A panel of FDA’s outside advisors unanimously voted, with one abstention, that future approvals of PI3K inhibitors should be supported by randomized data.
The 17-member ODAC panel was asked by federal regulators to discuss observed toxicities of the Phosphatidylinositol-3-kinase inhibitor class and whether randomized survival data are needed to support risk-benefit evaluations in patients with blood cancers. They returned, after listening to agency presenters, with a resounding “Yes.”
PI3K was once deemed part of a pathway considered the “master regulator” of cancer. But the class of PI3K inhibitors has garnered more scrutiny recently in hematological malignancies after renewed toxicity concerns, inadequate dose optimization, trial design limitations of single-arm studies and concerning overall survival trends.
ODAC reviewed data from PI3K inhibitors given FDA nods for various blood cancers, including Gilead’s Zydelig, Bayer’s Aliqopa, Secura Bio’s Copiktra and TG’s Ukoniq. The FDA’s reviewers, in their documents earlier this week, seemed to be in alignment with comments from oncology leader Richard Pazdur last week that accelerated approvals of PI3K inhibitors should not be based solely on single-arm trials.
“The bottom line is if we aren’t improving the length of life with any therapy but exposing patients to toxicity and therefore decreasing their quality of life, are we truly helping our patients? And I don’t believe so, ”Christopher Lieu, director of the University of Colorado’s Gastrointestinal Medical Oncology Program, said in his reasoning for voting yes.
“It’s perplexing to me the lack of appropriate dose-escalation studies for these agents, especially when they’re using combination with other existing regimens for the diseases,” Jorge Garcia, chair of Case Western Reserve University’s Division of Solid Tumor Oncology, said in his explanation.
During the Thursday meeting, some panel members asked FDA leaders to clarify whether their question was limited specifically to PI3K’s future development in hematological malignancies, to which the agency said yes, but that the learnings could inform thinking elsewhere across the drug class.
“We have this body of experience with these products in this class in multiple indolent lymphomas that have shown significant toxicities and concerns with dosing, and I think that has implications for future exploration of PI3K inhibitors within heme malignancies. And, of course, yes, we’ll take back conversations here and apply them or think about how they may apply to other scenarios, other indolent diseases in other spaces, ”said Nicole Gormley, director of the FDA’s division of hematologic malignancies within the Office of New Drugs.
FDA ODAC meeting screenshot
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The only member to abstain, Duke Medicine associate professor Anthony Sung, voiced reticence about voting on something that could impact future clinical development, noting the future can’t be predicted. Gormley replied nobody has a crystal ball.
“What if a new PI3K was developed that had phenomenal single-arm data? Would we still require a randomized trial in that setting? ” Sung asked the panel.
Gormley agreed with Sung that this ODAC meeting was different than ones past in that the advisors were asked to come up with forward-looking advice. But Gormley said the agency was seeking input so its advice to sponsors is “grounded in experience.”
“This consistent finding of concerning overall survival patterns, albeit early, is really unprecedented,” Gormley said. “And so 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 those products are safe and effective.”
“There are many ways that drug development can be expedited and it doesn’t all require a single-arm trial,” she added.
Gormley emphasized the FDA isn’t suggesting OS be the primary endpoint and noted the accelerated approval pathway can still happen with randomized trials.
The meeting was originally scheduled for two days, but the Friday session was canceled after TG Therapeutics pulled its sNDA for its so-called U2 combo therapy last week. TG also withdrew one component of U2, named umbralisib or Ukoniq, from its approved indications of two different lymphomas.
Other drugs at the heart of Thursday’s deliberations have seen some market withdrawals. Gilead swiped away Zydelig’s relapsed follicular B-cell non-Hodgkin’s lymphoma and relapsed small lymphocytic leukemia indications because of the “ongoing challenge” of enrollment for a confirmatory study of the drug.