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Future FDA approvals of four existing PI3K inhibitors for hematologic malignancies should have supporting survival data from randomized clinical trials, according to an advisory committee.

By a 16-0 vote, with one abstention, the Oncologic Drugs Advisory Committee (ODAC) decided that a pattern of worse overall survival (OS) with PI3K inhibitors in hematologic cancers warrants randomized controlled trial support to provide assurance of the drugs' when considering future approvals. Data summarized for the committee showed an excess of fatal adverse events (AEs) and high rates of severe and overall toxicity, which appeared to be class specific.

The negative data came from studies of patients with indolent lymphomas, which are associated with prolonged survival and for whom quality of life is a major consideration. Those factors were emphasized in concluding statements by ODAC chair Jorge Garcia, MD, of Case Western Reserve University in Cleveland.

"The concerns [were] a survival detriment, the benefit/risk ratio in that patient population with a long natural history, and the importance of quality of life as you prolong life for these patients," he said. "Certainly, PFS [progression-free survival], at least for most of us who voted yes, didn't appear to be a reasonable endpoint for this class of agents."

The meeting occurred against a backdrop the FDA staff report called "unprecedented in oncology": consistent findings of worse survival in multiple randomized trials of PI3K inhibitors despite a clear or potential PFS benefit.

"The overall survival information is early and represents a low number of events; yet, we have the same pattern observed across multiple trials," the authors of the FDA report stated. "Further, in each trial, there was a higher rate of death due to adverse events in the PI3K inhibitor arm, suggesting the potential detriment in overall survival may be due to toxicity."

Limited Dose Exploration

FDA staff faulted reliance on single-arm trials powered to assess response rate, not survival. Sponsors performed limited exploration of lower drug doses before settling on a maximum or near-maximum dose for registration trials. Subsequently, a relationship was observed for drug exposure and adverse events but not necessarily for drug exposure and efficacy. Analysis of safety data from single-arm trials was confounded by the absence of a control arm.

"Future studies should be designed with additional opportunities to evaluate patient safety, and there should be a high likelihood that when a study is completed, it can indicate an acceptable benefit-risk profile, which includes evaluation of the impact on survival as both a safety and efficacy metric," the report concluded.

Since 2014, the FDA has approved four PI3K inhibitors for hematologic indications. Sponsors for all four drugs have subsequently withdrawn accelerated approvals or new drug applications (NDAs) for indolent indications.

Idelalisib (Zydelig) led the way with a 2014 approval for chronic lymphocytic leukemia (CLL) and accelerated approval for follicular lymphoma (FL) and small lymphocytic leukemia (SLL). By 2016, three confirmatory randomized trials with the drug had shown worse survival, prompting the FDA to issue a safety alert. In February of this year, Gilead Sciences withdrew the FL and SLL indications.

Copanlisib (Aliqopa) received accelerated approval for FL in 2017, and duvelisib (Copiktra) received approval for CLL/SLL and accelerated approval for FL in 2018. Three years later, umbralisib (Ukoniq) received accelerated approval for FL and regular approval for marginal zone lymphoma (MZL), and TG Therapeutics submitted an NDA on the basis of the phase III UNITY trial. Additionally, Bayer submitted an NDA on the basis of a PFS benefit observed with copanlisib in the phase III CHRONOS-3 trial.

By the end of 2021, Secura Bio had withdrawn the FL indication for duvelisib after the phase III DUO trial showed a trend toward worse survival and an 11-month shorter median OS with the PI3K inhibitor. Bayer withdrew the NDA for copanlisib after CHRONOS-3 showed no survival benefit, accompanied by an increased number of treatment-related deaths.

The FDA issued a safety alert for umbralisib in early 2022 after a phase III trial showed increased mortality with the PI3K inhibitor. On April 15, 2022, TG Therapeutics withdrew umbralisib's FL and MZL indications.

'Perplexing,' Concerning Data

Following the near-unanimous vote, Garcia said, "It's perplexing to me, the lack of appropriate dose-escalation studies, especially when they're using combinations with our existing regimens for these diseases. Certainly the AE profile and the reduction in dose and drug discontinuations, as presented to the group, is quite perplexing to me, as well, and quite toxic, in my mind."

"I'm not a hematologist, but I would probably find it quite difficult to tell a patient that I have an agent that could reduce your tumor volume, possibly delay your progression, but at the price of significant toxicities. And oh, by the way, I can also impact your mortality in a detrimental manner," Garcia said.

With the increased number of treatment options available for indolent lymphomas, the argument cannot be made that PI3K inhibitors are filling an unmet need, said Jorge J. Nieva, MD, of the University of Southern California in Los Angeles.

"There is no unmet need, where approval based on a single-arm study would have been sufficient," said Nieva. "The current safety data justify raising the bar for new agents in the class to show that they are not causing long-term harm."

Mark Conaway, PhD, of the University of Virginia Cancer Center in Charlottesville, said the FDA staff report provided "ample evidence that randomized trials should be part of the approval process for PI3K inhibitors. I think [the data] also highlight the need for improvements in the design, conduct, and reporting of the dose-exploration trials leading up to the randomized trial."

The data also clearly showed "there is a class-effect toxicity that we need to keep in mind for the future with regard to dose-finding studies," said Massimo Cristofanilli, MD, of Weill Cornell Medicine in New York City. "Randomized studies are the only way to address acute and chronic toxicity to see whether these drugs have a future in hematologic malignancies."

Explaining his decision to abstain, Anthony D. Sung, MD, of Duke University in Durham, North Carolina, expressed concern that the vote might quash future development of an entire drug class.

Nicole Gormley, MD, director of hematologic malignancies at FDA, emphasized that the meeting was limited to consideration of how to proceed with the existing drugs and their use in hematologic malignancies. She pointed out that some of the agents have other approved indications, such as CLL, which would not be affected by the ODAC vote. The decision would not eliminate consideration of accelerated approval on the basis of single-arm trials or eliminate PFS as an endpoint in randomized trials.

The meeting did not include discussion of alpelisib (Piqray), a PI3K inhibitor that has an approved indication in breast cancer.

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