Cardiac Adverse Events in Patients Receiving Immune Checkpoint Inhibitors in the Adjuvant Setting: An FDA Pooled Analysis

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. By releasing blocks (checkpoints) on the immune system, they elicit powerful antitumor effects. Despite improving survival, ICIs are associated with serious cardiac toxicities. Previous reports have focused on advanced cancer; cardiotoxicity data are therefore limited in the curative setting. We evaluated ICI cardiotoxicity in the non-metastatic setting, where long-term cardiac safety is a growing public health concern.

Methods: ICIs approved in the adjuvant setting were pooled and trials with combination chemotherapy were excluded. Cardiac adverse events (AEs) and emerging cardio-metabolic risks (hyperglycemia, weight gain, hypothyroidism) were assessed. The relative risk (RR) of cardiotoxicity was assessed.

Results: Ten randomized controlled trials of atezolizumab, ipilimumab, nivolumab, and pembrolizumab in multiple solid tumors were evaluated; among 9244 patients, 5338 received ICIs. No trial performed routine cardiac monitoring. Six percent of ICI patients vs. 4.6% in placebo (RR 1.24, 95% CI 1.04, 1.49) had a cardiac AE and 13 (0.2%) of ICI patients experienced a fatal cardiac AE (RR 4.76, 95% CI 1.07, 21.06). Older age and male sex were associated with a higher risk for cardiac fatality. Arrhythmia was the most common cardiac AE; hypothyroidism was more frequent (14% vs. 2.5%) among ICI-treated patients.

Conclusion: This is the largest pooled analysis of cardiac AEs associated with ICIs in the adjuvant setting. Despite no formalized testing for subclinical cardiotoxicity, ICI treatment increased cardiac AEs. These findings are relevant for long-term cancer survivors, clinicians, and particularly in new drug development, where cardiotoxicity may be substantially underestimated.

Keywords: adjuvant; cancer; cardio oncology; cardiotoxicity; immune checkpoint inhibitors; immunotherapy.

FIGURE 1

Fatal cardiac adverse events in patients receiving ICIs. Thirteen patients in the FDA pooled analysis receiving ICIs (0.2%) experienced Grade 5 (fatal) cardiac AEs compared to 2 patients in the comparator arm (not pictured). Of these, n = 3 experienced cardiac arrest, n = 4 experienced an MI (myocardial infarction or myocardial ischemia), n = 3 myocarditis, n = 3 had heart failure (cardiac failure acute, cardiogenic shock, or cardiopulmonary failure), and 1 had a fatal arrhythmia.

FIGURE 2

Cardiac treatment emergent events. Using grouped terms, the % of all‐grade cardiac toxicities experienced by patients treated with ICIs vs. non‐ICI treatments in the adjuvant setting is shown. Six percent of patients (N = 304) treated with ICIs experienced cardiac TEAEs vs. 4.6% (N = 179) treated with non‐ICI therapies. Of these, the most common was arrhythmia. The terms arrhythmia, MI (including coronary artery disease), heart failure, myocarditis, pericardial effusion, and other cardiac disorders were GTs. Arrhythmia includes arrhythmia, tachycardia, bradycardia, extrasystoles, tachyarrhythmia. MI includes myocardial infarction, myocardial ischemia, silent MI, coronary artery stenosis, cardiac arrest, acute coronary syndrome, coronary artery disease: angina pectoris, arteriosclerosis coronary artery, coronary artery stenosis. Heart failure includes cardiac failure, cardiac failure congestive, cardiac failure chronic, cardiopulmonary failure, systolic dysfunction, left ventricular dysfunction, acute left ventricular failure. Myocarditis includes myocarditis, autoimmune pericarditis, immune‐mediated myocarditis, autoimmune myocarditis. Pericardial effusion includes pericardial effusion, cardiac tamponade. Other cardiac disorders included mitral valve incompetence, cardiac disorder, cardiovascular disorder, cardiovascular insufficiency, atrial enlargement, aortic valve incompetence, pericardial cyst, pleuro‐pericarditis, cardiogenic shock, cardiac septal hypertrophy, mitral valve prolapse, mitral valve incompetence, intracardiac thrombus, left ventricular enlargement.