Cardiovascular Toxicities Associated With Immune Checkpoint Inhibitor Treatment
In a pharmacovigilance study reported in The Lancet Oncology, Salem et al found that immune checkpoint inhibitors can cause “severe and disabling inflammatory cardiovascular immune-related adverse events” that need to be considered in patient care and clinical trial design.
Study Details
The study used VigiBase, the World Health Organization global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received immune checkpoint inhibitors with cardiovascular adverse event reporting in the full database from November 1967 through January 2018. Statistical analysis of the association between immune checkpoint inhibitors and cardiovascular adverse events was performed using reporting odds ratio (ROR) and information component (IC) methods; IC025 is the lower end of the IC 95% credibility interval and an IC025 value > 0 is considered significant.
Risk and Severity of Cardiovascular Adverse Events
A total of 31,321 adverse events were reported in patients who received immune checkpoint inhibitors and 16,343,451 adverse events were reported in patients treated with any drugs in the full database. Compared with the full database, immune checkpoint inhibitor treatment was associated with higher reporting of myocarditis (5,515 reports in full database vs 122 for immune checkpoint inhibitors, ROR = 11.21, 95% confidence interval [CI] = 9.36–13.43; IC025 = 3.20), pericardial disease (12,800 vs 95, ROR = 3.80, 95% CI = 3.08–4.62; IC025 = 1.63), and vasculitis (33,289 vs 82, ROR = 1.56, 95% CI = 1.25–1.94; IC025 = 0.03), including temporal arteritis (696 vs 18, ROR = 12.99, 95% CI = 8.12–20.77; IC025 = 2.59) and polymyalgia rheumatica (1,709 vs 16, ROR = 5.13, 95% CI = 3.13–8.40; IC025 = 1.33).
Patients with lung cancer accounted for 56% of cases of pericardial disease, and patients with melanoma accounted for 41% of myocarditis cases and 60% of vasculitis cases. Impaired vision was reported in 5 (28%) of 18 patients with temporal arteritis. The immune-related adverse events were severe in the majority of cases, including 47 (62%) of 76 vasculitis cases, 102 (84%) of 122 myocarditis cases, and 77 (81%) of 95 pericardial disease cases. Death occurred in 50% of myocarditis cases, 21% of pericardial disease cases, and 6% of vasculitis cases.
The investigators concluded, “Treatment with [immune checkpoint inhibitors] can lead to severe and disabling inflammatory cardiovascular [immune-related adverse events] soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy).”
The study was funded by The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014–2019, US National Cancer Institute and National Institutes of Health, James C. Bradford Jr. Melanoma Fund, and Melanoma Research Foundation.
Javid J. Moslehi, MD, of the Cardio-Oncology Program, Department of Medicine, Vanderbilt University Medical Center, is the corresponding author for The Lancet Oncology article.
Disclosure: See study authors’ full disclosures at thelancet.com.
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