FDA Grants Umbralisib Priority Review for Previously Treated MZL


The FDA has granted a priority review designation to a new drug application for umbralisib for the treatment of patients with previously treated marginal zone lymphoma who have received at least 1 prior anti-CD20–based treatment.

The FDA has granted a priority review designation to a new drug application (NDA) for umbralisib for the treatment of patients with previously treated marginal zone lymphoma (MZL) who have received at least 1 prior anti-CD20–based treatment.1 The agency also accepted an NDA for umbralisib as a treatment for patients with follicular lymphoma who have received at least 2 prior systemic therapies.

The application was primarily based on findings from the single-agent umbralisib MZL and follicular lymphoma cohorts of the phase 2B UNITY-NHL study, in which both cohorts met the primary endpoint of overall response rate (ORR), as confirmed by an Independent Review Committee (IRC).

Under the Prescription Drug User Fee Act, the FDA must make a decision on the MZL indication by February 15, 2021. The follicular lymphoma indication, which has been accepted for standard review, has an action date of June 15, 2021.

"We are extremely pleased with the FDA’s acceptance of our first NDA submission and look forward to working with the FDA during the review process,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, the developer of umbralisib, stated in a press release. “This is a significant achievement in our path towards accomplishing our goal of developing novel treatments for patients with B-cell diseases.”

In the multicenter, multi-cohort, phase 2b UNITY-NHL trial (UTX-TGR-205; NCT02742090), investigators evaluated umbralisib as a single agent or in various combination regimens in patients with previously treated non-Hodgkin lymphoma.

As of April 2019, enrollment on the MZL cohort was complete, with 72 patients enrolled between July 2017 and August 2018. Sixty-nine patients received umbralisib therapy, 42 of which had 9 months of follow-up; these patients comprised the data from the interim efficacy cohort presented during the 2019 AACR Annual Meeting.2

Patients were treated with 800 mg of umbralisib monotherapy daily until disease progression or unacceptable toxicity. To be eligible for enrollment, patients could have splenic, nodal, or extranodal MZL that required treatment; relapsed/refractory disease that progressed on 1 or more prior lines of therapy that included at least 1 CD20-directed regimen; and an ECOG performance status of 0 to 2.

In the interim efficacy population, 23 patients (55%) had extranodal disease, followed by 12 (29%) with nodal and 7 patients (17%) with splenic MZL; this was comparable with the safety population of all patients treated (n = 69). The median age in both cohorts was 67 (range, 34-81); there were more females in the interim efficacy (n = 25; 60%) and safety (n = 36; 52%) populations. The majority of patients in the interim efficacy group (n = 32; 76%) had received rituximab (Rituxan)-based chemoimmunotherapy compared with 50 (72%) in the safety population. Moreover, 8 patients (19%) in the interim efficacy cohort were refractory to their most recent therapy; in the safety population, 18 patients (26%) were refractory to their last treatment. Similarly, 6 (14%) and 15 patients (22%) were refractory to prior anti-CD20 therapy in the interim efficacy and safety populations, respectively.

The primary endpoint was ORR by IRC by 2007 International Working Group criteria; secondary endpoints included duration of response (DOR), progression-free survival (PFS), time to response, and safety.

At a median follow-up of 12.5 months (range, 8.3-18.5) in the interim efficacy population, the ORR was 52% as assessed by both IRC and investigator assessment. The complete response (CR) rates were 19% and 12%, and partial response rates were 33% and 40%, in the IRC- and investigator-assessed cohorts, respectively. The stable disease rates were 36% and 31%, respectively, and progressive disease rates were 7% and 10%. Additionally, the clinical benefit rate was 88% as determined by IRC assessment.

The median duration on treatment was 10.1 months (range, 5.6-15.7), and 55% of patients remain on therapy; this includes all patients who were in CR via IRC assessment.

When stratified by MZL subtype, the ORRs by IRC were 57%, 42%, and 43% for extranodal, nodal, and splenic disease, respectively. Moreover, for patients who had prior chemoimmunotherapy (n = 32), the ORR was 53% via IRC; the ORR was 38% in those who were refractory to their last line of therapy (n = 8).

The median time to initial response was 2.7 months, and 86% of patients (n = 36) experienced a reduction in tumor burden. The median DOR has not been reached (95% CI, 8.4—not estimable) and the median PFS has not been reached. The estimated 1-year PFS rate was 66%.

Ten patients (24%) discontinued therapy for disease progression, 5 (12%) for treatment-related adverse event (TRAE), 2 (5%) due to a non-TRAE, 1 (2%) withdrew consent, and 1 (2%) discontinued due to the investigator’s decision.

Umbralisib was found to be well tolerated in all treated patients, with the highest grade 3 or higher adverse effect (AE) being diarrhea (10%). Grade 3 infections—comprising bronchitis, pneumonia, and influenza—occurred in 3 patients.

The median duration of exposure to umbralisib was 6.9 months. AEs that led to dose reductions occurred in 6 patients (9%), and 10 patients (14%) discontinued umbralisib for AEs that were potentially treatment related. No deaths have occurred.

AEs of interest and long-term tolerability were also reported. For patients on study for more than 6 cycles, 41 patients were evaluable. The median age was 66 (range, 34-80) and the median number of prior therapies was 2 (range, 1-6). Beyond diarrhea (24%; grade 3/4, 5%), all-grade AEs of interest occurring following 6 cycles with the PI3K-delta inhibitor were alanine aminotransferase (ALT; 2%) and pneumonitis (2%; grade 3/4, 2%).

The elevated ALT and aspartate aminotransferase levels appeared time related, as all but 1 case occurred within the first 6 cycles of umbralisib treatment. However, grade 3/4 diarrhea occurred before and after the 6 cycles. There were no treatment discontinuations for treatment-related AEs after 6 months.

Follow-up is continuing for mature overall response, duration, and safety analysis, and phase 3 trials with umbralisib are planned in MZL as well as other subtypes of indolent NHL.

In October 2019, topline findings were announced from the follicular lymphoma cohort (n = 118) of the UNITY-NHL trial.3 Here, results reported thus far showed that umbralisib achieved the primary endpoint of a target ORR of 40% to 50% in the cohort, which was comprised of patients who had received 2 or more prior lines of treatment, including an alkylating agent and a CD20-targeting monoclonal antibody.

Previously, the FDA granted umbralisib a breakthrough therapy designation for MZL and an orphan drug designation for MZL and follicular lymphoma.

“If approved, we believe umbralisib could become an important treatment option for patients with previously treated MZL and follicular lymphoma,” Weiss concluded in the press release. “We look forward to presenting the data from the UNITY-NHL trial that supported this NDA submission by year end.”


  1. TG Therapeutics Announces FDA Acceptance of New Drug Application for Umbralisib as a Treatment for Patients with Previously Treated Marginal Zone Lymphoma and Follicular Lymphoma. News release. Published August 13, 2020. Accessed August 13, 2020. https://bit.ly/2PMpbXj.
  2. Fowler NH, Samaniego F, Jurczak , 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. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CT132.
  3. TG Therapeutics Announces Positive Results from the UNITY-NHL Phase 2b Pivotal Trial Evaluating Umbralisib Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma. Published October 28, 2019. Accessed October 29, 2019. https://bit.ly/32YHDAN.
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