Immune Checkpoint Inhibitors-Associated Cardiotoxicity

Abstract

Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49−2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01−1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85−4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies.

Keywords: cardiac adverse events; cardiotoxicity; immune checkpoint inhibitors; real-world database.

Figure 1

Patient selection flowchart.

Figure 2

Cumulative incidence of cardiotoxicity after competing risk regressions, adjusted for covariates. (a) By first ICI agent(s), aHR (95% CI). Nivolumab: 1.00 (reference); atezolizumab: 1.11 (0.71–1.72), p = 0.65; avelumab: 1.92 (0.85–4.34), p = 0.12; cemiplimab: 0.64 (0.08–4.75), p = 0.66; durvalumab: 1.01 (0.47–2.16), p = 0.97; ipilimumab: 2.00 (1.49–2.70), p < 0.01; pembrolizumab: 1.21 (1.01–1.46), p = 0.04; combination (niv + ipi): 1.18 (0.85–1.64), p = 0.32. (b) By ICI Class, aHR (95% CI). PD-1: 1.00 (reference); CTLA4: 1.77 (1.34–2.34), p < 0.01; PD-L1: 1.04 (0.74–1.46), p = 0.82; combination (niv + ipi): 1.06 (0.78–1.45), p = 0.71. ICI: immune checkpoint inhibitor; CTLA-4: Cytotoxic T-lymphocyte associated-antigen-4; PD-1: programmed death receptor-1; PD-L1: programmed death-ligand 1; Combo (ipi+niv): combination of ipilimumab and nivolumab; aHR: adjusted hazard ratio; 95% CI: 95% confidence interval.

Figure 3

Kaplan–Meier estimate of overall survival. CAE: cardiac adverse event. ICI: immune checkpoint inhibitor.

Figure 4

Time to myocarditis diagnosis and time to death from myocarditis diagnosis in patients who developed myocarditis and died during the study period (n = 55).