Better Data Needed to Approve Future PI3K Inhibitors for Blood Cancers, FDA Panel Recommends

A panel of experts on the FDA’s Oncologic Drugs Advisory Committee voted that all future approvals of PI3K inhibitors to treat blood cancer be backed by randomized clinical trial data.

A team of experts on the Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) recently voted in favor of the recommendation that future FDA approvals of PI3K inhibitors to treat blood cancers should be supported by randomized clinical data.

Sixteen members of ODAC voted in favor of the measure, while one member did not vote.

“The bottom line is, if we aren’t 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,” Dr. Christopher Lieu, associate director for Clinical Research and co-director of Gastrointestinal Medical Oncology at University of Colorado Cancer Center in Aurora, said in a press release.

Over the past few years, several PI3K inhibitors have received FDA approval in the hematologic space based on single-arm findings, which is a study setting that includes a sample of patients who are given the study drug and then followed over time for observation. In a single-arm study, patients are not randomized to receive a comparator treatment — whether that be an FDA-approved drug or placebo.

Some of the approvals based on single-arm studies included Zydelig (idelalisib), which was approved in July 2014 for chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), and follicular lymphoma; Aliqopa (copanlisib), which was approved in September 2017 for previously treated relapsed follicular lymphoma; Copiktra (duvelisib), which was approved in September 2018 for previously treated CLL and SLL; and Ukoniq (umbralisib), which was approved for marginal zone lymphoma (MZL) and follicular lymphoma in February 2021 following one previous anti-CD20 therapy and three systemic therapies, respectively.

However, two of these drugs have since been removed from the market. Copiktra was withdrawn from its relapsed/refractory follicular lymphoma indication in December 2021 after a drug and holding discussion with the FDA. Although development was set to continue for patients with T-cell lymphoma, the regulatory organization cited that the cost, logistics and timing for the post-marketing requirements were no longer warranted.

Read more: Adding Copiktra to Standard of Care Chemotherapy Combination in CLL Could Improve Outcomes, But Not Without Toxicities

An application for Ukoniq and ublituximab was also withdrawn for CLL and SLL in April 2022. Additionally, in light of this decision, Ukoniq was withdrawn from sale in its approved indications for MZL and follicular lymphoma. The decision was based on an increasing imbalance in overall survival (the length of time between treatment and death) data between study groups in the phase 3 UNITY-CLL trial.

Despite yielding promising responses and improved progression-free survival (the amount of time between treatment and disease worsening) in patients with hematologic cancers, the ODAC panel cited that randomized data in this class of drug highlighted a high rate of fatal side effects and other serious side effects compared with single-arm research, where all patients in the trial received a PI3K inhibitor, which was not compared to other treatments. In particular, the panel stated that single-arm studies have limitations that could provide challenges in balancing efficacy and side effects.

Specifically, patients with CLL and indolent non-Hodgkin lymphoma appear to experience a worse overall survival following treatment with a PI3K inhibitor compared with patients in the control group. The class of drug has also raised safety concerns, with gamma- and delta-isoform–specific inhibitors, which yield side effects such as colitis (or inflammation of the inner lining of the colon), pneumonia and rashes leading to some fatal infections. Other concerns include the issue as to whether dosage levels have been properly assessed to combat toxicities and maintain efficacy — a problem that could be addressed with randomized clinical research.

“While we definitely want to expedite drug development and make sure 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,” Dr. Nicole Gormley, acting division director of hematology products for the FDA, concluded.

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