Report: Opdivo/Yervoy Combo May Threaten the Heart

Data link lifesaving drugs to myocarditis in small number of patients

Checkpoint inhibitors are popular treatments for cancers, but a new article in the New England Journal of Medicine warns that combining the checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy)––both marketed by Bristol-Myers Squibb––could lead to death in a small number of patients. According to the article, two melanoma patients receiving combination treatment with nivolumab and ipilimumab died from fulminant myocarditis. Autopsies showed that the immune systems of both patients had attacked their hearts.

According to the article, myocarditis has occurred in 0.27% of patients treated with nivolumab and ipilimumab in pharmacovigilance studies, suggesting that the patients in the new report had experienced a rare, potentially fatal, T-cell–driven drug reaction.

Those aren’t the only patients who have developed myocarditis after receiving a nivolumab/ipilimumab combination. According to The New York Times, doctors have reported 18 cases out of 20,594 patients who were treated with the checkpoint inhibitors. Of those 18 patients, six have died, with five of them having received a combination of the two drugs, the Times said.

“This is a new complication of potentially lifesaving drugs,” senior author Dr. Javid J. Moslehi told the Times. “We’re working to develop treatments for it. Our job is not to say the drugs are bad, but to say, ‘How can we deal with it?’”

In addition to nivolumab and ipilimumab, two other checkpoint inhibitors are on the market: pembrolizumab (Keytruda, Merck) and atezolizumab (Tecentriq, Genentech).

The potential for adverse effects on the heart with checkpoint inhibitors has prompted some hospitals to add extra cardiac testing for patients taking more than one checkpoint drug, with the aim of catching problems early enough to prevent permanent damage. If the tests find signs of trouble, steroids and other drugs may stop the immune system’s assault.

In December 2014, nivolumab was approved by the FDA for patients with advanced melanoma who are nonresponsive to other drugs or cannot be treated with surgery. The drug is also indicated for patients with metastatic squamous non–small-cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Nivolumab works by inhibiting the programmed death-1 (PD-1) cellular pathway, which blocks the body’s immune system from attacking cancerous cells. Nivolumab was the first PD-1 inhibitor to receive regulatory approval.

Ipilimumab is a monoclonal antibody that blocks the CTLA-4 molecule. It was approved in 2011 for use in patients with late-stage melanoma that cannot be removed by surgery. In 2015, the FDA expanded the approved use of ipilimumab to include patients with stage III melanoma, to lower the risk that the melanoma will return after surgery.

Sources: BioSpace; November 3, 2016; NEJM; November 3, 2016; and New York Times; November 2, 2016.