Umbralisib Shows Promise in Relapsed/Refractory Marginal Zone Lymphoma

By Megan Brooks

April 04, 2019

NEW YORK (Reuters Health) - Umbralisib, an investigational oral inhibitor of PI3K-delta, has significant activity against relapsed/refractory marginal-zone lymphoma (MZL) and manageable side effects, according to early results from an ongoing phase 2b trial.

The findings were presented at the American Association for Cancer Research (AACR) annual meeting in Atlanta.

MZL is an indolent B-cell lymphoma accounting for roughly 10% of non-Hodgkin lymphoma cases. Although responses are high to frontline therapy with rituximab alone or in combination with chemotherapy, most patients eventually progress. These individuals have "limited treatment options," Dr. Nathan Fowler, of The University of Texas MD Anderson Cancer Center in Houston, explained during an April 1 press briefing.

Umbralisib, which is being developed by TG Therapeutics, has breakthrough-therapy designation by the U.S. Food and Drug Administration for relapsed/refractory MZL. It uniquely inhibits CK1-epsilon, which may make it more tolerable than first-generation PI3K-delta inhibitors, according to the company.

A total of 72 patients with relapsed/refractory MZL have enrolled in the UNITY-NHL trial, 69 have received treatment with umbralisib 800 mg orally once daily until disease progression or unacceptable toxicity.

In an interim efficacy analysis of 42 patients followed for a median of 12.5 months, the overall response rate to umbralisib is 52%, with a complete response (CR) rate of 19%, and a partial response rate of 33%. The median time to initial response was 2.7 months, Dr. Fowler reported.

"Durable responses were observed and toxicity did not appear to be worsening with prolonged exposure and this is a bit different from what we have seen with some of the other drugs in this class," he noted.

More than half (55%) of patients remain on umbralisib in the study. The chief reasons for stopping the drug were disease progression (24%), umbralisib-related adverse event (12%), unrelated adverse event (5%), withdrawal of consent (2%) and investigator decision (2%).

According to TG Therapeutics (, interim safety data for all 69 treated patients with a median duration of exposure of 6.9 months found no unexpected toxicities.

The most common adverse events were diarrhea, nausea and fatigue, with most of these grade 1 events. The most common grade 3 or higher adverse events were neutropenia, diarrhea and an increase in ALT/AST liver enzymes. No events of colitis or pneumonitis had been reported.

"All the adverse events we have seen in the trial are to be expected with this class of drugs," Dr. Fowler said in an AACR news release. "Moreover, we were able to manage the side effects for the patients, making umbralisib a well-tolerated treatment.

"The adverse event and clinical activity data," he added, "are highly encouraging at this early timepoint. We are excited to continue following patients for a longer time to further establish the long-term activity and side effects of umbralisib. With the results reported so far, umbralisib has the potential to make a real difference for patients with relapsed/refractory marginal zone lymphoma."

Briefing moderator Dr. Louis Weiner of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., said these are "very interesting and provocative early findings" and it will be interesting to see more data from the trial to determine if the findings "hold up, which they most likely seem that they will."

Phase 3 studies of umbralisib are planned in MZL and other indolent NHL subtypes.

This study was funded by TG Therapeutics. Dr. Fowler serves on scientific advisory boards for TG Therapeutics and also receives research funding from the company.


AACR 2019 Annual Meeting.