Cancer Drug Combination Is Potent, in Response and Side Effects

Immune system-based treatments for melanoma worked better together than separately in a study by Bristol-Myers Squibb Co., showing patients may respond more to combinations of the drugs -- if they’re willing to deal with the increased side effects.

The 945-patient study tested a combination of two Bristol-Myers drugs, Yervoy and Opdivo, in patients with advanced melanoma who hadn’t previously been treated. The trial found that 58 percent of those who received both drugs had significant tumor shrinkage, compared with 44 percent in the group that took Opdivo alone and 19 percent for just Yervoy. Combination patients also went months longer without their cancer progressing.

Yet patients in the combination group had a far higher rate of toxic side effects including diarrhea and elevated liver enzymes. There was a 36 percent dropout rate due to side effects in patients who got the combination, compared with 7.7 percent for Opdivo alone and 15 percent for Yervoy. The study was funded by Bristol-Myers and presented at the American Society of Clinical Oncology’s annual meeting in Chicago.

The response rate for the combination was spectacular, said Antoni Ribas, a melanoma specialist at the University of California, Los Angeles. Combining immune-therapy drugs “gives a very realistic chance of getting rid of metastatic melanoma in a substantial number of patients.” he said in an e-mail.

Concerning Toxicity

But the high rate of side effects may prevent the combination from becoming a standard treatment for everyone with advanced melanoma, said Ribas, who has studied immunotherapy drugs from companies competing with Bristol-Myers. In the trial, more than half the patients getting the combination experienced significant side effects.

“At this point, I don’t think it is practice-changing,” said Lynn Schuchter, an ASCO spokeswoman and chief of hematology/oncology at the University of Pennsylvania’s Abramson Cancer Center. “The toxicity is concerning.”

Another worry is the price of the drugs, which are called immune therapies because they harness the body’s immune system to attack cancer. Opdivo costs about $150,000 a year, and Yervoy costs about $130,000 for a four-dose-regimen, making the annual cost of the combination more than $250,000, at current prices.

Nonetheless, “the combination takes the progression-free survival of patients to a completely new high,” Fouad Namouni, Bristol-Myers’ global development leader for Opdivo and Yervoy, said in a telephone interview.

Hot Competition

Bristol-Myers is in a race with AstraZeneca Plc, Roche Holding AG and Merck & Co. to produce therapies and combinations of immune-boosting oncology drugs with the potential for use in multiple forms of cancer.

The drugs have fueled optimism among investors, who have also been quick to punish companies when drug trial results disappoint. Bristol-Myers shares fell the most in almost three years on Friday after the company reported results from a separate study of Opdivo in lung cancer that fell short of investors’ expectations.

One strategy companies are using to distinguish themselves is by testing combinations of the drugs, in hopes of improving upon the efficacy of single drugs. The new Bristol-Myers study is one of the biggest tests yet of such an approach.

Experts said there were encouraging signs in the data despite the high dropout rate.

“You can treat people until they get to this ‘super-immune’ response,” said Michael Atkins, deputy director of Georgetown University’s Lombardi Comprehensive Cancer Center. “Discontinuing is not necessarily a bad thing; ultimately people do want to get off their therapy.”

The study hasn’t yet produced overall survival data.

Moderate Treatment?

Atkins, who has served on the advisory board for Bristol-Myers, said there could be a way to moderate the treatment to reduce its toxicity, or that doctors could offer therapies to counteract the side effects once they start mounting.

“The key in oncology is to have something that looks like it works, then it becomes the job of academic medicine to come up with ways to use it better,” he said. “This is leading the way.”

Patients who dropped out of the trial due to the side effects still continued to see benefits from the therapies -- a sign their immune systems had already been revved up by the drugs.

“Almost all of them continued to respond, which tells you something about soliciting the memory of the immune system,” Namouni said.

Individual Decision

Ultimately, “it is going to be an individual decision” as to whether to use the combination or not, said Jedd Wolchok, a melanoma expert at Memorial Sloan Kettering Cancer Center who led the trial. “There isn’t one message for every patient.”

Patients given the combination of drugs went a median of 11.5 months until their disease progressed, compared with 6.9 months for the patients who took Opdivo and 2.9 months for Yervoy.

Opdivo blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking cancer cells. Yervoy works by a hitting a different molecular target to activate the immune system against cancer.

For more, read this QuickTake: Cancer Coup

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