Hot immuno-oncology combos can trigger rare but fatal heart damage: NEJM

Manipulating the immune system to fight cancer does come with risks, scientists say.

Two prominent doctors have flagged a serious and unexpected side effect linked to the immuno-oncology drugs taking cancer treatment by storm: heart damage that can be fatal.

In a New England Journal of Medicine article, authors highlight two melanoma patients who died of myocarditis two weeks after beginning treatment with Bristol-Myers Squibb’s Opdivo and Yervoy. Right now, patients aren’t routinely monitored for such heart problems, because the risk wasn’t known, the scientists said.

That combination of drugs is one of many in testing that marry checkpoint inhibitors with one another, and with other powerful treatments. And it’s likely that other regimens come with the same risk. “My sense is that this is a class effect, not limited to one drug,” Dr. Javid Moslehi, a specialist in heart risks from cancer therapies, told the Associated Press.

Opdivo is a PD-1 checkpoint inhibitor, while Yervoy works against a different checkpoint, CTLA-4. They’re far from the only drugs of this type in the burgeoning immuno-oncology field. Merck & Co.’s Keytruda and Roche’s recently approved Tecentriq also work in the PD-1/PD-L1 pathway, and a variety of other drugmakers are testing CTLA-4s. The idea behind all these drugs is to enlist the body’s own immune system to help attack cancer.

Moslehi, who also served as lead author of the NEJM article, said the new red flag is not a reason to shy away from the new generation of treatments, which have been dramatically effective in some groups of patients, and deliver solid results more broadly. The meds have transformed cancer treatment and for some offer the “potential for cure,” Moslehi told the New York Times.

It’s a reason to monitor patients--and to look for ways to circumvent heart-related side effects.

“This is a new complication of potentially lifesaving drugs,” Moslehi told the newspaper. “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?’”

Because the risks appear to be greater for those taking more than one checkpoint inhibitor--as with the Opdivo-Yervoy combo--some hospitals have already added heart-related tests for those patients, the NYT says.

The potent one-two punch of these combos may be enough to outweigh the risks when doctors are deciding how to treat their patients. Indeed, that’s the operating theory behind a slew of clinical trials now combining Opdivo, Keytruda, Tecentriq and Yervoy with other meds, including existing drugs and experimental, next-gen therapies, such as the CTLA-4 drugs working their way toward the market.

And as scientists and oncologists well know, every drug comes with potential side effects. More drugs equal more side effects, plus the risk of interactions that could be even more risky. In this case, with checkpoint inhibitors designed to throw off the immune system’s self-imposed limits, the risk is that the mechanisms that usually target disease will begin to attack the body itself.

The NEJM article highlights those risks in a very specific way--attacks on the heart and other muscles--and shows that the road to developing and marketing these latest cancer cocktails will have many unexpected bumps.

Many drugmakers are relying on their new immuno-oncology meds to augment their portfolios--and sales--as they lose exclusivity on older products. Roche, for instance, faces biosimilar competition for its biggest sellers in the coming years, including Rituxan, Herceptin and Avastin. It’s looking to Tecentriq, as well as some other new meds, to help fill those gaps.

Meanwhile, Merck is already giving up sales to biosimilar Remicade in Europe, and its cholesterol remedy Zetia loses patent protection next year. Cubicin, the high-powered antibiotic Merck acquired with Cubist last year, will also face earlier-than-expected competition from generics, thanks to patent disputes that went against Merck.

The risk of this type of myocarditis--where the immune system attacks the heart itself--is small, the NEJM article notes. Among 20,594 patients receiving either Opdivo, Yervoy or both, 18 cases of serious heart inflammation cropped up, the researchers found, based on data as of April of this year. That’s a rate of less than one-tenth of 1%. Among patients on both drugs, the risk was a little more than one-quarter of 1%, or about 1 in 400 patients.

As the AP notes, after the heart-related deaths surfaced, the study authors asked BMS to check patient safety records, so BMS scientists contributed to the study.