Federal advisers this week supported the efforts of pharmaceutical companies in 4 of 6 cases in which these firms are fighting to maintain cancer indications for approved drugs. They voted against them in two cases.
The staff of the US Food and Drug Administration (FDA) will now consider these votes as they decide what to do regarding the six cases of what they have termed “dangling” accelerated approvals.
“One of the reasons I think we’re convening today is to prevent these accelerated approvals from dangling ad infinitum,” commented one of the members of the advisory panel.
In these cases, companies have been unable to prove the expected benefits that led the FDA to grant accelerated approvals for these indications.
These accelerated approvals, which are often based on surrogate endpoints, such as overall response rates, are granted on the condition that further findings show a clinical benefit ― such as in progression-free survival or overall survival ― in larger trials.
The FDA tasked its Oncologic Drugs Advisory Committee (ODAC) with conducting the review of the six accelerated approvals for cancer indications at a 3-day meeting (April 27–29).
These reviews were only for specific cancer indications and will not lead to the removal of drugs from the market. These drugs have already been approved for several cancer indications. For example, one of the drugs that was reviewed, pembrolizumab (Keytruda), is approved in the United States for 28 indications.
The FDA is facing growing pains in its efforts to manage the rapidly changing landscape for these immunotherapy checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials, owing in part to the agency’s willingness to accept surrogate markers for accelerated approvals. Although some companies have struggled with these, others have built strong cases for the use of their checkpoint inhibitors for these indications.
ODAC panelists, for example, noted the emergence of nivolumab (Opdivo) as an option for patients with gastric cancer as a reason for seeking to withdraw an indication for pembrolizumab (Keytruda) for this disease.
Just weeks before the meeting, on April 16, the FDA approved nivolumab plus chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This was a full approval based on data showing an overall survival benefit from a phase 3 trial.
On April 29, the last day of the meeting, the ODAC panel voted 6-2 against maintaining pembrolizumab’s indication for the use as monotherapy for an advanced form of gastric cancer. This was an accelerated approval (granted in 2017) that was based on overall response rates from an open-label trial.
That last day of the meeting also saw another negative vote. On April 29, the ODAC panel voted 5-4 against maintaining an indication for nivolumab for hepatocellular carcinoma (HCC) for patients previously treated with sorafenib (Nexavar). This was an accelerated approval that was granted in 2017. The FDA said that it had requested ODAC’s feedback on this indication because of the recent full approval, which was based on an overall survival benefit (in May 2020) of another checkpoint inhibitor for HCC, atezolizumab (Tecentriq), in combination with bevacizumab (Avastin) for patients with unresectable or metastatic diseases who have not received prior systemic therapy.
There was one last vote on that third day of the meeting, and it was postive. The ODAC panel voted 8-0 in favor of maintaining the indication for the use as monotherapy of pembrolizumab for patients with HCC who have previously been treated with sorafenib.
The FDA altered the composition of the ODAC panel during the week, adding members in some cases who had expertise in particular cancers. That led to different totals for the week’s ODAC votes, as shown in the tallies summarized below.
On the first day of the meeting (April 27), the ODAC panel voted 7-2 in favor of maintaining a breast cancer indication for atezolizumab (Tecentriq). This covered the use of the immunotherapy in combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.
The second day of the meeting (April 28) also saw two positive votes. The ODAC panel voted 10-1 for maintaining the indication for atezolizumab for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial. The panel also voted 5-3 for maintaining the indication for pembrolizumab for locally advanced or metastatic urothelial carcinoma for patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1.
The FDA is not bound to follow the voting and recommendations of its advisory panels, but it usually does so.
Managing Shifts in Treatment
In both of the cases in which ODAC voted against maintaining indications, Richard Pazdur, MD, the FDA’s top regulator for cancer medicines, jumped into the debate. Pazdur countered arguments put forward by representatives of the manufacturers as they sought to maintain indications for their drugs.
Merck officials and representatives argued for pembrolizumab, saying that maintaining the gastric cancer indication might help patients whose disease has progressed despite earlier treatment. Pazdur emphasized that the agency would help Merck and physicians to have access to pembrolizumab for these patients even if this one indication were to be withdrawn. But Pazdur and ODAC members also noted the recent shift in the landscape for gastric cancer, with the recent approval of a new indication for nivolumab.
“I want to emphasize to the patient community out there. We firmly believe in the role of checkpoint inhibitors in this disease,” the FDA’s Pazdur said during the discussion of the indication for pembrolizumab for gastric cancer. “We have to be cognizant of what is the appropriate setting for that, and it currently is in the first line.”
