March 12, 2018

Cancer immunotherapy drugs linked with more serious heart effects

Vanderbilt University Medical Center investigators have identified a growing number of serious and sometimes fatal cases of heart problems among cancer patients treated with some forms of immunotherapy.

Douglas Johnson, MD, MSCI, left, Joe-Elie Salem, MD, PhD, Javid Moslehi, MD, and colleagues are studying the heart risks associated with some forms of immunotherapy. (photo by Anne Rayner)

Vanderbilt University Medical Center investigators have identified a growing number of serious and sometimes fatal cases of heart problems among cancer patients treated with some forms of immunotherapy.

The new study led by first author Javid Moslehi, MD, assistant professor of Medicine and director of the VUMC Cardio-Oncology Program, was published in Lancet. Douglas Johnson, MD, MSCI, assistant professor of Medicine and director of the Melanoma Program at Vanderbilt-Ingram Cancer Center (VICC), is corresponding author for the study. Joe-Elie Salem, MD, PhD, cardio-oncology fellow at VUMC, is second author.

The investigators searched the World Health Organization’s database of individual safety case reports (VigiBase), and identified 101 reports of severe myocarditis following treatment with immune checkpoint inhibitor (ICI) drugs. Among these patients, 46 (46 percent) died following treatment with the ICIs.

Myocarditis is an inflammation of the heart muscle that also can affect regulation of the heart’s electrical system. This inflammation can reduce the heart’s ability to pump blood to other parts of the body and can disrupt the heart’s normal rhythm, leading to heart attacks.

“We have been tracking these cases of severe myocarditis and deaths for the past year to gain a better understanding of the frequency of these events and the speed of myocarditis onset following the initial exposure to immune checkpoint inhibitors,” Moslehi said.

“It was interesting to note that three-fourths of these patients were not receiving other cardiovascular or diabetes medications at the time of treatment, which suggests that these patients did not have an underlying diagnosed cardiac or diabetes-related condition.”

Immunotherapies that attack cancer cells by stimulating the immune system are gaining traction as an effective form of cancer treatment, and immune checkpoint drugs were among the first to be approved.

The immune checkpoint signaling pathway in cancer cells involves the programmed death 1 (PD-1) receptor and its ligands (PD-L1/2). Therapies that block the PD-1/PD-L1 pathway have proved effective in the treatment of several types of cancer, including melanoma, non-small cell lung cancer (NSCLC) and renal cancer.

Other immunotherapy agents that block the CTLA-4 antigen activate the immune system’s T cells and enables them to destroy tumor cells.

But it appears that in some patients this heightened immune response also targets heart muscle.

In the study, a majority of the cancer patients were treated with a single anti-PD-1 drug, while 27 percent of patients were treated with a combination anti-PD-1/PD-L1 plus an anti-CTLA-4 therapy.

“We have always been concerned about the potential for off-target immune responses to these new immunotherapies and this study is the first to track the growing number of reports of myocarditis and other serious events with the use of single agents or combination therapies,” Johnson said.

The precise timing of myocarditis development in relation to the initiation of ICI therapy was available in 33 patients in the VigiBase database. Of these, the median onset was 27 days with 76 percent of cases occurring in the first six weeks.

Heart issues weren’t the only serious side effects that these patients experienced. Other high-grade, immune-related adverse events occurred in 42 percent of patients; myositis or muscle inflammation (25 percent), and myasthenia gravis, a neuromuscular ailment (11 percent).

Among all cases, fatality rates were higher with combination anti-PD-1/PD-L1 plus anti-CTLA-4 therapies (67 percent) than with single agent anti-PD-1/PD-L1 therapy (36 percent). Deaths also occurred in three of five patients who developed myocarditis following treatment with an immunotherapy drug called ipilimumab.

The authors said it is too early to determine whether the incidence of severe myocarditis differs between anti-PD-1 and anti-PD-L1 agents.

“While these cases are infrequent, we must work to determine the causes and potential remedies for these serious events,” Johnson said.

Other investigators include Jeffrey Sosman, MD, Northwestern University and Robert H. Lurie Cancer Center, and Bénédicte Lebrun-Vignes, Sorbonne Universités, Paris, France.

Funding was provided by The Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN), “Plan Cancer 2014-2019” by the National Cancer Institute, a division of the National Institutes of Health (K23 CA204726; and the James C. Bradford Jr. Melanoma Fund.