Umbralisib Hits Primary Endpoint in Follicular Lymphoma Subgroup of Pivotal Study

Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics

Michael S. Weiss

Umbralisib (TGR-1202) met the primary endpoint of overall response rate (ORR) in the follicular lymphoma cohort of the pivotal phase IIb UNITY-NHL trial, according to TG Therapeutics, Inc., the developer of the PI3K-delta inhibitor.¹

An Independent Review Committee (IRC) determined that umbralisib achieved the predetermined target ORR of 40% to 50% in the 118-patient follicular lymphoma cohort. All patients had received ≥2 prior lines of treatment, including an alkylating agent and a CD20-targeting monoclonal antibody.

TG Therapeutics reported in a press release that umbralisib was well tolerated, with no new safety signals emerging. The company plans to share the data at an upcoming medical meeting.

“We are extremely pleased to announce that the UNITY-NHL follicular lymphoma cohort evaluating umbralisib monotherapy met the primary endpoint of ORR. There are no fully approved drugs for patients with follicular lymphoma that have progressed following two or more prior lines of therapy and we are excited by the potential to offer a novel treatment for this underserved population. We look forward to sharing these results with the FDA and discussing submission opportunities for accelerated approval of umbralisib in follicular lymphoma," Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, said in the press release.

“These are very exciting times for TG and with two additional major events targeted to occur over the next several months, including commencing our first NDA filing for umbralisib in patients with relapsed/refractory marginal zone lymphoma and results from our UNITY-CLL phase III trial, we expect that excitement to continue,” Weiss added.

In the ongoing, open-label, multicenter, multicohort phase IIb UNITY-NHL trial (NCT02793583), investigators are evaluating umbralisib as a single agent or in various combination regimens in patients with previously treated non-Hodgkin Lymphoma (NHL). Specific NHL subtypes being evaluated include diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma (MZL). Patients are randomized to umbralisib alone, umbralisib plus ublituximab, or umbralisib plus ublituximab and bendamustine (Treanda).

Previous UNITY-NHL results presented at the 2019 AACR Annual Meeting showed that single-agent umbralisib had an ORR of 52% in patients with relapsed/refractory MZL.²

Seventy-two patients with MZL were enrolled between July 2017 and August 2018. Sixty-nine patients had received umbralisib therapy at the time of the data reporting, 42 of whom had 9 months of follow-up—these patients comprised the data from the interim efficacy cohort.

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 prior lines of therapy that included at least 1 CD20-directed regimen; and an ECOG performance status ≤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 determined by an IRC by 2007 International Working Group criteria; secondary endpoints included duration of response, progression-free survival, 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.

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.

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

In January 2019, the FDA granted umbralisib a breakthrough therapy designation for the treatment of adult patients with MZL who have received 1 prior anti-CD20 regimen, based on interim data from the UNITY-NHL cohort.

References

1. 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.
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.