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.