FDA Will Reassess 6 Immunotherapy Accelerated Approvals

Six indications for immune checkpoint inhibitors (ICIs) granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) will hold a special 3-day public hearing on April 27 to 29 to allow expert commentary and patient testimony about the drugs, which are being used to treat triple-negative breast cancer (TNBC), metastatic urothelial carcinoma (mUC), gastric cancers, and hepatocellular carcinoma (HCC), the agency said Thursday. Based on the testimony, ODAC will consider whether the approvals should be withdrawn and whether additional trials should be conducted.¹

The hearings will involve 2 indications for atezolizumab (Tecentriq), 3 for pembrolizumab (Keytruda), and 1 for nivolumab (Opdivo). Specifically, these indications will be reviewed:

• Atezolizumab―in combination with nab-paclitaxel (Abraxane) for the treatment of patients with PD-L1–positive unresectable locally advanced or metastatic TNBC; and as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy
• Pembrolizumab—as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy; for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that express PD-L1 and has progressed after 2 or more prior lines of therapy; and for patients with HCC previously treated with sorafenib (Nexavar)
• Nivolumab—as a single agent for patients with HCC who previously received sorafenib

The FDA announced the hearings after a flurry of ICI indications were voluntarily withdrawn by pharmaceutical companies, starting in December 2020, as part of what the FDA described as an industry-wide evaluation of accelerated approvals in oncology “in which confirmatory trials did not confirm clinical benefit.”¹

As part of the voluntary withdrawals, Bristol Myers Squibb and Merck said they will discontinue indications for nivolumab and pembrolizumab, respectively, for patients with metastatic small cell lung cancer whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy; AstraZeneca will withdraw an indication for durvalumab (Imfinzi) for patients with locally advanced or mUC that has progressed after chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy; and Genentech will halt an indication for atezolizumab for patients with mUC previously treated with platinum-based chemotherapy.

Under the accelerated approval program, drugs are able to gain indications more quickly than through a regular approval timeline based on a surrogate end point. Pharmaceutical companies are then required to conduct a trial that confirms a clinical benefit; if the study is successful, the FDA grants regular approval status.²

The FDA’s Oncology Center of Excellence, which reviews and expedites the development of cancer drugs, requested the April hearings. The center is headed by Richard Pazdur, MD, a 2019 Giants of Cancer Care® award winner for Community Outreach who also is serving as acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” Pazdur said in a statement.1 “The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn.”

The hearings will give oncology experts outside of the FDA and patients with cancer an opportunity to describe their experiences with the drugs, said Pazdur. “After this advisory meeting, our staff will consider the committee’s comments and will make final decisions regarding continuing approval of each indication,” he said.

The accelerated approval pathway, introduced in 1992, has been “an extremely important mechanism to promote development of and access to therapies for serious or life-threatening illnesses,” according to a report by Friends of Cancer Research. Cancer therapies approved through the pathway reached patients a median of 3.4 years earlier than they would have if their status was dependent upon a primary clinical end point such as overall survival for approval, the report noted.³

Since the program began, only 6% of accelerated approvals for oncology drugs have been withdrawn, including the 4 recent ICI indications, the FDA said.¹

Other indications for the ICIs under review are not affected by the April hearings or the announced withdrawals.

References

1. FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA. March 11, 2021. Accessed March 11, 2021. https://bit.ly/3cgG1bm
2. Accelerated approval program. FDA. Updated October 26, 2020. Accessed March 11, 2021. https://bit.ly/30y2209
3. Optimizing the use of accelerated approval. Friends of Cancer Research; 2020. Accessed March 11, 2021. https://bit.ly/38vV28l