FDA Accepts BLA for Ublituximab/Umbralisib in CLL and SLL

FDA

The FDA has accepted a biologics license application (BLA) for ublituximab in combination with umbralisib (Ukoniq) in the treatment of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), according to an announcement from TG Therapeutics, Inc.¹

The application was based on data from the phase 3 UNITY-CLL trial (NCT026112311), which showed that the ublituximab/umbralisib significantly improved progression-free survival (PFS) over obinutuzumab (Gazyva) plus chlorambucil in patients with CLL.^2,3

The median PFS in the investigative arm was 31.9 months (95% CI, 28.2-35.8) vs 17.9 months (95% CI, 16.1-22.6) in the control arm (HR, 0.546; 95% CI, 0.413-0.720; P <.0001). The PFS rate at 24 months with the ublituximab/umbralisib was 60.8% vs 40.4% with obinutuzumab/chlorambucil.²

Among a subgroup of patients who were treatment naïve, the median PFS in the investigative and control arms was 38.5 months (95% CI, 33.2–not evaluable) vs 26.1 months (95% CI, 19.4-33.1), respectively (HR, 0.482; 95% CI, 0.316-0.736; P <.001). The 24-month PFS rates in these arms were 76.6% and 52.1%, respectively.²

In a patient subset comprised of those who had previously received a median of 2 therapies (range, 1-9), the median PFS was also improved with ublituximab/umbralisib over obinutuzumab/chlorambucil, at 19.5 months and 12.9 months, respectively (HR, 0.601; 95% CI, 0.415-0.869; P <.01).

The FDA is slated to make a decision on the application by March 25, 2022, under the Prescription Drug User Fee Act.

“We are extremely pleased that ublituximab BLA has been accepted by the FDA,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, stated in a press release. “This is an important milestone for us as it brings us one step closer to our goal of providing a novel combination treatment option to patients with both treatment naïve and relapsed or refractory CLL or SLL. We look forward to collaborating with the FDA throughout this review process.”

In the phase 3 trial, investigators set out to compare ublituximab/umbralisib with the active control regimen of obinutuzumab/chlorambucil in patients with treatment-naïve or relapsed/refractory CLL.

In the trial, participants were randomized into 1 of the following 4 arms: ublituximab monotherapy, umbralisib monotherapy, ublituximab plus umbralisib, or obinutuzumab plus chlorambucil. For the prespecified interim analysis, investigators evaluated the contribution of ublituximab/umbralisib in the combination arm and permitted the termination of the monotherapy arms. The trial then continued enrollment in a 1:1 ratio to 2 combination arms: ublituximab/umbralisib and obinutuzumab/chlorambucil.

A total of 421 patients were included in the primary analysis of the trial; 57% of these patients were treatment naïve, while 43% had relapsed or refractory disease. Patients on the investigative arm received oral umbralisib at a once-daily dose of 800 mg until either progressive disease or treatment discontinuation. Ublituximab was administered intravenously (IV) at a dose of 150 mg on day 1, followed by 750 mg on day 2, and 900 mg on days 8 and 15 of cycle 1; day 1 of cycles 2 to 6, and on day 1 every 3 cycles following cycle 6.

In the control arm, IV obinutuzumab was delivered at a dose of 1000 mg on days 1 and 2 (100 mg on day 1 followed by 900 mg on day 2), 8, and 15 of cycle 1; and day 1 of cycles 2 to 6. Oral chlorambucil was given at a dose of 0.5 mg/kg on days 1 and 15 of cycles 1 to 6. Each treatment cycle was 28 days.

The primary end point of the trial was PFS per independent review committee (IRC), and secondary end points included overall response rate (ORR) per IRC, complete response (CR), and safety evaluated from the first dose of treatment up until 30 days after the last dose.

Additional data presented during the 2020 ASH Annual Meeting demonstrated the ublituximab/umbralisib induced an ORR of 83.3% (n = 210) compared with 68.7% (n = 211) with obinutuzumab/chlorambucil (P <.001). Among responders in the ublituximab/umbralisib arm, 5% experienced a CR or CR with incomplete marrow recovery; 79% of patients in this arm experienced a partial response (PR) to treatment. In the obinutuzumab/chlorambucil arm, 1% achieved a CR, while 67% had a PR.

A stratified analysis revealed that the ORR in the subset of patients who were treatment naïve was slightly higher than those who received previous treatment, at 84% and 82%, respectively. In a subset of patients who had prior BTK inhibition, the ORR with ublituximab/umbralisib was 57%. In the obinutuzumab/chlorambucil arms, these rates were 78%, 57%, and 25%, respectively.

Grade 3 or 4 adverse effects of clinical interest in the investigative and control arms included elevated alanine aminotransferase (8.3% vs 1.0%, respectively), elevated aspartate aminotransferase (5.3% vs 2.0%), noninfectious colitis (1.9% vs 0%), infectious colitis (0.5% vs 0.5%), pneumonitis (0.5% vs 0%), rash (2.4% vs 0.5%), and opportunistic infections (5.8% vs 1.5%). More patients in the ublituximab/umbralisib arm discontinued treatment due to toxicities vs those in the obinutuzumab/chlorambucil arm (n = 35 vs 16, respectively).

Previously, in October 2020, the FDA granted a fast track designation to ublituximab/umbralisib for the treatment of patients with CLL. Time-limited ublituximab/umbralisib is also under examination in combination with venetoclax (Venclexta) vs continuous ublituximab/umbralisib in patients with newly diagnosed or relapsed/refractory CLL, as part of the phase 3 ULTRA-V trial (NCT03801525).

References

1. TG Therapeutics announces FDA acceptance of biologics license application of ublituximab in combination with UKONIQ (umbralisib) as a treatment for patients with chronic lymphocytic leukemia and small lymphocytic leukemia. News release. TG Therapeutics, Inc. May 25, 2021. Accessed May 25, 2021. https://bit.ly/3yOj3mG
2. Gribben JG, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL Study. Blood. 2020;136(suppl 1):37-39. doi:10.1182/blood-2020-134783
3. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019;134(21):1811-1820. doi:10.1182/blood.2019002118