The surge was the result of rapid clinical progress from a type of cancer immunotherapy known as a checkpoint inhibitor, which, when it works, can be very effective. Seven such drugs have now been approved across more than 75 oncology indications. Thirty-five of those indications were cleared on an accelerated basis because of data showing tumor shrinkage. Each cost more than $100,000 per patient per year.
Up until recently, ten of those approvals were "dangling," Pazdur and Beaver wrote, meaning they'd failed confirmatory trials but were still on the market. After the FDA started its review, drugmakers voluntarily withdrew use of their drugs in four of those indications. The agency then scheduled three days of public debate about the other six approvals, which were for the drugs Keytruda, Tecentriq and Opdivo in breast, bladder, stomach and liver cancer. "The FDA sees this as a necessary step," Pazdur and Beaver wrote.
Critics argue the meeting was at best long overdue and potentially even unnecessary. "There was no reason for the meeting," said Gyawali. "The FDA could have simply withdrawn the approvals."
Instead, the FDA now faces a tougher choice after panelists voted in favor of maintaining four of the six accelerated approvals despite negative findings in confirmatory trials.
Oncology Drugs Advisory Committee vote tallies, April 27-29
Drug nameIndication discussedCommittee vote on whether to maintain approval
Tecentriq Triple-negative breast cancer 7 Yes, 2 No
Keyturda First-line bladder cancer 5 Yes, 3 No
Tecentriq First-line bladder cancer 10 Yes, 1 No
Keytruda Third-line stomach cancer 2 Yes, 6 No
Keytruda Second-line liver cancer 8 Yes, 0 No
Opdivo Second-line liver cancer 4 Yes, 5 No
Across the meeting's three days, panelists repeatedly expressed reservations about withdrawing treatments for patients with few other options. Each of the immunotherapy indications up for debate covered use in treating tumors with poor prognoses. Gastric cancer, for which Keytruda became the first approved immunotherapy in 2017, has a five-year survival rate of 5%. Triple-negative breast cancer, an aggressive, tough-to-treat form of the disease, has mainly only been treated with chemotherapy.
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In triple-negative breast cancer, most panelists were willing to overlook the failure of Roche's Tecentriq in confirmatory testing, citing the promising data from the earlier trial that led to approval.
"There were multiple possible reasons other than lack of efficacy that might play into the failure of the confirmatory trial to show benefit," said Philip Hoffman, a professor of medicine at the University of Chicago and a panel member. "I don't feel there is enough evidence to say no to this and would agree that [the approval] should continue."
Similarly, in advanced bladder cancer, panel members were concerned that pulling the approval of Keytruda would be harmful to a particular group of patients who aren't eligible for chemotherapy.
"I think that there's a clear unmet need," said Christopher Lieu, a professor of medicine at the University of Colorado. These patients "have incredibly limited options."
The two times the committee members voted against maintaining an accelerated approval — for Keytruda in gastric cancer and for Opdivo in liver cancer — they appeared to be swayed in part by the knowledge that other immunotherapies had since been proven effective.
Pazdur, the FDA's top cancer drug evaluator, also stepped in to make a forceful case against the approvals.
"We are disappointed with today's outcome for patients, and we will work closely with the FDA as it completes its review," said Ian Waxman, Bristol Myers's development lead for gastrointestinal cancers, in a statement following the meeting.
The actual business impact of the FDA withdrawing Keytruda and Opdivo in stomach and liver cancers would be "inconsequential" to their developers, worte Daina Graybosch, an analyst at SVB Leerink, in an investor note. But the votes, and any FDA action that follows, could still send a message.
For one, the panel voted to withdraw the two approvals with the weakest evidence — each based on response rates of less than 15% — and "poor proposals" to confirm their benefit, Graybosch wrote. If drugmakers aim to narrow their approvals to subgroups with the highest need — as Bristol Myers did in liver cancer — they need specific evidence that their treatments work in those groups. Bristol Myers didn't have that type of data, while Merck, whose Keytruda approval in liver cancer was upheld, did. Panelists and the FDA were also very sensitive to any changes that could upend the standard of care.
Drugmakers appear able to use regimens combining chemotherapy and immunotherapy in earlier lines of metastatic disease to confirm what's seen in a monotherapy study in more advanced settings. But new combinations or confirmatory tests in early-stage cancer, like immediately after surgery, seem "more of a stretch for the FDA," Graybosch noted.
Even with positive votes, the four indications backed by the committee will likely remain controversial and, with them, the accelerated approval program.
"The process seems to have spun a little bit out of control," said Hertler, of New Century.
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