Umbralisib-ublituximab combination extends PFS in CLL
The combination of umbralisib and ublituximab significantly improved PFS compared with chemoimmunotherapy for patients with chronic lymphocytic leukemia, according to study results presented at the virtual ASH Annual Meeting and Exposition.
The regimen appeared effective for both untreated patients and those with relapsed or refractory disease, results of the randomized phase 3 UNITY-CLL trial showed.
“The findings from the phase 3 UNITY-CLL trial are very promising, particularly for those patients who are CLL treatment naive,” researcher John G. Gribben, MD, DSc, FRCP, FMedSci, FRCPath, professor of medical oncology at Barts Cancer Institute in London, told Healio. “The combination of umbralisib and ublituximab exhibited a well-tolerated safety profile.”
Umbralisib (TGR-1202, TG Therapeutics) is a dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-delta and casein kinase-1-epsilon. Ublituximab (TG-1101, TG Therapeutics) is a glycoengineered monoclonal antibody that targets a specific epitope on the CD20 antigen found on mature B lymphocytes.
The combination, referred to as U2, has demonstrated promising activity and good tolerability among heavily pretreated patients with CLL. In October, the FDA granted fast track designation to the combination for treatment of adults with CLL.
Gribben and colleagues conducted the multicenter UNITY-CLL trial to evaluate the combination vs. a standard chemoimmunotherapy regimen of obinutuzumab (Gazyva, Genentech/Roche) and chlorambucil for patients with treatment-naive and relapsed/refractory CLL.
The analysis included 421 adults (median age, 67 years; range, 36-91; 66% men) who required treatment per International Workshop on Chronic Lymphocytic Leukemia criteria. All patients had adequate organ function and ECOG performance status of 2 or less.
More than half (57%) of patients were treatment naive; 43% had relapsed or refractory disease and had received a median one prior treatment.
Ten percent of patients had 17p deletion, 20% had 11q deletion, and 56% had no IGHV mutations.
Researchers randomly assigned patients to U2 (n = 210) or obinutuzumab and chlorambucil (n = 211) administered in 28-day cycles.
Those assigned U2 received oral umbralisib dosed at 800 mg once daily until disease progression or removal from treatment, plus ublituximab dosed at 900 mg IV on days 1 to 2 (split dosing of 150 mg on day 1 and 750 mg on day 2), 8 and 15 of the first cycle, day 1 of the second through sixth cycles, and on day 1 every three cycles thereafter.
Those assigned standard chemotherapy received obinutuzumab via IV dosed at 1,000 mg on days 1 to 2 (split dosing of 100 mg on day 1 and 900 mg of day 2), 8 and 15 of the first cycle and day 1 of the second through sixth cycles, plus oral chlorambucil dosed at 0.5 mg/kg on day 1 and day 15 of the first six cycles.
PFS as assessed by independent review committee served as the primary endpoint.
Key secondary endpoints included overall response rate, complete response, undetectable minimal residual disease, duration of response and safety, assessed between the first dose and 30 days after the last dose of study medication in each treatment group.
Median follow-up was 36.2 months.
Patients assigned U2 achieved significantly longer PFS (median, 31.9 months vs. 17.9 months; HR = 0.54; 95% CI, 0.41-0.72). A higher estimated percentage of patents assigned the experimental regimen remained progression free at 24 months (60.8% vs. 40.4%).
The PFS benefit with U2 appeared consistent across subgroups, including those who were treatment naive (median, 38.5 months vs. 26.1 months; HR = 0.48; 95% CI, 0.31-0.73) and those with relapsed or refractory disease (median, 19.5 months vs. 12.9 months; HR = 0.6; 95% CI, 0.41-0.86).
“Importantly for the treatment-naive population, there are a number of censored events above the median in the U2 arm, suggesting that perhaps with longer follow-up we may see a further prolongation of the PFS outcome for the patients on the U2 regimen,” Gribben told Healio. “The censored events for the obinutuzumab-chlorambucil arm are already below the median.”
Independent review committee assessment showed a higher ORR with U2 (83.3% vs. 68.7%; P < .001).
The analysis included 26 patients (6%) who received prior ibrutinib (Imbruvica; Janssen, Pharmacyclics). Of these, 14 were assigned U2 and 12 were assigned obinutuzumab-chlorambucil. In this subgroup, results showed a higher ORR with U2 than obinutuzumab-chlorambucil (57% vs. 25%).
Investigators continue to analyze minimal residual disease data.
Median treatment duration was 23 months (range, 0.1-49) for the U2 group and 5 months (range, 0.1-7) for the obinutuzumab-chlorambucil group.
Patients assigned U2 appeared more likely to develop grade 3 or grade 4 diarrhea (12.1% vs. 2.5%), elevated alanine transaminase or aspartate transaminase levels (8.3% vs. 2%), colitis (3.4% vs. 0%) or pneumonitis (2.9% vs. 0%).
Patients assigned standard chemoimmunotherapy appeared more likely to develop grade 3 or grade 4 neutropenia (34.7% vs. 30.6%), thrombocytopenia (13.1% vs. 3.4%) or infusion-related reactions (3.5% vs. 1.9%).
A higher percentage of patients assigned U2 discontinued treatment due to adverse events (16.5% vs. 7.6%).
“The number of patients with at least one adverse event [was] comparable between the two arms,” Gribben said. “The number of grade 3 or higher adverse events [was] higher in the U2 [group] but, of course, remembering the more than fourfold longer exposure of U2.”
Results of UNITY-CLL support TG Therapeutics’ rolling biologics license application submission to the FDA, Gribben said.
“This trial represents the first successful randomized trial of a PI3K inhibitor in treatment-naive CLL, a setting where previous PI3K inhibitors have not been able to be safely administered,” Gribben told Healio. “If approved, U2 would be a welcome addition to the treatment options currently available for [patients with CLL].”
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Gribben JG. Abstract 543. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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