Two Deaths Linked to Bristol-Myers Squibb's Yervoy-Opdivo Combo

November 3, 2016
By Alex Keown, BioSpace.com Breaking News Staff

NEW YORK – Checkpoint inhibitors have become popular treatments for cancers, but a new article in the New England Journal of Medicine (NEJM) may give physicians pause before prescribing them to patients. The article notes that some combination treatments could lead to death in a small number of patients.

According to the NEJM article, two patients taking a combination treatment of Bristol-Myers Squibb ’s Opdivo and Yervoy died from myocarditis. According to the study abstract, pharmacovigilance studies show that a minute percent of patients, 0.27% percent, who were treated with a combination of ipilimumab and nivolumab, were subject to “a rare, potentially fatal, T-cell–driven drug reaction.”

“In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates,” according to the article abstract.

The two patients in question both had advanced forms of melanoma, the New York Times said. Melanoma, the most aggressive type of skin cancer, is the leading cause of death from skin cancer. Both patients, a man and woman both in their sixties, developed heart problems and died a few weeks following a single intravenous combination treatment of Opdivo and Yervoy. Neither patient had a history of heart disease, the Times said. When both patients began having heart problems, including inflammation of the heart and abnormal rhythms, they were treated with high doses of steroids, but to no avail. Following autopsies of both patients, doctors found that the immune systems of both patients had attacked their hearts, “rejecting them as if they were transplants,” the Times reported.

Those two patients are not the only ones to have developed myocarditis as a result of the combination of Opdivo and Yervoy. The Times said doctors have reported 18 cases out of the 20,594 patients who took the Bristol-Myers checkpoint inhibitors. Out of those 18 patients, six have died, with five of them having taken a combination of the two drugs, the Times said.

Investors have not reacted in a negative way by dumping shares of BMS this morning, although the stock is slightly down from its opening price of $50.51. Still, the death of the two patients is not the news that BMS was wanting in relation to Opdivo, particularly after the drug failed to meet its endpoints in a Phase III trial as a monotherapy for a “broad patient population” in lung cancer.

In March 2015, Opdivo was approved for treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Opdivo is an immuno-therapy drug delivered via injection that harnesses the patient’s own immune system to fight cancerous cells. Opdivo works by inhibiting the cellular pathway known as PD-1 protein on cells that blocks the body’s immune system from attacking cancerous cells. In December 2014, Opdivo was approved by the U.S. Food and Drug Administration for patients with advanced melanoma who no longer respond to other drugs, or cannot be treated via surgery. In March 2015, it was approved for treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Opdivo was the first PD-1 inhibitor to receive regulatory approval.

Yervoy, a monoclonal antibody that blocks a molecule known as CTLA-4, was approved in 2011 for use in patients with late-stage melanoma that could not be removed by surgery. Last year, the FDA expanded the approved use of Yervoy to include patients with stage III melanoma, to lower the risk that the melanoma will return following surgery.

While the NEJM article specifically cited combinations of Yervoy and Opdivo, Merck and Genentech will certainly be paying close attention, since their drugs, Keytruda and Tecentriq are also approved checkpoint inhibitors.