Cardiac Issues Related to Checkpoint Inhibitors Still Largely Understudied

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IMMUNE CHECKPOINT inhibitors represent a giant step forward in the treatment of many cancers, and as these agents have “come of age” in the past few years, so has the collective understanding of their potential for causing adverse events. Although checkpoint inhibitors are known to be associated with a broad array of autoimmune side effects, cardiac issues related to checkpoint inhibitors are still not well understood, according to Michael S. Ewer, MD, JD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Serious cardiac events are said to occur in about 1% of patients on [checkpoint inhibitors]. But that figure may not represent the actual scope of the problem.”
— Michael S. Ewer, MD, JD, PhD

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Checkpoint inhibitors have the potential to induce long-term remission, or perhaps even cure in some patients, but research has still not unlocked the capability to identify those who will benefit from those who will experience life-threatening adverse events, including potentially fatal myocarditis. According to Dr. Ewer, the improved ability to identify these subgroups is essential.

“This is in some ways analogous to the introduction of many of the drugs we’ve used to treat cancer until now,” he said at the 2018 Multinational Association of Supportive Care in Cancer (MASCC)/ International Society of Oral Oncology (ISOO) Annual Meeting in Vienna.1 “At first, we really didn’t know what to expect.”

Moving Into First-Line Setting

CHECKPOINT INHIBITORS are used with varying success to treat an increasing number of cancers. Noncardiac side effects such as diarrhea, fatigue, nausea, pruritus, and rash are far more common than cardiac side effects, as serious cardiac events are said to occur in about 1% of patients on these agents. But, according to Dr. Ewer, that figure may not represent the actual scope of the problem.

Although the necessary algorithms and risk-factor guidance to predict who may be at increased risk for cardiotoxicity with checkpoint inhibitor therapy are not yet available, these agents are increasingly being approved by the U.S. Food and Drug Administration as first-line treatments, underscoring the need for vigilant patient surveillance.

Broad Spectrum of Side Effects

CARDIAC ADVERSE events exist in the form of myocardial inflammation, contractile dysfunction, and dysrhythmia. In rare instances, these events may be severe or fatal, and conversely, the possibility exists that less severe cases may be overlooked. For example, changes in an electrocardiogram (ECG) in an asymptomatic patient could be mistaken for something like stress-induced ischemia or cardiomyopathy, when it actually may be correlated with checkpoint inhibitor–related myocarditis. Dr. Ewer asserted that it is reasonable to obtain a baseline ECG reading in patients and to repeat ECG if any cardiac signs or symptoms (ie, change in activity, palpitations, chest pain) are observed.

Although there are no broadly accepted guidelines for the management of cardiac events, current treatment strategies include high-dose corticosteroids, with or without mycophenolate, infliximab (Remicade), or antithymocyte globulin.

As with other treatment-induced toxicities, the observed cardiac involvement in these patients may constitute a spectrum that varies from mild to severe, underlining the importance of further research in this area, he noted.

Financial Toxicity of Immune Checkpoint Inhibitors

BEYOND RESEARCH on the efficacy and safety of these agents, Dr. Ewer argued that future cost-effective analyses should provide estimates of cost for a quality life-year per patient. This comment is due to the fact that checkpoint inhibitors are expensive, with many priced at more than $100,000 for a course of treatment. Presently, the cost of these agents is prohibitive for most patients, thereby inhibiting clinical observation of their effects on a broad scale. “The drug costs are problematic for society and are a matter for serious public health debate regarding utilization in the absence of strong evidence for broader benefit among those undergoing treatment,” he said. ■

DISCLOSURE: Dr. Ewer has served as a consultant for AstraZeneca, Bayer, and Boehringer-Ingelheim.


1. Ewer MS: Cardiac issues related to checkpoint inhibitors. 2018 MASCC/ISOO International Symposium on Supportive Care in Cancer. Invited Lecture. Presented June 29, 2018.

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