- Bristol Myers Squibb has withdrawn its immunotherapy Opdivo in liver cancer roughly three months after a Food and Drug Administration advisory panel recommended not to uphold the drug's 2017 approval in that indication.
- The FDA granted Opdivo monotherapy an accelerated clearance in second-line liver cancer based on a Phase 2 study showing a minority of patients responded to treatment. But Bristol Myers wasn't able to confirm, in further testing, that Opdivo helped patients live longer, and other immunotherapies have since proven effective against the disease, leading panelists to vote in April against the drug's continued use.
- The withdrawal doesn't impact use of Opdivo in combination with Bristol's other immunotherapy, Yervoy, in the same setting in liver cancer, or as a monotherapy in any other indication. But it is the latest result from an ongoing push by U.S. regulators to pull accelerated cancer drug approvals that lack confirmatory data.
Opdivo's 2017 clearance in liver cancer was a milestone, representing the first time an immunotherapy had become available to treat the disease.
But that approval was also one of several given to immunotherapies based on improvements in surrogate markers — like tumor shrinkage — likely, yet not guaranteed, to predict a clinical benefit. As of late April, 85% of the accelerated approvals issued over the past 10 years were for cancer drugs, and 35 of them went to immunotherapies for different indications, two of the FDA's top oncology reviewers wrote in a piece published in the New England Journal of Medicine.
By that time, however, many of those approvals faced increased scrutiny because they'd failed confirmatory trials but were still on the market. The FDA began an industry-wide review of those clearances, leading immunotherapy developers Merck & Co., Bristol Myers, Roche and AstraZeneca to voluntarily pull their drugs in certain lung and bladder cancers. That evaluation intensified when the agency scheduled a three-day hearing to review the merits of six such approvals, among them Opdivo's in liver cancer.
FDA advisers voted to uphold four of the six approvals reviewed at the hearing, fueling further criticism that the agency isn't keeping drugmakers to the terms of the accelerated approval pathway. Still, the two negative votes have had an impact. Merck pulled Keytruda's gastric cancer indication on July 7, and Bristol has now followed suit with Opdivo in liver cancer.
In a statement, Bristol senior vice president and head of oncology development Jonathan Cheng said the company was "disappointed" by the position taken by the FDA and its advisers, noting that Opdivo "helped usher in an entirely new way" to treat the disease and is the most commonly used drug in second-line liver cancer. But Cheng expressed support for the accelerated approval pathway nonetheless, calling it "integral to enabling people with difficult to treat cancers to gain access to certain safe and effective therapies sooner."
The actual business impact of the withdrawals of Keytruda and Opdivo in stomach and liver cancers is likely to be inconsequential to their developers, some analysts have said. But the decisions could nonetheless send a message. Following the FDA meeting, SVB Leerink analyst Daina Graybosch noted that those two approvals had the weakest evidence, each based on response rates of less than 15%, and "poor proposals to confirm their benefit."
Merck has said Keytruda is expected to be withdrawn in six months. Bristol didn't specify when it will take action.