FDA Approval Sought for Ublituximab/Umbralisib Combo in CLL

A rolling submission of a biologics license application (BLA) to the FDA has been initiated for the CD20-directed monoclonal antibody ublituximab in combination with the PI3K-delta and CK1-epsilon inhibitor umbralisib (U2 regimen) for the treatment of patients with chronic lymphocytic leukemia (CLL).¹

“The initiation of a BLA submission for ublituximab in combination with umbralisib is an important milestone for us, and one that brings us one step closer to our goal of developing combination therapies for patients in need,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, stated in a press release.

“This application, as well as the recently granted fast track designation, is supported by the UNITY-CLL phase 3 trial which met its primary end point of improvement in progression-free survival [PFS] compared with obinutuzumab [Gazyva] plus chlorambucil and will be presented in an oral presentation at the 2020 ASH Annual Meeting beginning this weekend,” Weiss added.

Positive topline results from UNITY-CLL (NCT02612311) showed that the doublet resulted in a statistically significant improvement in PFS (P <.0001) when compared with obinutuzumab/chlorambucil in treatment-naïve patients with relapsed or refractory disease.² Based on these data, an independent review panel recommended to stop the trial early.

In the phase 3 trial, patients with both untreated and relapsed or refractory CLL were randomized to 1 of 4 arms: single-agent ublituximab, single-agent umbralisib, the U2 combination, or obinutuzumab plus chlorambucil. Discontinuation of the 2 single-agent arms was permitted if the U2 combination yielded positive data. If this proved to be true, randomization continued with either the U2 combination or obinutuzumab/chlorambucil.

A total of 420 patients were enrolled to the trial and were randomized to either U2 or obinutuzumab/chlorambucil; the majority, or 60%, of these patients were treatment naïve, while 40% had relapsed or refractory disease. The primary end point of the trial was PFS.

Prior to this trial, several novel combinations comprised of umbralisib and/or ublituximab have demonstrated encouraging data in CLL. Specifically, the triplet regimen of pembrolizumab (Keytruda) and the U2 doublet elicited an objective response rate of 90% in patients with relapsed/refractory CLL.³ Results from the phase 1/2 trial demonstrated that 9 of 10 patients who received the regimen responded to it; this included 1 complete response (CR) and 8 partial responses.

Additionally, data from a phase 1/2 dose-escalation study showed that the U2 doublet plus venetoclax (Venclexta) resulted in a CR rate of 44% when used in patients with chronic, relapsed or refractory CLL.⁴ Following 12 treatment cycles of the triplet, the ORR was reported to be 100%; this included a 44% CR rate.

When investigators assessed peripheral blood, 100% of patients had minimal residual disease (MRD) negativity. When looking at the bone marrow, 78% had MRD negativity (< .01%), while 22% were determined to be MRD intermediate (.01% to 1.0%). Notably, no patients experienced disease progression at a median follow-up of 6.4 months.

Another combination comprised of ibrutinib (Imbruvica) and ublituximab resulted in a PFS improvement per an independent review committee (IRC) versus ibrutinib monotherapy in patients with relapsed or refractory CLL who were determined to have high-risk disease, according to results from the phase 3 GENUINE trial (NCT02301156).5 Additionally, the doublet elicited an ORR of 78% versus 45% with single-agent ibrutinib; the CR rates were 7% and 0%, respectively.

With regard to MRD status, 19% of patients who received the ublituximab doublet achieved MRD negativity versus 2% of those on single-agent ibrutinib. Moreover, more than half, or 66%, of patients experienced more than a 75% reduction in lymph node size with the doublet versus 52% with the monotherapy.

“I want to thank the patients, caregivers, and research teams who participated in our clinical trials and helped to advance the U2 combination to this stage,” added Weiss in the release. “We believe, if approved, U2 has the potential to become an important treatment option to both [patients with] frontline and relapsed/refractory CLL.”

In August 2020, the FDA granted a priority review designation to a new drug application (NDA) for umbralisib for the treatment of patients with previously untreated marginal zone lymphoma (MZL) who received at least 1 prior anti-CD20–based therapy. The regulatory agency also accepted an NDA for the use of the agent in patients with follicular lymphoma who have received at least 2 previous systemic therapies.

The application was primarily based on data from the umbralisib monotherapy MZL and follicular lymphoma cohorts of the phase 2b UNITY-NHL trial (NCT02793583). Both cohorts met the primary end point of ORR, as confirmed by an IRC.⁶ The FDA is anticipated to make a decision on the MZL indication by February 15, 2021 and on June 15, 2021 for the follicular lymphoma indication.

References

1. TG Therapeutics initiates rolling submission of biologics license application to US Food and Drug Administration for ublituximab in combination with umbralisib as a treatment for patients with chronic lymphocytic leukemia. News release. TG Therapeutics, Inc. December 1, 2020. Accessed December 1, 2020. https://bit.ly/3muaDKm.
2. 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. TG Therapeutics, Inc. May 5, 2020. Accessed December 1, 2020. https://bit.ly/3fq9Ire.
3. 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. Blood. 2018;132(suppl 1):297. doi:10.1182/blood-2018-99-117526
4. A phase 1/2 study of umbralisib ublituximab and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):360. doi:10.1182/blood-2019-123404
5. Sharman JP, Brander DM, Mato AR, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: results of the GENUINE phase 3 study. J Clin Oncol. 2017;35 (suppl 15):7504. doi:10.1200/JCO.2017.35.15_suppl.7504
6. 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. TG Therapeutics, Inc. August 13, 2020. Accessed December 1, 2020. https://bit.ly/2PMpbXj.