Abstract
Simple SummaryWith nonspecific activation of the immune system, immune checkpoint inhibitors (ICIs) can lead to off-target immune-related adverse events (irAEs) to every organ system. Immune-related cardiotoxicity is rare but often fatal. Large population-based studies examining different ICI-associated cardiotoxicity across cancer types and agents are limited. Using data from a large network of health care organizations, this study aims to: (1) provide an estimate of the incidence of ICI-associated cardiotoxicity, (2) to determine patient and clinical characteristics associated with the risk of developing ICI-associated cardiotoxicity, and (3) to assess the overall survival of patients experiencing ICI-associated cardiotoxicity compared to patients who did not develop cardiotoxicity after ICI use.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.
Highlights
IntroductionImmune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate T cells and initiate an adaptive immune response, thereby allowing the immune system to recognize abnormal cancerous cells [1]
Immune checkpoint inhibitors (ICIs): immune checkpoint inhibitor; a highly elevated risk (aHR): adjusted hazard ratio; 95% confidence intervals (95% CI): 95% confidence interval; cytotoxic T-lymphocyte associated-antigen-4 (CTLA-4): Cytotoxic
Site variables are not mutually exclusive and patients may have multiple cancer sites. After adjusting for these differences, patients who initiated on monotherapy with ipilimumab or pembrolizumab had a higher risk of developing cardiac adverse event (CAE) within one year compared to nivolumab monotherapy
Summary
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate T cells and initiate an adaptive immune response, thereby allowing the immune system to recognize abnormal cancerous cells [1]. Durable tumor responses and improvement in overall survival have been shown in numerous randomized clinical trials in patients treated with ICIs [1]. It was estimated that 43.6% of cancer patients in the US were eligible for ICI therapy in 2018 [3]. The FDA has approved more indications for ICIs [2] and the number of eligible patients is likely to be even higher. Not all patients respond to ICIs and the overall response rate (ORR)
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