Umbralisib A Potential New Treatment for Marginal Zone Lymphoma


by Dr. C.H. Weaver M.D. 6/2019

More than half of the individuals with recurrent marginal zone lymphoma (MZL) treated with the experimental PI3K delta inhibitor umbralisib experienced a response to treatment according to clinical trial results presented at the 2019 American Association for Cancer Research annual meeting.

Marginal zone lymphomas are typically first treated with the anti-CD20 therapy using Rituxan (rituximab) as a single drug or in combination with chemotherapy. Rituxan based therapy has improved outcomes but MZL eventually relapses, and these individuals have limited treatment options.

In January, the FDA granted a breakthrough therapy designation to umbralisib for adults with MZL who have had at least one anti-CD20 treatment.

About Umbralisib

Phosphatidylinositol 3-kinases (PI3K), are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. Umbralisib (TGR-1202) is an orally available PI3K delta inhibitor, targeting the delta isoform selectivity over the alpha, beta, and gamma isoforms of PI3K. The delta isoform of PI3K is strongly expressed in blood cells and is believed to be important in the proliferation and survival of B-cell lymphocytes.

About The UNITY-NHL Clinical Trial

Patients with MZL that had previously received ≥1 prior therapy, including at least one CD20 monoclonal antibody-containing regimen were enrolled in the study evaluating umbralisib. Patients received 800 mg orally once daily until progression or unacceptable toxicity.

Initial results from the found that 55% of treated patients had a complete or partial response at 6 months, and one in five had complete remission. The clinical benefit rate was 84 percent and tumors were reduced in 91 percent of patients with at least one post-baseline assessment.

The most common side effects were diarrhea, nausea, fatigue, headache, cough, and decreased appetite affected between 20-30 percent of patients. Neutropenia occurred in 8% of patients.

The results now need to be confirmed in other studies. Phase III clinical trials are ongoing in MZL and other B-cell malignancies, including follicular lymphoma and chronic lymphocytic leukemia.


Umbralisib Shows Early Promise for Patients with Marginal Zone Lymphoma
Umbralisib Shows Early Promise for Patients with Marginal Zone Lymphoma

ATLANTA — The investigational therapeutic umbralisib, which targets the molecule PI3K-delta, was well tolerated and highly active in patients with relapsed/refractory marginal zone lymphoma, according to early results from the UNITY-NHL phase II clinical trial, which were presented at the AACR Annual Meeting 2019, March 29–April 3.As of October 20, 2018, 55 percent of patients who had at least six months of follow-up had a partial or complete response following umbralisib treatment. The median duration of response had not been reached. Updated data will be presented at the meeting, according to Nathan H. Fowler, MD, associate professor of medicine and director of clinical research in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston. In January 2019, the U.S. Food and Drug Administration (FDA) granted umbralisib breakthrough therapy designation for the treatment of adults with marginal zone lymphoma who have received at least one anti-CD20 treatment. Breakthrough therapy designation is an FDA strategy to expedite assessment of therapeutics for life-threatening diseases such as cancer.“Marginal zone lymphoma is an uncommon, slow-growing type of non-Hodgkin lymphoma,” said Fowler. “Rituximab, either alone or in combination with chemotherapy, has improved outcomes for patients, but in most cases the disease eventually relapses, and these individuals have limited treatment options.“Umbralisib is a small-molecule inhibitor that targets PI3K-delta, which is a component of a signaling pathway that has a key role in promoting the survival and expansion of many types of cells, and has also been shown to uniquely inhibit CK1 epsilon,” continued Fowler. “Our exciting results suggest that this oral targeted therapeutic has significant activity against relapsed/refractory marginal zone lymphoma and offers hope for patients.”As of October 20, 2018, 69 patients with relapsed/refractory marginal zone lymphoma had been enrolled on the trial and received 800 milligrams of umbralisib orally once daily until disease progression or unacceptable toxicity. At that time, 38 patients had at least six months of follow-up.Among the 38 patients, the median follow-up time was 9.6 months. Four had a complete response and 17 had a partial response, as assessed by the investigators, for an overall response rate of 55 percent. An additional 11 patients had stable disease, for a clinical benefit rate (complete response, partial response, and stable disease) of 84 percent. Progression-free survival at 12 months was 71 percent.The most common adverse event of any grade was diarrhea, which affected 45 percent of the 38 patients. Nausea, fatigue, headache, cough, and decreased appetite affected between 20 percent and 30 percent of patients. The most common grade 3/4 adverse events were neutropenia, febrile neutropenia, and diarrhea, which affected 8 percent, 5 percent, and 5 percent of the 38 patients, respectively. 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,” said Fowler. “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 are highly encouraging at this early timepoint,” added Fowler. “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.”According to Fowler, the main limitations of the data presented are that it was based on a small number of patients and a short follow-up time. This study was funded by TG Therapeutics. Fowler serves on scientific advisory boards for TG Therapeutics, Bayer, Gilead Sciences, and Verastem Oncology; he also receives research funding from TG Therapeutics.


Non Hodgkins Lymphoma