FDA panel: PI3K inhibitor approvals for blood cancers should be backed by randomized data
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The FDA Oncologic Drugs Advisory Committee voted Thursday in favor of randomized data to support future approvals of phosphatidylinositol-3-kinase inhibitors, which are being developed for patients with hematologic malignancies.
The 16-0 vote, with one abstention, followed more than 3 hours of presentations and discussion on toxicities associated with PI3K inhibitors, trials that have shown a potential detriment in OS, limited exploration of dosing, and the limitations of single-arm trials that served as the basis for approvals of these drugs.
“This is a very different advisory committee meeting,” said Nicole Gormley, MD, of the division of hematologic malignancies II in the FDA Office of Oncologic Diseases. “It is future-thinking and forward-looking. We want to make sure that our forward-thinking advice that we give to sponsors is grounded in our experience.”
The meeting occurred less than a week after TG Therapeutics voluntarily withdrew applications for the combination of umbralisib (Ukoniq) and ublituximab to treat patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (SLL), based on concerning OS data from the randomized phase 3 UNITY-CLL trial. The company also halted sales of umbralisib for certain patients with marginal zone lymphoma and follicular lymphoma, indications for which the PI3K inhibitor had been granted accelerated approval last year.
Three other PI3K inhibitors have been FDA approved for hematologic malignancies:
- Idelalisib (Zydelig, Gilead Sciences) received accelerated approval for relapsed follicular lymphoma and SLL and regular approval for relapsed CLL in July 2014. Three randomized trials of the agent in combination regimens for CLL and non-Hodgkin lymphoma were later terminated because of increased deaths, and the FDA issued a safety alert. Earlier this year, Gilead voluntarily withdrew the follicular lymphoma and SLL indications after being unable to conduct clinical trials to verify benefit.
- Copanlisib (Aliqopa, Bayer) received accelerated approval in September 2017 for relapsed follicular lymphoma. The randomized phase 3 CHRONOS-3 trial, which investigated the agent plus rituximab (Rituxan; Genentech, Biogen) vs. placebo and rituximab for relapsed indolent non-Hodgkin lymphoma, showed higher rates of grade 3 and serious adverse events in the copanlisib arm, as well as a higher number of deaths due to adverse events. In December, the FDA withdrew a supplemental new drug application based on CHRONOS-3 to support copanlisib for adults with indolent non-Hodgkin lymphoma.
- Duvelisib (Copiktra, Secura Bio) received regular approval for patients with relapsed or refractory CLL or SLL and accelerated approval for follicular lymphoma in September 2018. The randomized phase 3 DUO trial of the agent vs. ofatumumab among this patient population showed higher rates of toxicities in the duvelisib arm — a difference, as observed in the CHRONOS-3 trial, that was driven by PI3K-associated toxicities. The final survival analysis of DUO showed a higher rate of deaths and shorter median OS in the duvelisib arm. In December, Secura Bio voluntarily withdrew the follicular lymphoma indication.
“This degree of safety findings that we’re seeing, and overall survival results across multiple products [and] multiple hematologic indications, all showing a consistent finding of concerning overall survival patterns, albeit early, is really unprecedented,” Gormley said. “While we definitely want to expedite drug development and make sure that there are new therapies available to patients as soon as possible, it’s imperative in our view that we ensure that those products are safe and effective.”
Committee members expressed support for randomized studies to ensure the safety and efficacy of PI3K inhibitors.
“The bottom line is, if we are improving length of life with any therapy but exposing patients to toxicity and, therefore, decreasing their quality of life, are we truly helping our patients? I don’t believe so,” committee member Christopher H. Lieu, MD, associate professor of medicine-medical oncology, associate director for clinical research and co-director of gastrointestinal medical oncology at University of Colorado School of Medicine, said after casting his vote.
Committee member Anthony D. Sung, MD, associate professor of medicine at Duke University, abstained from the vote. He said he agreed the PI3K inhibitors discussed were “highly problematic” and randomized studies should have been conducted in that context.
“However, I still feel uncomfortable labeling an entire class and requiring future drugs in that class to be supported by randomized data,” he said. “I think if the phase 1 data are concerning, then absolutely a randomized study should be needed. If the phase 1 data are not concerning, then I don’t know if a randomized study should be needed in that case.”
Richard Pazdur, MD, director of FDA’s Oncology Center of Excellence, said the agency would “demonstrate the appropriate flexibility” based on results of earlier studies.
“We’re just asking, Should randomized studies be done? We’re not asking for overall survival to be the primary endpoint for the trial, but a randomized trial does allow us to at least do a descriptive analysis of that endpoint that cannot be obtained from a single-arm trial,” Pazdur said.
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FDA Oncologic Drugs Advisory Committee Meeting, April 21, 2022. www.fda.gov/media/157757/download.
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