AACR: TG Therapeutics' umbralisib shrinks tumors in 52% of lymphoma patients

TG Therapeutics plans to submit umbralisib for accelerated approval by the end of the year. (Pixabay)

TG Therapeutics’ PI3K delta inhibitor, umbralisib, put up encouraging phase 2b data in marginal zone lymphoma, shrinking tumors in more than half of the patients followed long enough to be evaluated. Of these patients, nearly one-fifth were in complete remission—that is, their cancer was undetectable after treatment. 

The interim data were presented at the annual meeting of the American Association of Cancer Research by Nathan Fowler, M.D., of the University of Texas MD Anderson Cancer Center, who served as study chair for the marginal zone lymphoma (MZL) arm of the UNITY-NHL study. The trial is testing umbralisib as a single agent, as well as in combination with another TG drug, ublituximab, or with both ublituximab and the chemo drug bendamustine, in multiple types of non-Hodgkin lymphomas (NHL), such as follicular lymphoma and chronic lymphocytic leukemia (CLL), in addition to MZL. 

The MZL arm enrolled 69 patients with relapsed or refractory MZL who had received prior therapy, including with at least one anti-CD20 drug, most commonly rituximab (Roche's Rituxan). The efficacy data come from 42 patients who had received at least one dose of umbralisib and undergone at least nine months of follow-up by the cutoff date. Umbralisib partially shrank the tumors in one-third of those patients and eliminated the cancer in 19% of patients. 

Though a complete response doesn’t mean the cancer is gone for good, it’s still good news for patients with a cancer that tends to return after first-line treatment. 

“Most patients who are first diagnosed with marginal zone lymphoma will be treated with a combination of chemotherapy or RItuxan. Patients that are not good candidates for chemotherapy will just get Rituxan alone at that point,” TG Therapeutics CEO Michael Weiss told FierceBiotech. “That’s about all we’ve got available in first-line treatments today. Patients who can tolerate what they call chemoimmunotherapy—Rituxan and chemo—do pretty well for a reasonable amount of time, but most patients will progress.” 

“No one is actually cured,” he said. 

Once a patient relapses, there aren’t many options. Doctors may prescribe more chemo, with or without Rituxan. And though Johnson & Johnson's Janssen and AbbVie got their BTK inhibitor Imbruvica (ibrutinib) approved for MZL in early 2017, that drug got a conditional nod and is in the process of a confirmatory trial in this indication. Imbruvica has a host of FDA nods under its belt, as both a first- and second-line treatment for CLL, as well as for previously treated mantle cell lymphoma and Waldenström macroglobulinemia. 

“[Imbruvica] is relatively new to the [MZL] space, so there’s not a good sense of how frequently it’s used today. But it is certainly a good treatment option for patients in that setting,” Weiss said. 

RELATED: AbbVie, Johnson & Johnson grab another Imbruvica nod with early OK in rare blood cancer 

Data show that about the same proportion of patients respond to umbrasilib as to Imbruvica, but Weiss thinks umbralisib could work even better than Imbruvica. 

Phase 2 data for 60 patients with relapsed or refractory MZL showed that only 3% of patients had a complete response to Imbruvica, while 45% had a partial response. 

“The percentage of patients with a complete response with ibrutinib is very rare ... If a doctor is worried about which drug they are going to use first, if they had a choice of these two, certainly the one that gives the opportunity for a complete response would be attractive,” Weiss said. Additionally, the median time it took for MZL patients to mount a response to umbralisib was shorter than that for Imbruvica in trials—2.7 months versus 4.5 months—though the only way to accurately evaluate the drugs against one another would be a head-to-head study. 

That’s not to say that TG wants to scupper umbralisib’s potential rival. The drugs have different side effects—Imbruvica’s are more cardiac-related, such as bleeding, bruising and high blood pressure, while umbralisib’s include elevated liver enzyme levels and diarrhea—which means that a patient who may not be able to tolerate one drug may be able to handle the other. And not having “overlapping toxicities” means the pair could potentially be used together, Weiss said. 

It all depends on umbralisib’s approval, of course, but Weiss thinks there is “a lot of flexibility in how physicians could use these drugs, but certainly, having two drugs available to their patients with different tolerability profiles is an advantage for everybody,” he said. 

TG Therapeutics is still waiting for efficacy data from 27 patients, but Weiss expects the final data set will look similar to the interim readout. The company will then sit down with the FDA to discuss how much more follow-up time the agency would like to see before TG files an NDA. It plans to submit a filing by the end of the year.