Dan Nguyen, Junaid Nabi, Wesley H. Chou, Joachim Noldus, Rana R. McKay, Kerry Laing Kilbridge, Quoc-Dien Trinh

• \(\bf Background:\) Treatment options for many cancers include immune checkpoint inhibitor (ICI) monotherapy and combination therapy with impressive clinical benefit across cancers. We sought to define the comparative cardiac risks of ICI combination and monotherapy. \(\bf Methods:\) We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac ADRs (cADRs), such as carditis, heart failure, arrhythmia, myocardial infarction, and valvular dysfunction, related to ICI therapy. To explore possible relationships, we used the reporting odds ratio (ROR) as a proxy of relative risk. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance. \(\bf Results:\) We found 2278 cADR for ICI monotherapy and 353 for ICI combination therapy. Combination therapy was associated with significantly higher odds of carditis (ROR 6.9, 95% CI: 5.6–8.3) versus ICI monotherapy (ROR 5.0, 95% CI: 4.6–5.4). Carditis in ICI combination therapy was fatal in 23.4% of reported ADRs, compared to 15.8% for ICI monotherapy (P = 0.058). \(\bf Conclusions:\) Using validated pharmacovigilance methodology, we found increased odds of carditis for all ICI therapies, with the highest odds for combination therapy. Given the substantial risk of severe ADR and death, clinicians should consider these findings when prescribing checkpoint inhibitors.