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The FDA has begun an investigation into the safety of the lymphoma drug umbralisib (Ukoniq) after preliminary data from a clinical trial suggested an increased mortality risk in patients treated with the PI3K inhibitor.

The potential adverse safety signal arose from the phase III UNITY-CLL trial comparing umbralisib plus the anti-CD20 antibody ublituximab versus obinutuzumab (Gazyva) plus chlorambucil for chronic lymphocytic leukemia. Umbralisib indications for relapsed/refractory marginal zone lymphoma and follicular lymphoma.

"Because of the seriousness of this safety concern and the similarities between the two types of cancer for which this drug is approved and the type of cancer that was studied in the clinical trial, we are alerting patients and healthcare professionals that we are re-evaluating this risk against the benefits of Ukoniq for its approved uses," noted an .

The FDA Oncologic Drugs Advisory Committee (ODAC) may also convene to consider the findings of the safety evaluation and "explore" the continued marketing of umbralisib. Additionally, the agency has halted enrollment in other ongoing clinical trials of umbralisib during the review of the UNITY-CLL data, according to the safety communication.

Late last year, umbralisib sponsor TG Therapeutics issued a acknowledging that the FDA plans to convene ODAC to consider the UNITY-CLL data within the context of the ongoing review of the company's application for approval of the umbralisib/ublituximab (U2) combination.

"We believe Ukoniq is a unique PI3K inhibitor, with a differentiated toxicity and tolerability profile and believe the data submitted thus far are supportive of approval of U2 in CLL," said Michael S. Weiss, CEO of TG Therapeutics.

Overall survival (OS) is a secondary endpoint of the UNITY-CLL trial. According to TG Therapeutics, the FDA requested an early OS assessment, which showed the U2 arm had a 23% higher mortality, a difference that did not achieve statistical significance. After excluding deaths associated with COVID-19, the survival hazard with U2 decreased to 4%, essentially the same as in the control arm.

"The overall survival results are preliminary, and the company will continue to evaluate the endpoint over time as more events are evaluable and will continue to analyze how COVID-19 may be impacting the analysis," the statement continued.

Although ODAC has yet to announce a date for the umbralisib review, the FDA indicated that the meeting would occur in March or April, according to TG Therapeutics.

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