Pazdur noted that two studies had failed to confirm the expected benefit from pembrolizumab for patients with more advanced disease. Still, if “small numbers” of patients with advanced disease wanted access to Merck’s drug, the FDA and the company could accommodate them. The FDA could delay the removal of the gastric indication to allow patients to continue receiving it. The FDA also could work with physicians on other routes to provide the medicine, such as through single-patient investigational new drug applications or an expanded access program.
“Or Merck can alternatively give the drug gratis to patients,” Pazdur said.
#ProjectFacilitate for Expanded Access
One of Merck’s speakers at the ODAC meeting, Peter Enzinger, MD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, objected to Pazdur’s plan.
A loss of the gastric indication for pembrolizumab would result in patients with advanced cancer missing out on a chance to try this therapy. Some patients will not have had a chance to try a checkpoint inhibitor earlier in their treatment, and a loss of the indication would cost them that opportunity, he said.
“An expanded access program sounds very nice, but the reality is that our patients are incredibly sick and that weeks matter,” Enzinger said, citing administrative hurdles as a barrier to treatment.
“Our patients just don’t have the time for that, and therefore I don’t think an expanded access program is the way to go,” Enzinger said.
Pazdur responded to these objections by highlighting an initiative called Project Facilitate at the FDA’s Oncology Center for Excellence. During the meeting, Pazdur’s division used its @FDAOncology Twitter handle to draw attention to this project.
OCE's #ProjectFacilitate is available M-F 8 am to 4:30 pm Eastern to help oncology providers make Expanded Access requests for investigational drug products for patients with cancer who have exhausted available therapies. Learn more: https://t.co/gOnfsuhaTz#ExpandedAccess pic.twitter.com/sDU5JTf3jj
— FDA Oncology (@FDAOncology) April 29, 2021
ODAC panelist Diane Reidy-Lagunes, MD, of Memorial Sloan Kettering Cancer Center, New York City, said she had struggled with this vote. She was one of the two panelists to vote in favor of keeping the indication.
“This is also incredibly hard for me, I actually changed it at the last minute,” she said of her vote.
But Reidy-Lagunes said she was concerned that some patients with advanced disease might not be able to get a checkpoint inhibitor.
“With disparities in healthcare and differences in the way that patients are treated throughout our country, I was nervous that they may not be able to get treated,” she said. She noted that she shared her fellow panelists’ doubts about use of pembrolizumab as third-line treatment, owing to negative results in trials.
ODAC member David Mitchell, who served as a consumer representative, also said he found the vote on the gastric indication for pembrolizumab to be a difficult decision.
“As a patient with incurable cancer who’s now being given all three major classes of drugs to treat my disease in combination, these issues really cut close to home,” Mitchell said.
He said the expectation that the FDA’s expanded access program could help patients with advanced disease try pembrolizumab helped him decide to vote with the 6-2 majority against maintaining this gastric cancer approval.
His vote was based on “the changing treatment landscape.” There is general agreement that the patients in question should receive checkpoint inhibitors as first-line treatment, not third-line treatment, Mitchell said. The FDA should delay a withdrawal of the approval for pembrolizumab in this case and should allow a transition for those who missed out on treatment with a checkpoint inhibitor earlier in the disease course, he suggested.
“To protect the safety and well-being of patients, we have to base decisions on data,” Mitchell said. “The data don’t support maintaining the indication” for pembrolizumab.
Close Split on Nivolumab
In contrast to the 6-2 vote against maintaining the pembrolizumab indication, the ODAC panel split more closely, 5-4, on the question of maintaining an indication for the use as monotherapy of nivolumab in HCC.
ODAC panelist Philip C. Hoffman, MD, of the University of Chicago, was among those who supported keeping the indication.
“There’s still an unmet need for second-line immunotherapy because there will always be some patients who are poor candidates for bevacizumab or who are not tolerating or responding to sorafenib,” he said.
ODAC panelist Mark A. Lewis, MD, of Intermountain Healthcare, Salt Lake City, Utah, said he voted “no” in part because he doubted that Bristol-Myers Squibb would be able to soon produce data for nivolumab that was needed to support this indication.
Kerry Dooley Young is a freelance journalist based in Washington, D.C. She earlier covered health policy and the federal budget for Congressional Quarterly/CQ Roll Call and the pharmaceutical industry and the Food and Drug Administration for Bloomberg. Follow her on Twitter at @kdooleyyoung.