FDA Schedules ODAC Meeting for Ublituximab/Umbralisib Combo in CLL/SLL

FDA

The FDA has scheduled a meeting of the Oncologic Drugs Advisory Committee (ODAC) to review the pending biologics license application (BLA)/supplemental new drug application (sNDA) for the combination of ublituximab and umbralisib (Ukoniq; U2) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

Discussion topics slated to appear during the meeting, which is expected to take place in March or April 2022, will include:

• The benefit-risk of the U2 combination in the treatment of CLL or SLL,
• The benefit-risk of Ukoniq in relapsed/refractory marginal zone lymphoma (MZL) or follicular lymphoma (FL),
• As part of the benefit-risk analysis, the overall safety profile of the U2 regimen, including serious and grade 3/4 adverse effects (AEs), discontinuations due to AEs, and dose modifications.

TG Therapeutics noted in a press release that the agency's concerns appear to originate from an early analysis of overall survival from the phase 3 UNITY-CLL trial (NCT026112311), of which the applications are based on.

“We appreciate the FDA’s efforts in reviewing the U2 BLA/sNDA and its interest in obtaining the perspective of the ODAC regarding the benefit-risk of Ukoniq and the U2 combination," Michael S. Weiss, chairman and chief executive officer of TG Therapeutics, the developer of both agents, stated in a press release. "We believe Ukoniq is a unique PI3K inhibitor, with a differentiated toxicity and tolerability profile and believe the data submitted thus far are supportive of approval of U2 in CLL.”

The FDA was initially expected to make a decision on the applications by March 25, 2022. However, the company added that given the March or April 2022 timeline of the ODAC meeting, it is unlikely that the FDA will make a decision on the BLA/sNDA by the Prescription Drug User Fee Act goal date of March 25, 2022.

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

Patients were randomized into 1 of the following 4 arms: single-agent ublituximab, single-agent umbralisib, 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 study 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; 57% of these patients were treatment naïve; 43% had relapsed/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 was progression-free survival (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.

Data showed that the ublituximab/umbralisib significantly improved PFS over obinutuzumab 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.

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.

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).

Further findings that were during the 2020 ASH Annual Meeting showed that ublituximab/umbralisib elicited an ORR of 83.3% (n = 210) compared with 68.7% (n = 211) with obinutuzumab/chlorambucil (P <.001).⁴ 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.

Regarding safety, grade 3/4 AEs 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 AEs vs those in the obinutuzumab/chlorambucil arm (n = 35 vs 16, respectively).

“We look forward to the ODAC meeting as we believe it will provide us an opportunity to highlight the important role U2 can play in the treatment of CLL," Weiss concluded. "As we have noted previously, while many patients with CLL are well-served with currently available therapies, there exists an underserved population, which for a variety of reasons, including tolerability concerns, access issues, and treatment failure, would benefit from an alternative treatment option.”

References

1. TG Therapeutics Provides Regulatory Update. TG Therapeutics. News release. November 30, 2021. Published November 30, 2021. https://bit.ly/3d6biPa
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