On February 23, 2021 TG Therapeutics, Inc. (NASDAQ: TGTX) reported the publication of final results from the Phase 3 GENUINE trial evaluating ublituximab, the Company’s investigational glycoengineered anti-CD20 monoclonal antibody, in combination with ibrutinib, in patients with relapsed or refractory high-risk chronic lymphocytic leukemia (CLL), in The Lancet Haematology (Press release, TG Therapeutics, FEB 23, 2021, View Source [SID1234575477]).

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer stated, "The Phase 3 data published yesterday, and previously presented, demonstrated that the addition of ublituximab to ibrutinib significantly improved overall response rate, complete response rate as well as prolonged progression-free survival. Significant unmet need still exists within the CLL landscape, and patients with high-risk relapsed or refractory CLL progress more rapidly than those without high-risk cytogenetics. The outcome of the GENUINE study is therefore very encouraging, and we believe these data are supportive of pursuing combination strategies with ublituximab for high-risk CLL patients." Mr. Weiss continued, "We look forward to bringing ublituximab to market as soon as possible as we pursue completion of a BLA submission with the FDA in the first half of 2021 for the combination of ublituximab plus umbralisib for patients with CLL."

Jeff P. Sharman, MD, Director of Research at Willamette Valley Cancer Institute and Medical Director of Hematology Research for The US Oncology Network and Study Chair for the GENUINE trial stated, "The utility of adding anti-CD20 therapy in combination with BTK inhibitors, such as ibrutinib, has long been unclear with prior studies using rituximab having failed to demonstrate an improvement in long-term outcomes. These results published from the GENUINE study are encouraging and may suggest that next generation anti-CD20 antibodies could have value in combination approaches to treating CLL."

The manuscript includes data from 126 patients with relapsed or refractory high-risk CLL who were randomized on study, of which 117 received at least one dose of treatment and were included in safety analyses, with 59 receiving ublituximab plus ibrutinib and 58 receiving ibrutinib monotherapy. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles with up to 150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15 of cycle 1, and continuing at 900 mg on day 1 of cycles 2 through 6. Beyond cycle 6, ublituximab was given at 900 mg every 3 months. Ublituximab and ibrutinib were continued until unacceptable toxicity, disease progression, or withdrawn consent. The primary endpoint was independent review committee (IRC) assessed overall response rate (ORR) per iwCLL 2008 criteria. Key highlights from this manuscript include:

The IRC-assessed ORR among treated patients was 90% (53 of 59) in the ublituximab-ibrutinib arm and 69% (40 of 58) in the ibrutinib arm (p=0.0060), with a CR/CRi rate of 20% (12 of 59) and 5% (3 of 58), respectively (p=0.024).
After a median follow-up of 41.6 months, median IRC-assessed progression-free survival (PFS) in all treated patients was not reached in the ublituximab-ibrutinib group (95% CI, not estimable [NE]) after 15 PFS events and 35.9 months (95% CI, 17·0-NE) in the ibrutinib group after 25 PFS events (hazard ratio [HR], 0.46; 95% CI, 0.24-0.87).
The most common grade 3/4 adverse events in the ublituximab-ibrutinib group and the ibrutinib group were neutropenia (19%; 12%), anaemia (8%; 9%), and diarrhea (10%; 5%).
These data are described further in the manuscript entitled, "A Phase 3, Randomized Trial of Ublituximab Plus Ibrutinib for Patients With Relapsed/Refractory High-Risk Chronic Lymphocytic Leukaemia," which was published [online yesterday] in The Lancet Haematology. The online version of the article can be accessed at https://www.thelancet.com/journals/lanhae/home.