A panel of external advisors to the FDA 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 agencies to discuss observed toxicities of the phosphatidylinositol 3-kinase inhibitor class and whether randomized survival data are needed to support risk-benefit assessments in patients with blood cancers. After listening to agency moderators, they returned with a resounding “yes.”
PI3K was once thought to be part of a signaling pathway believed to be the “master regulator” of cancer. But the class of PI3K inhibitors has recently come under closer scrutiny in hematologic malignancies following renewed concerns about toxicity, inadequate dose optimization, study design limitations in single-arm studies, and overall survival trends.
ODAC reviewed data from PI3K inhibitors approved by the FDA for various blood cancers, including Gilead’s Zydelig, Bayer’s Aliqopa, Secura Bio’s Copiktra, and TG’s Ukoniq. FDA reviewers in their papers earlier this week appeared to agree with comments made last week by leading oncologist Richard Pazdur that accelerated approvals of PI3K inhibitors should not be based solely on single-arm trials.
“The bottom line is that we really help our patients if we don’t extend life expectancy with any therapy, but instead expose the patients to toxicity and thus reduce their quality of life? And I don’t think so,” said Christopher Lieu, director of the University of Colorado’s Gastrointestinal Medical Oncology Program, in his rationale for the yes vote.
“It is perplexing to me that there are no appropriate dose escalation studies for these agents, particularly when used in combination with other existing regimens for the diseases,” Jorge Garcia, chair of Case Western Reserve University’s Department of Solid Tumor Oncology, said in his statement.
During Thursday’s meeting, some panel members asked FDA executives to clarify whether their question was specifically limited to the future development of PI3K in hematological malignancies, to which the agency said yes, but that the findings inform thinking elsewhere across the drug class could.
“We have this experience with these products in this class in multiple indolent lymphoma, which have shown significant toxicities and dosing concerns, and I think this has implications for future research into PI3K inhibitors in heme malignancy. And of course, yes, we’re going to take the conversations back here and apply them or think about how they might apply to other scenarios, other indolent diseases in other areas,” said Nicole Gormley, director of the FDA’s division of hematologic malignancies within the FDA Bureau of New Drugs.
Screenshot of the FDA ODAC session
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The only member who abstained, Duke Medicine Associate Professor Anthony Sung, expressed reluctance to vote on something that could impact future clinical development, noting that the future cannot be predicted. Gormley replied that no one has a crystal ball.
“What if a new PI3K were developed that had phenomenal one-armed data? Would we still need a randomized trial in this setting?” Sung asked the panel.
Gormley agreed with Sung that this ODAC meeting differed from previous ODAC meetings in that the advisors were asked to provide forward-looking advice. However, Gormley said the agency is looking for input, so its advice to sponsors is “based on experience”.
“This consistent finding of worrying patterns of overall survival, albeit early, is truly unprecedented,” Gormley said. “While we definitely want to accelerate drug development and ensure that new therapies are available to patients as quickly as possible, we believe it is essential to ensure that these products are safe and effective.”
“There are many ways to accelerate drug development, and not all of them require a one-arm study,” she added.
Gormley emphasized that the FDA is not proposing that OS be the primary endpoint, noting that the accelerated pathway is still possible in randomized trials.
The meeting was originally scheduled for two days, but Friday’s session was canceled after TG Therapeutics withdrew its sNDA for its so-called U2 combo therapy last week. TG has also withdrawn a component of U2 called Umbralisib or Ukoniq from its approved indications for two different lymphomas.
Other drugs that were the focus of Thursday’s deliberations have seen some market withdrawals. Gilead has swept away Zydelig’s recurrent follicular B-cell non-Hodgkin lymphoma and indications for recurrent small lymphocytic leukemia due to the “ongoing challenge” of enrolling in a confirmatory study of the drug.