The U.S. Food and Drug Administration (FDA) approved a combination of Bristol-Myers Squibb‘s immune checkpoint inhibitors Opdivo (nivolumab) and Yervoy (ipilimumab) for the treatment of hepatocellular carcinoma (HCC) patients who received prior treatment with Nexavar (sorafenib), the company said.
The FDA’s accelerated approval followed the agency’s granting of breakthrough therapy designation and priority review status for the same indication, and was based on promising response rates and duration of responses seen in patients receiving the combination in the CheckMate-040 Phase 1/2 clinical trial (NCT01658878).
Accelerated approval is a form of conditional approval given to a medication that addresses an unmet need in a serious medical condition, providing it has shown benefits on surrogate or interim measures in a clinical trial. The continued use, and full approval, of the Opdivo-Yervoy combo will require further verification and description of clinical benefit in a confirmatory study.
“The incidence of liver cancer is rising in the United States, and HCC is the most common and aggressive form of the disease,” Andrea Wilson, president and founder of Blue Faery: The Adrienne Wilson Liver Cancer Association, said in a press release.
Opdivo and Yervoy are two immunotherapies falling under the umbrella of immune checkpoint inhibitors. Both are antibodies, but they target different proteins involved in the processes used by cancer cells to escape the immune system. Opdivo targets the PD-L1 protein on cancer cells, and Yervoy targets the CTLA-4 protein on T-cells — immune cells with the ability to fight tumors.
The two medications work in a complementary way, and their combined use has been approved for cancers of the kidney and colon, as well as melanoma.
“We recognize there is a critical need to provide patients with aggressive forms of cancer, like HCC, new treatment options that may offer clinically meaningful and ultimately durable responses,” said Adam Lenkowsky, general manager at Bristol Myers Squibb.
CheckMate-040 was an open-label study designed to assess the safety and efficacy of Opdivo combinations in patients with advanced HCC — the most common type of liver cancer — who did not respond to or were intolerant of standard treatment with Nexavar.
The accelerated approval was based on a part of the trial that tested a combination of Opdivo and Yervoy in 49 patients. They received Opdivo at a dose of 1 mg/kg, and Yervoy at 3 mg/kg, both delivered into the vein every three weeks for four doses, and 240 mg Opdivo every two weeks thereafter until signs of disease progression or toxicity.
After a minimum follow-up of 28 months, 33% of patients had responded to the combination, including 8% who showed no signs of cancer (complete response). Responses lasted from 4.6 months to more than 30.5 months, with 88% of them lasting at least six months. About a third of those (31%) responded to the combination for over two years.
Response rates were similar when the analysis was conducted by a blinded review committee: 35% of patients had a significant reduction in tumor burden, and 12% had complete responses.
Serious adverse reactions to the combo treatment were recorded in 59% of patients, and 29% discontinued treatment because of them. An additional 65% had to delay treatment due to adverse events.
The most common adverse reactions were fever, diarrhea, anemia, signs of liver damage, poorly functional adrenal glands, fluid build up in the abdomen, bleeding in the esophagus, low sodium levels, and lung inflammation.
“The overall response rate observed in the Opdivo plus Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option for patients,” said Anthony B. El-Khoueiry, MD, lead investigator and associate professor of clinical medicine and phase I program director at the Keck School of Medicine, University of Southern California (USC) and the USC Norris Comprehensive Cancer Center.
The accelerated approval “provides a new option for patients with HCC previously treated with sorafenib, giving the community more hope,” Wilson said.
However, the continued approval of the Opdivo-Yervoy combo treatment for HCC relies on the confirmation of clinical benefits in Phase 3 clinical trials. One such study is the CheckMate 9DW trial (NCT04039607), currently recruiting participants worldwide.
