The combination of 2 novel agents—umbralisib and ublituximab (U2)—represents a promising new treatment option for patients with chronic lymphocytic leukemia (CLL). In the phase 3 multicenter clinical trial UNITY-CLL, the median progression-free survival (PFS) was significantly longer with U2 than with standard-of-care chemoimmunotherapy, reported John G. Gribben, MD, DSc, FRCP, Centre Lead, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, England, at ASH 2020.
“UNITY-CLL is the first randomized trial of a PI3K delta inhibitor, umbralisib, in treatment-naïve CLL, establishing a new mechanism of action in this treatment setting,” said Dr Gribben.
U2 is a combination regimen of 2 novel nonchemotherapy agents:
Umbralisib is an oral, once-daily, novel dual inhibitor of PI3Kδ and casein kinase 1ε with more than 1000-fold greater selectivity for PI3K delta compared with the alpha and beta isoform, and is more than 200-fold more selective for PI3K delta relative to the xxx isoform, resulting in lower rates of immune-mediated adverse events compared with older generations of PI3K delta inhibitors.
Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20.
Phase 3 UNITY-CLL Study
The phase 3 study UNITY-CLL included 421 patients with treatment-naïve or relapsed or refractory CLL who required treatment. The patients were randomized to the novel U2 regimen or to a chemoimmunotherapy regimen with obinutuzumab (Gazyva) plus chlorambucil.
At baseline, the median patients’ age was 68 years, 66% were male, and 57% were treatment-naïve. Among the 43% of patients with relapsed or refractory CLL, the median number of previous therapies was 1 in the chemoimmunotherapy arm and 2 in the U2 arm. Anti-CD20 antibody and chemoimmunotherapy were each used in more than 80% of patients in both arms. Features of high-risk CLL included 10% with deletion (del) 17p, 20% with del 11q, and 55% with no IGHV mutation.
With a median follow-up of 36.2 months, the median PFS by independent review committee was 31.9 months in the U2 arm versus 17.9 months in the chemoimmunotherapy arm (hazard ratio [HR], 0.546; P <.0001). The 24-month PFS rate was 60.8% and 40.4%, respectively. The PFS benefit was similar among most subgroups.
In the treatment-naïve population, median PFS was 38.5 months in the U2 arm versus 26.1 months with chemoimmunotherapy (HR, 0.482; P <.001). In the previously treated population, the U2 regimen also prolonged the median PFS versus chemoimmunotherapy: 19.5 months versus 12.9 months, respectively (HR, 0.601; P <.01).
The objective response rate (ORR) was 83.3% with the U2 regimen versus 68.7% with chemoimmunotherapy. The ORR advantage of U2 was apparent in the treatment-naïve group (84% vs 78%) and in the previously treated group (82% vs 57%).
Patients who had previously received a Bruton tyrosine kinase (BTK) inhibitor had lower response rates: the ORR was 57% in the U2 arm and 25% in the chemoimmunotherapy arm. The U2 regimen resulted in a disease control rate of 93%.
“U2 responses were durable, with 62% [of patients] maintaining response at 2 years,” said Dr Gribben.
“The U2 regimen is being explored as a backbone for triplet combinations, including combinations with venetoclax [Venclexta] and BTK inhibitors,” said Dr Gribben.
Continuous treatment with U2 resulted in a more than 4-fold longer exposure and adverse event reporting period compared with chemoimmunotherapy. The median treatment exposure was 21 months in the U2 group versus 5 months in the chemoimmunotherapy group.
Serious adverse events occurred in 46.1% of the U2 arm and 23.5% in the chemoimmunotherapy arm, and the rates of grade 3 or 4 adverse events were 82.0% and 66.0%, respectively.
The most common grade 3 or 4 adverse events with U2 treatment were neutropenia (31%) and diarrhea (12%).
Treatment discontinuation because of adverse events occurred among 16.5% of patients randomized to U2 and 7.6% assigned to chemoimmunotherapy. The most common PI3K-specific adverse events in the U2 group were elevations in liver enzymes.
Anticipated FDA Approval
The FDA granted a fast-track review and an orphan drug designation for the combination of umbralisib plus ublituximab for the treatment of CLL.
In addition, umbralisib monotherapy is scheduled for an FDA approval later this year for marginal-zone lymphoma and for follicular lymphoma.