This week, federal advisers supported the efforts of pharmaceutical companies in 4 of 6 cases in which those companies are struggling to maintain cancer indications for approved drugs. They voted against it in two cases.
U.S. Food and Drug Administration (FDA) staff will now consider these votes as they decide what to do about the six cases of what they have called “hanging” accelerated approvals.
“One of the reasons I think we are convening today is to prevent these accelerated approvals from hanging ad infinitum,” one member of the advisory group commented.
In these cases, companies have been unable to demonstrate the expected benefits that led the FDA to grant expedited approvals for these indications.
These accelerated approvals, which are often based on substitute substitution criteria, such as overall response rates, are granted provided that other findings show a clinical benefit, such as progression-free survival or overall survival, in larger trials. .
The FDA commissioned its oncology drug advisory committee (ODAC) to conduct the review of the six accelerated approvals for cancer indications at a 3-day meeting (April 27-29).
These reviews referred only to specific indications about cancer and will not lead to the removal of drugs from the market. These drugs have already been approved for various indications for cancer. For example, one of the drugs reviewed, pembrolizumab (Keytruda), is approved in the United States for 28 indications.
The FDA is facing growing pain 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, in part because of the agency’s willingness to accept substitute markers for accelerated approvals. . While some companies have struggled with these, others have created 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 to try to withdraw an indication of pembrolizumab (Keytruda) for this disease.
A few weeks before the April 16 meeting, the FDA approved nivolumab plus chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This is a full approval based on data showing an overall survival benefit of a phase 3 trial.
On April 29, the last day of the meeting, the ODAC group voted 6-2 against maintaining the indication for use of pembrolizumab as monotherapy for an advanced form of gastric cancer. That was one accelerated approval (granted in 2017) this was based on the overall response rates of an open-label trial.
Another negative vote also took place on the last day of the meeting. On April 29, the ODAC court voted 5 to 4 against maintaining a nivolumab indication for hepatocellular carcinoma (HCC) for patients previously treated with sorafenib (Nexavar). It was an expedited approval that was granted in 2017. The FDA said it had requested ODAC’s comments on this indication due to the recent full approval, which was based on an overall survival benefit (as of May 2020) of another checkpoint inhibitor for HCC, atezolizumab (Tecentriq), in combination with bevacizumab (Avastin) for patients with non-resectable or metastatic diseases who have not received prior systemic therapy.
There was one last vote that third day of the meeting and it was positive. The ODAC court voted 8-0 in favor of maintaining the indication for use as pembrolizumab monotherapy for HCC patients who have previously been treated with sorafenib.
The FDA modified the composition of the ODAC panel during the week, adding members in some cases who had experience with particular cancers. This resulted in different totals for the ODAC votes for the week, as shown in the accounts summarized below.
On the first day of the meeting (April 27), the ODAC court voted 7-2 in favor maintain an indication for breast cancer by atezolizumab (Tecentriq). This covered the use of immunotherapy in combination with nab-paclitaxel for patients with locally advanced triple negative or non-resectable metastatic. Lung cancer whose tumors express PD-L1.
The second day of the meeting (April 28) was also seen two positive votes. The ODAC group voted 10-1 to maintain the indication for azolizumab for the first-line treatment of ineligible cisplatin patients with advanced / metastatic urothelial carcinoma, pending the final overall survival results of the IMvigor130 trial. The group also voted 5-3 to maintain 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 required to follow the votes and recommendations of its advisory panels, but it usually does.
Management of changes in treatment
In both cases where ODAC voted against maintaining indications, Richard Pazdur, MD, the FDA’s top regulator of cancer drugs, jumped into the debate. Pazdur countered the arguments put forward by the representatives of the manufacturers while trying to maintain the indications of their medicines.
Merck officials and representatives defended pembrolizumab, saying maintaining the indication for gastric cancer could help patients whose disease has progressed despite previous treatment. Pazdur stressed that the agency would help Merck and doctors have access to pembrolizumab for these patients, even if that indication was withdrawn. But Pazdur and ODAC members also noted the recent shift in the gastric cancer landscape, with the recent approval of a new indication for nivolumab.
