Umbralisib Receives Breakthrough Designation from FDA for Marginal Zone Lymphoma

Umbralisib was granted a breakthrough therapy designation by the FDA for the treatment of adult patients with marginal zone lymphoma who have received 1 prior anti-CD20 regimen.

Michael S. Weiss

Umbralisib (TGR-1202) was granted a breakthrough therapy designation by the FDA for the treatment of adult patients with marginal zone lymphoma (MZL) who have received 1 prior anti-CD20 regimen.

The designation, announced by TG Therapeutics, Inc., the developer of the PI3K-delta inhibitor, is based on interim data from a cohort of the ongoing, registration-directed phase II UNITY-NHL trial that is evaluating umbralisib monotherapy in patients with MZL.

“We look forward to working closely with the FDA to bring umbralisib, our novel PI3K-delta inhibitor, to patients as quickly as possible. MZL patients who fail initial chemoimmunotherapy are left with limited treatment options,” said Michael S. Weiss, executive chairman and chief executive officer, TG Therapeutics, in a press release. “We believe umbralisib can play an important role in fulfilling this unmet medical need. The MZL single agent umbralisib cohort of the UNITY-NHL study is fully enrolled and we look forward to reporting topline results from this cohort by mid-year and presenting the data at a major medical meeting in 2019.”

The phase IIb UNITY-NHL clinical trial (NCT02793583) is investigating umbralisib as monotherapy or as part of a doublet or a triplet in patients across a number of relapsed/refractory NHL subtypes. The doublet includes the CD20-targeted monoclonal antibody ublituximab (TG-1101), and the triplet includes ublituximab and bendamustine.

The UNITY-NHL study is enrolling patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), and MZL. Umbralisib is being tested as monotherapy in FL, SLL, and MZL, while the DLBCL subtype is being treated with doublet or triplet therapy. Each lymphoma subtype has its own eligibility criteria.

The annual incidence of MCL is approximately 7500 newly diagnosed patients, and is the third most common B-cell NHL, accounting for approximately 8% of all NHL cases. Additionally, there are 3 subtypes of MZL: extranodal MZL of the mucosal-associated lymphoid tissue, nodal marginal zone lymphoma, and splenic marginal zone lymphoma.

Phase I/II data on umbralisib in combination with ublituximab and pembrolizumab (Keytruda) were recently presented at the 2018 ASH Annual Meeting, which showed that the triplet elicited a 90% response rate in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and a 50% response rate in patients with Richter’s transformation (RT).2

At a median follow-up of 15.6 months, the median progression-free survival (PFS) had not yet been reached for patients with CLL (95% CI, 5.4—not reached). The 12-months PFS rate was 89%.

Among all 15 patients across the trial, there was 1 dose-limiting toxicity of transient elevated liver function test (LFT) that resolved at the 200-mg pembrolizumab dose in a patient with CLL. The maximum-tolerated dose for the 3+3 study design had not been reached.

The most common grade 3/4 adverse events included neutropenia (n = 5), thrombocytopenia (n = 2), fatigue (n = 1), anemia (n = 1), and nausea (n = 1). Grade 3/4 LFT elevations occurred in 3 patients. There were no cases of grade 3/4 diarrhea and no events of colitis. There were no cases of grade 3/4 pembrolizumab-associated autoimmune events.

Single-agent activity with umbralisib has been reported in relapsed/refractory CLL as well. In a phase II study presented at the 2018 European Hematology Association Congress, umbralisib showed promising safety results and induced durable responses in high-risk patients with relapsed/refractory disease.3At a median follow-up of 9.5 months, the median PFS and overall survival were not reached.

All patients (N = 50) in the multicenter study had discontinued treatment with a BTK or PI3K inhibitor. These data include 47 patients evaluable for safety and 46 evaluable for the primary endpoint of PFS.

Durable responses were observed despite patients’ high-risk status. As of the data cutoff, 47% of patients had been on umbralisib longer than they had received their prior kinase inhibitor. The median time on prior treatment was 9 months (range, 1-38).

Regarding safety, the most common grade 3/4 adverse event (n = 16) was neutropenia (15%), followed thrombocytopenia (9%), diarrhea (6%), anemia (2%), and pyrexia (2%).


  1. TG Therapeutics Receives Breakthrough Therapy Designation from the U.S. Food and Drug Administration for Umbralisib for the Treatment of Marginal Zone Lymphoma. TG Therapeutics. Published January 22, 2019." . Accessed January 22, 2019.
  2. Mato AR, Svoboda J, Luning Prak ET, et al. Phase I/II Study of umbralisib (TGR-1202) in combination with ublituximab (TG-1101) and pembrolizumab in patients with relapsed/refractory CLL and Richter’s Transformation. In: Proceedings from the 2018 ASH Annual Meeting; December 4-8, 2018; San Diego, CA. Abstract 297.
  3. Mato AR, Schuster SJ, Lamanna N, et al. A phase 2 study to assess the safety and efficacy of umbralisib (TGR-1202) in patients with chronic lymphocytic leukemia (CLL) who are intolerant to prior BTK or PI3K delta inhibitor therapy. In: Proceedings from the 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S808.