Cardiovascular adverse events in immune checkpoint inhibitor clinical trials: A U.S. Food and Drug Administration pooled analysis.

3009 Background: Immune checkpoint inhibitors (ICI) have been approved for numerous cancers and have transformed patient outcomes. There is a growing recognition of immune-related adverse events (AE), including cardiovascular (CV) AE. While rare cases of fulminant myocarditis have been reported, the full extent of CV AE remains unknown. Methods: This exploratory observational study pooled data from prospective ICI trials submitted to FDA in initial or supplemental Biologics License Applications until 1/2018. To systematically categorize CV AE, we combined CV MedDRA Preferred terms with a focus on the underlying pathology. Descriptive statistics were used to characterize the incidence of CV AE by exposure to ICI and calculate relative risks (RR) between arms of interest. To account for bias with respect to duration of exposure, we based our analyses on the first 6-month treatment window. Results: Within 59 trials (N = 21,664), ICI therapy was associated with higher rates of myocarditis, vasculitis, ischemia, arrhythmia, and pericardial disease compared to non-ICI therapy. When ICIs were used in combination, CV AE increased across most categories compared to monotherapy. Five fatal cases of myocarditis were reported with ICI therapy. Conclusions: To our knowledge, this is the largest report of CV AE associated with ICI in clinical trials. Our results show that combination ICI therapy appears to be associated with an increase in observed incidence rates of CV AE relative to ICI monotherapy. CV AE for patients with/without ICI. Grouping Incidence Rates (%) Relative Risks All ICI N = 18605 Combo N = 1533 Mono N = 17072 Non-ICI N = 3059 ICI/Non-ICI Combo/Mono CHF 0.53 0.65 0.52 0.78 0.67 1.27 Arrhythmia 5.56 8.41 5.31 5.03 1.11 1.59 Myocarditis 0.03 0.13 0.02 0 * 7.42 Valvular 0.03 0.2 0.02 0.13 0.25 11.14 Vasculitis 0.04 0.07 0.04 0.03 1.32 1.59 Vascular/Thromboembolic/Bleeding 8.93 11.61 8.69 10.33 0.86 1.34 HTN 3.86 5.28 3.73 9.25 0.42 1.42 Sudden Cardiac Death 0.3 0.46 0.28 0.42 0.70 1.62 Vascular/PVD 0.27 0.52 0.25 0.56 0.48 2.12 Pericardial/Pericarditis 0.7 0.26 0.74 0.62 1.13 0.35 Ischemia 0.58 1.3 0.51 0.42 1.35 2.56 *not available due to 0 events in the Non-ICI group