Umbralisib: Potential Option for Relapsed or Refractory Marginal Zone Lymphoma

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UMBRALISIBan investigational PI3K-delta inhibitor—produced impressive results as monotherapy in patients with relapsed or refractory marginal zone lymphoma, according to an interim analysis of the phase II UNITY-NHL trial presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting. The overall response rate with single-agent umbralisib in this relapsed or refractory population was 52%, with tolerability that did not worsen over prolonged exposure to the drug.1

Nathan H. Fowler, MD

Nathan H. Fowler, MD

Novel therapies are needed for this group of patients who represent an unmet need. This response rate was deemed “highly active as a single agent” by presenting author 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, Houston.

“Our results suggest that this oral targeted therapeutic has significant activity against relapsed or refractory marginal zone lymphoma and offers hope for patients,” Dr. Fowler told listeners.

About the Disease and Drug

MARGINAL ZONE lymphoma is an indolent B-cell lymphoma that comprises about 10% of all non-Hodgkin lymphomas. There are three subtypes: splenic, nodal, and extranodal. Response rates for front-line CD20-directed therapy are high, but most patients will relapse and require salvage therapy. Therapeutic options are limited for patients whose disease progresses on CD20-based therapy, as well as for those who are poor candidates for chemotherapy-based regimens.

Umbralisib joins other PI3K pathway inhibitors such as idelalisib and duvelisib, but the investigational drug has a unique mechanism of action in that it is selective to the PI3K-delta isoform. Thus, it is associated with low rates of immune-related toxicity, according to longer-term experience in more than 1,000 patients, Dr. Fowler noted. The dose of umbralisib selected for phase II and III trials is 800 mg/d given orally.

At the AACR meeting, Dr. Fowler presented an interim analysis of phase IIb data for a cohort of 42 evaluable patients with marginal zone lymphoma who were treated with umbralisib until disease progression in the UNITY-NHL trial, in which several cohorts of patients were treated with umbralisib as monotherapy and in combination with chemotherapy. Based on these data, in January 2019, the U.S. Food and Drug Administration granted umbralisib Breakthrough Therapy designation for the treatment of adults with marginal zone lymphoma who have received at least one anti-CD20 treatment.

“Single-agent umbralisib was active across all subtypes of marginal zone lymphoma.”
— Nathan H. Fowler, MD

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Study Details

THE COHORT included 72 patients with marginal zone lymphoma enrolled between July 2017 and August 2018, 42 of whom were evaluable with 9 months of follow-up and are the focus of this report. All patients had relapsed or refractory disease after one or more lines of at least one CD20-directed therapy. The primary endpoint was overall response rate by independent review.

At baseline, the 3 subtypes of marginal zone lymphoma were represented in the interim efficacy population, with extranodal disease present in 55%, nodal disease in 29%, and splenic disease in 1%. The median age was 67 years, and 60% of patients were female. The median number of prior therapies was 2 (range = 1–6); 93% of patients had received rituximab or rituximab-based chemotherapy. Other therapies included radiation (7%), stem cell transplant (2%), lenalidomide (5%), and ibrutinib (5%). About 19% were refractory to the most recent therapy, and 15% were refractory to prior anti-CD20 therapy.

Safety and Efficacy

ADVERSE EVENTS of all grades reported in umbralisib-treated patients primarily included diarrhea, nausea, fatigue, elevated liver enzymes, headache, cough, and decreased appetite. No grade 5 events were reported and grade 4 events were rare. Colonoscopies were not mandated in this trial but no evidence of colitis was observed.

“With the results reported so far, umbralisib has the potential to make a real difference for patients with relapsed or refractory marginal zone lymphoma.”
— Nathan H. Fowler, MD

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In the interim-efficacy population, the median duration of exposure to umbralisib was 10 months. At a median follow-up of 12.5 months, 55% of patients were still on study treatment. A total of 10 patients (24%) discontinued treatment due to disease progression, and 5 patients (12%) discontinued treatment due to an umbralisib-related adverse event.

“Single-agent umbralisib was active across all subtypes of marginal zone lymphoma,” Dr. Fowler noted. The best overall response rate according to both independent review and investigator assessment was 52%. Complete response rates were 19% and 12%, respectively; partial response rates were 33% and 40%, and stable disease rates were 36% and 31%. 

“The clinical benefit rate by independent review was 88%,” Dr. Fowler told the audience. “All patients in complete response remain on study.”


  • Umbralisib is a more potent, selective, investigational PI3K inhibitor than first-generation drugs in its class.
  • Phase II results in relapsed or refractory marginal zone lymphoma were encouraging.
  • The new agent will be studied further and is a potential new option that is active and safe in the treatment of all subtypes of relapsed/refractory marginal zone lymphoma.

By independent review, overall response rates were 53% for patients who had received prior chemoimmunotherapy and 38% for patients whose disease was refractory to their last line of chemotherapy. The median time to initial response was 2.7 months. As illustrated by a waterfall plot, 86% of all patients had a reduction in tumor burden from baseline. “Several patients had tumor shrinkage that did not meet the full criteria for response,” Dr. Fowler noted.

The median duration of response and median progression-free survival had not been reached at the time of data cutoff. Patients will continue to be followed for mature overall response, duration of response, and toxicity.

“The adverse event and clinical activity data are highly encouraging at this early time point. 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 or refractory marginal zone lymphoma. We are planning phase III trials in marginal zone lymphoma and other indolent non-Hodgkin lymphoma subtypes,” Dr. Fowler said.

DISCLOSURE: The UNITY-NHL study was funded by TG Therapeutics. Dr. Fowler is on the scientific advisory boards of TG Therapeutics, Bayer, Gilead Sciences, and Verastem Oncology and has received research funding from TG Therapeutics.


1. Fowler NH, Samaniego F, Jurczak W, et al: Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open-label, registration-directed phase II study. 2019 AACR Annual Meeting. Abstract CT132. Presented April 1, 2019.

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