“I want to highlight the patient community out there. We strongly believe in the role of checkpoint inhibitors in this disease,” Pazdur of the FDA said during the discussion on the indication for pembrolizumab for gastric cancer. “We need to be aware of what the right context is for that, and it’s currently on the front line.”
Pazdur noted that two studies had not confirmed the expected benefit of pembrolizumab for patients with more advanced disease. However, if a “small number” of patients with advanced disease wanted to access Merck’s drug, the FDA and company could accommodate them. The FDA could delay the removal of the gastric indication to allow patients to continue receiving it. The FDA could also work with doctors on other routes to provide the drug, such as using a single-patient drug applications for new drug research or an expanded access program.
“Or Merck can also administer the drug for free to patients,” Pazdur said.
#ProjectFacilitate for extended access
One of Merck’s speakers at the ODAC meeting, Peter Enzinger, MD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, opposed Pazdur’s plan.
Loss of gastric indication of pembrolizumab would cause patients with advanced cancer to lose the opportunity to try this therapy. Some patients will not have had the opportunity to try a checkpoint inhibitor prior to treatment and loss of indication would cost them that opportunity, he said.
“An extended access program sounds great, but the reality is that our patients are incredibly ill and the weeks are important,” Enzinger said, citing administrative hurdles as a barrier to treatment.
“Our patients just don’t have the time for that, so I don’t think that’s the way to follow an expanded access program,” Enzinger said.
Pazdur responded to these objections by highlighting an initiative called Project Facilitate at the FDA’s Center for Oncological Excellence. During the meeting, Pazdur’s division used its Twitter manager @FDAOncology 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 speaker Diane Reidy-Lagunes, MD, of the Memorial Sloan Kettering Cancer Center in New York City said she had fought with that vote. She was one of two people who voted in favor of keeping the indication.
“This is also incredibly tough for me, in fact I changed it at the last minute,” he said of his vote.
But Reidy-Lagunes said she was concerned that some patients with advanced disease might not get a checkpoint inhibitor.
“With differences in health care and differences in how patients are treated across our country, I was nervous that they could not be treated,” he said. He noted that he shared the doubts of his fellow panelists about the use of pembrolizumab as a third-line treatment, due to the negative results of the trials.
ODAC member David Mitchell, who acted as a consumer representative, also said he considered voting on the gastric indication for pembrolizumab to be a difficult decision.
“As an incurable cancer patient who now receives the top three classes of medications to treat my disease in combination, these problems are reduced very close to home,” Mitchell said.
He said the expectation that the FDA’s expanded access program could help patients with advanced disease test pembrolizumab helped him decide to vote with a 6-2 majority against maintaining that approval of gastric cancer.
His vote was based on “changing the landscape of treatment.” There is general agreement that patients in question should receive checkpoint inhibitors as first-line and not third-line treatment, Mitchell said. The FDA should delay withdrawal of pembrolizumab approval in this case and should allow a transition for those who stopped having treatment with a checkpoint inhibitor before the course of the disease, he suggested.
“To protect patient safety and well-being, we need to base decisions on data,” Mitchell said. “Data do not support the indication” for pembrolizumab.
Close Split to Nivolumab
In contrast to the 6-2 vote against maintaining the indication for pembrolizumab, the ODAC panel split more closely, 5-4, on the issue of maintaining an indication for use as nivolumab monotherapy in HCC. .
ODAC panelist Philip C. Hoffman, MD, of the University of Chicago, was one of those who supported maintaining the indication.
“There is still an unmet need for second-line immunotherapy because there will always be some patients who are poor candidates for bevacizumab or who do not tolerate or respond 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 Bristol-Myers Squibb would be able to produce nivolumab data soon. necessary to support this indication.
Kerry Dooley Young is a freelance journalist based in Washington, DC. He previously covered health policy and the federal budget for the convening of the Quarterly Congress / QC and the pharmaceutical industry and Bloomberg’s Food and Drug Administration. Follow her on Twitter at @kdooleyyoung.
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