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Umbralisib Plus Ublituximab Yields Longer PFS in Patients With TN, PT CLL
According to the phase 3 UNITY-CLL study, umbralisib plus ublituximab has a tolerable safety profile and prolonged progression free survival (PFS) compared to chemoimmunotherapy (CIT) in patients with both treatment naïve (TN) and previously treated (PT) chronic lymphocytic leukemia (CLL); these data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.
“This is the first randomized phase 3 trial of a PI3K in TN CLL, establishing a new mechanism of action in this setting,” explained Ryan Jacobs, MD, Department of Hematology, Lymphoma Division, Assistant Professor of Medicine, Levine Cancer Institute/Atrium Health, Charlotte, North Carolina, and co-investigators.
Umbralisib is a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, and is pharmacologically distinct from other PI3K inhibitors, said Dr Jacobs. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20.
Thus, Dr Jacobs et al presented results from the randomized, multicenter trial on patients treated with umbralisib plus ublituximab by treatment status.
In all, 210 patients with TN (n=119) or PT (n=91) CLL requiring treatment per iwCLL criteria, with adequate organ function, and an ECOG PS ≤2 were enrolled and randomized to receive umbralisib plus ublituximab, obinutuzumab plus chlorambucil, umbralisib monotherapy, or ublituximab monotherapy. Umbralisib was given orally at 800mg once a day until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900mg on days 1 and 2 (split 150/750mg), 8, and 15 of cycle 1; day 1 of cycles 2 through 6; and on day 1 of every 3 cycles after cycle 6.
Stratification factors included treatment status and deletion 17p status. The primary end point was independent review committee (IRC)-assesssed PFS of umbralisib plus ublituximab compared to obinutuzumab plus chlorambucil. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response (CR), undetectable minimal residual disease (uMRD), duration of response (DOR), and safety, assessed from the first dose until 30 days after the last dose.
As of the data cutoff of May 1, 2020, patients treated with umbralisib plus ublituximab had a median follow-up of 35.27 months. The median PFS for TN patients given umbralisib plus ublituximab was 38.5 months (95% CI, 33.2-NE), with an estimated 24-months PFS of 76.6 percent. The IRC-assessed ORR was 84 percent (95% CI, 77.5%-90.6%). The median duration of exposure to umbralisib and ublituximab was 26.5 and 29.5 months, respectively.
In TN patients, adverse events (AEs) of special interest of grade ≥3 included neutropenia (24.1%), diarrhea (13.8%), ALT increased (12.1%), AST increased (7.8%), non-infectious colitis (2.6%), infusion-related reaction (IRR, 0.9%), and pneumonitis (0.9%). Discontinuations of either drug due to grade ≥3 AEs of special interest occurred in 5.2 percent (neutropenia), 2.6 percent (diarrhea), 3.4 percent (ALT increase), 1.7 percent (AST increase), 1.7 percent (colitis), 0.9 percent (ORR), and 0.9 percent (pneumonitis) of patients.
For PT patients who had a median of 2 prior lines of therapy, the median PFS was 19.5 months (95% CI, 14.6-27.7) with an estimated 24-month PFS of 41.3 percent. The IRC-assessed ORR was 82.4 percent (95% CI, 74.6%-90.2%). Among 14 patients who were previously treated with ibrutinib, the ORR was 57 percent. The median duration of exposure to umbralisib and ublituximab was 15.6 months and 14.6 months, respectively.
In PT patients, AEs of special interest of grade ≥3 included neutropenia (40.0%), diarrhea (10%), IRR (3.3%), ALT increase (3.3%), AST increase (2.2%), and non-infectious colitis (2.2%). Discontinuation of either drug due to grade ≥3 AEs of special interest occurred in 1.1% (ALT increase), 1.1% (AST increase), and 1.1% (colitis) of patients.
“U2 demonstrated a tolerable safety profile in both the TN and PT populations. These results mark the first randomized Phase 3 trial of a PI3K in TN CLL, establishing a new mechanism of action in this setting,” concluded Dr Jacobs et al.—Emily Bader
Jacobs R, Jurczak W, Flinn I, et al. Efficacy and Safety of Ublituximab in Combination with Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia (CLL) By Treatment Status: A Sub-Analysis of the Phase 3 Unity-CLL Study. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 3726.
