Checkpoint inhibitor monotherapy is associated with less cardiac toxicity than combination therapy
Cone EB, Haeuser L, Reese S, Marchese M, Nabi J, Abdollah F, Kilbridge K, and Trinh Q. Checkpoint inhibitor monotherapy is associated with less cardiac toxicity than combination therapy. European Urology Open Science 2020; 19:e1101.
European Urology Open Science
Introduction & Objectives: Immune checkpoint inhibitors (ICIs) demonstrate impressive clinical benefit across a variety of cancers. NCCN guidelines for several cancers including renal cell carcinoma now support ICI monotherapy and combination therapy with ipilimumab. Cardiac toxicity is a rare but catastrophic adverse event associated with ICIs. We sought to define the comparative cardiac risk profile of ICI combination versus monotherapy in a real world setting.
Materials & Methods: We used VigiBase, the World Health Organization database of case safety reports, which collects data from more than 130 countries to identify drug-associated adverse events. Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac adverse events (AE) related to monotherapy (nivolumab, ipilimumab, pembrolizumab) or combination therapy (ipilimumab/nivolumab). To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR >1 reflects a disproportionality signal that more AEs are observed than expected due to chance.
Results: We found 7,644, 25,016, and 14,681, and 5,191 AEs for ipilimumab, nivolumab, pembrolizumab, and combination therapy respectively. No signal existed for overall cardiac events, but combination therapy was associated with significantly higher odds of pericarditis or myocarditis (ROR 6.9, 95% CI 5.7—8.3) versus pembrolizumab (5.6, 4.9—6.4), nivolumab (5.1, 4.6-5.7), or ipilimumab monotherapy (1.9, 1.4-2.7). Pericarditis and myocarditis with combination therapy was fatal for 23% of reported AEs, compared to 14%, 14%, and 20% for ipilimumab, nivolumab, and pembrolizumab (p=0.003) respectively.
Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of myocarditis and pericarditis for all ICI, with the highest odds for combination therapy. These adverse events were often fatal. Further research is needed to identify patients at high risk for immunotherapy related cardiac toxicity.