FDA Oncologic Drugs Advisory Committee Meeting, April 21, 2022. www.fda.gov/media/157757/download.
FDA Oncologic Drugs Advisory Committee Meeting, April 21, 2022. www.fda.gov/media/157757/download.
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:
“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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