A group of advisers to the Food and Drug Administration this week recommended the agency maintain four of six recent cancer immunotherapy approvals despite a lack of evidence the medicines help patients live longer.
The positive votes, which took place over an unusual three-day meeting, could push the FDA to keep drugs from Roche, Bristol Myers Squibb and Merck & Co. on the market while the companies complete additional studies to confirm their benefit. The FDA typically, though not always, follows the advice of its advisory committees.
If the FDA does adhere to the panel votes, regulators could fuel further criticism that the agency isn't holding drugmakers to the terms of the accelerated approval pathway it's used to make new cancer drugs available quickly.
"This meeting seemed like a justification to continue approvals, rather than to take action," said Bishal Gyawali, an oncologist and scientist at the Queen's University Cancer Research Institute in Ontario, Canada.
The meeting showcased the tradeoffs of clearing a drug before it's fully proven, as well as the scrutiny regulators face when those decisions appear to backfire. The advisory committee, made up of oncologists and patient representatives, struggled at times with their votes, wary of taking treatment options away from cancer patients who don't have many — even though the available data don't definitively support their benefit.
"The fundamental difficulty is we're sitting here, as practicing physicians, watching all of these new drugs pour onto the market, and we're left trying to determine what their real value is," said Andrew Hertler, an oncologist and the chief medical officer of New Century Health.
Each of the six approvals debated at the meeting were cleared under an accelerated approval program that was enacted in 1992 to get drugs for diseases with few, if any, treatment options onto market faster. The approvals are made based on surrogate markers that are likely, but not guaranteed, to predict a benefit.
In cancer, for instance, the surrogate marker is often measuring how much a tumor shrinks following treatment. Drugmakers are required to confirm surrogate data with additional testing evaluating a more stringent clinical measure, such as how long a cancer patient survives. If a drug fails to do so, the FDA can withdraw its conditional OK.
Yet that rarely happens. In the roughly 30-year history of the program, just 6% of accelerated cancer drug approvals have been withdrawn. That's despite the fact many post-marketing trials either take years to begin or aren't finished. Some immunotherapy approvals, for example, stood for multiple years even though confirmatory studies failed, spurring criticism of the agency.
Since late last year, the FDA has appeared to signal a stricter approach. The agency began an industry-wide review, reevaluating some of the torrent of speedy oncology approvals it granted over the past decade. Some 85% of the accelerated approvals issued during that period were for cancer drugs, wrote Richard Pazdur, head of the FDA's Oncology Center of Excellence, and Julia Beaver, the center's chief of medical oncology, in a piece recently published in The New England Journal of Medicine.
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 name||Indication discussed||Committee 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.
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.