FDA Pulls Lymphoma Approvals for PI3K Inhibitor Umbralisib

The FDA has withdrawn approval of the PI3K inhibitor umbralisib (Ukoniq) for marginal zone lymphoma (MZL) and follicular lymphoma because of safety concerns, the agency announced in a safety communication.

The action follows an earlier safety communication about a possible increased risk of death among patients treated with umbralisib. In response to safety concerns about the entire class of PI3K inhibitors, the FDA Oncologic Drugs Advisory Committee (ODAC) in April voted 16-0 in favor of requiring survival data from randomized trials to support future applications for PI3K approvals.

Just a week before the ODAC meeting, TG Therapeutics announced withdrawal of a supplemental biologics license application for the combination of ublituximab and umbralisib for chronic lymphocytic leukemia and small lymphocytic lymphoma. At the same time, the company announced withdrawal of the approved indications for MZL and follicular lymphoma. Development of anti-CD20 ublituximab for relapsing forms of multiple sclerosis will continue.

“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq,” the FDA stated in the latest safety communication. “As a result, we determined the risks of treatment with Ukoniq outweigh its benefits.”

At the ODAC meeting, an FDA staff report described the concerns about PI3K inhibitors as “unprecedented in oncology.” Multiple trials of different drugs in the class had shown worse overall survival despite a clear benefit for progression-free survival.

“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 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.”