U2 Regimen Improves PFS in Previously Treated and Relapsed/Refractory CLL Cohorts

The combination of umbralisib (TGR-1202), a PI3K delta inhibitor plus ublituximab (TGTX-1101; U2), a glycoengineered anti-CD20 monoclonal antibody, improved progression-free survival (PFS) compared with obinutuzumab (Gazyva) plus chlorambucil in patients with chronic lymphocytic leukemia (CLL) achieving the primary end point of the global phase III UNITY-CLL trial, announced TG Therapeutics, Inc.¹

Both patients with CLL who were previously untreated and those with relapsed/refractory disease achieved PFS benefit, according to the topline results. The company is planning for a regulatory submission of the combination by the end of 2020 and expects to present the full data at an upcoming medical meeting this year.

"It’s extremely gratifying to see positive results for this important trial exploring the combination of umbralisib and ublituximab in patients with both front-line and relapsed/refractory CLL. Today’s outcome marks the first successful Phase 3 trial of a PI3K delta-based regimen in a CLL patient population that included previously untreated patients,” John Gribben, MD, DSc, professor, Medical Oncology, Barts Cancer Institute and global study chair for the UNITY-CLL study, said in a statement.

The improvement in PFS, which was assessed by an Independent Review Committee, was statistically significant (P <.0001). The study has been stopped early for superior efficacy.

The interim analysis was conducted by an independent data safety monitoring board, who made the recommendation to stop the study early following the positive data.

“Interestingly, this marks the first time a PI3K delta-based regimen has successfully met its primary end point in a CLL phase III study that included previously untreated patients. We believe this speaks to the differentiation of umbralisib,” said Michael S. Weiss, executive chairman and chief executive officer, TG Therapeutics, during a webcast.²

UNITY-CLL is a randomized, controlled study comparing the U2 combination to obinutuzumab plus chlorambucil in patients with either treatment-naïve or relapsed/refractory CLL. Patients were randomized to 1 of 4 therapy arms, including ublituximab alone, umbralisib alone, U2, or the control arm of anti-CD220 monoclonal antibody obinutuzumab plus chlorambucil chemotherapy. However, a prespecified analysis determined that the single-agent cohorts could be terminated, so patients were randomized 1:1 to either U2 or the control.¹

Enrollment for the study was completed in October 2017, and approximately 420 patients enrolled in the 2 cohorts of the study. Overall, 60% of patients were treatment-naïve and 40% had relapsed/refractory disease. The primary end point is superior PFS, and the secondary end point is overall response rate (ORR).

The U2 regimen is currently being evaluated in combination with venetoclax (Venclexta) as treatment of patients with relapsed/refractory CLL in a phase I/II clinical trial. At the 2019 American Society of Hematology Annual Meeting, study findings indicated that the triplet regimen induced a complete response rate of 44% in this patient population, and the objective response rate at the end of 12 cycles of treatment was 100%.

In March 2020, umbralisib also received an Orphan Drug Designation for the treatment of patients with follicular lymphoma, based on data from the phase IIb UNITY-NHL clinical trial. TG Therapeutics announced that the trial had met its primary end point of ORR. All patients achieved an ORR in the target range of 40% to 50% with U2 treatment.

Investigators hope to publish these interim results soon, according to a webcast from TG Therapeutics.² A safety analysis will be conducted in the future as well.

“CLL remains incurable and new treatment options are still very much needed, particularly those that provide a differentiated mechanism and safety profile from our currently available treatment options,” Gribben concluded.¹

_Reference

1. _{TG Therapeutics Announces Positive Topline Results from the UNITY-CLL Phase 3 Study Evaluating the Combination of Umbralisib and Ublituximab (U2) for the Treatment of Patients with Chronic Lymphocytic Leukemia [news release]. New York, NY: TG Therapeutics; May 5, 2020. https://bit.ly/3b1DnUh. Accessed May 5, 2020.}
2. _{Weiss M. TG Therapeutics Update Conference Call & Webcast. TG Therapeutics website. https://bit.ly/2L3DkwJ. Accessed May 5, 2020.}