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A chemotherapy-free investigational combination reduced the risk of disease progression or death versus chemoimmunotherapy with chlorambucil plus obinutuzumab (Gazyva) for patients with chronic lymphocytic leukemia (CLL), a phase III trial showed.

Among over 400 patients in UNITY-CLL, which involved both treatment-naive and relapsed/refractory disease, median progression-free survival (PFS) reached 31.9 months with umbralisib plus ublituximab versus 17.9 months with chlorambucil-obinutuzumab (HR 0.546, 95% CI 0.413-0.720, P<0.0001), reported John Gribben, MD, DSc, of the Barts Cancer Institute in London.

The PFS rate at 3 years was 60.8% with the so-called U2 combination compared to 40.4% with chemoimmunotherapy, according to findings presented at the American Society of Hematology virtual meeting.

In the treatment-naive setting, median PFS was 38.5 months with umbralisib-ublituximab versus 26.1 months with chlorambucil-obinutuzumab (HR 0.482, 95% CI 0.316-0.736, P<0.001), with 3-year rates of 76.6% and 52.1%, respectively.

"UNITY-CLL is the first randomized trial of a PI3K-delta inhibitor -- namely umbralisib -- in treatment-naive CLL, establishing a new mechanism of action in this treatment setting," said Gribben, adding that the benefit was irrespective of prior treatment status.

For the previously treated group, median PFS was 19.5 months with the U2 regimen compared to 12.9 months with chemoimmunotherapy (HR 0.601, 95% CI 0.415-0.869, P<0.01), with 3-year rates of 41.3% versus 24.8%, respectively.

Overall response rates were also significantly higher with U2 in the overall population (83.3% vs 68.7%; P<0.001) and across subgroups:

• Treatment-naive: 84% vs 78%
• Previously treated: 82% vs 57%
• Prior Bruton tyrosine kinase (BTK) inhibition: 57% vs 25%

Responses with U2 proved durable, with 62% of patients retaining their response at 2 years.

BTK and BCL2 inhibitors such as ibrutinib (Imbruvica) and venetoclax (Venclexta) have dramatically changed the CLL treatment landscape in recent years, but not all patients are ideal candidates for these drugs, Gribben explained.

While approved in later lines, earlier-generation PI3K-delta inhibitors in treatment-naive CLL have failed due to high rates of toxicity and treatment discontinuation, leading to early termination of trials.

Umbralisib is a novel, dual inhibitor of PI3K-delta and casein-kinase 1-epsilon (CK1-epsilon) that has demonstrated low rates of treatment toxicity and discontinuation. The drug has been shown to be well tolerated in heavily pretreated CLL in combination with ublituximab, a novel anti-CD20 monoclonal antibody.

Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, told 番茄社区app that the median PFS of 38.5 months with U2 in the upfront setting is perhaps not as high as would be expected with a BTK or BCL2 inhibitor, so the combination will likely be reserved for later lines.

"With the possible exception, I think, of older patients with significant cardiac or renal comorbidities, which are places where I've used PI3-kinase inhibitors prior to those other classes sometimes," she said. "This does provide a good option for those patients even in frontline."

But she added that the introduction of next-generation covalent BTK inhibitors has broadened the competitive landscape for these very comorbid older patients. "I've become a little more comfortable with those BTK [inhibitors] even in the setting of some of those patients," she said.

Brown also highlighted the reduced toxicity with the U2 regimen compared with other PI3K inhibitors tested in frontline.

"The side effect profile still carried many of the PI3-kinase inhibitor-type toxicities, just at a lower rate than we have seen with the other drugs," she said.

With a median treatment exposure of 21 months with the U2 regimen and 5 months with fixed-duration chlorambucil-obinutuzumab, adverse events (AEs) of any grade occurred in 100% and 97%, respectively. The U2 regimen had higher rates of diarrhea (56% vs 22%), nausea (51% vs 38%), infusion-related reactions (46% vs 25%), fatigue (35% vs 30%), cough (29% vs 18%), headache (26% vs 18%), pyrexia (25% vs 20%), chills (24% vs 17%), urinary tract infections (22% vs 12%), and dizziness (21% vs 9%). Chlorambucil-obinutuzumab had higher rates of neutropenia (40% vs 34%) and thrombocytopenia (23% vs 9%).

Grade ≥3 AEs occurred in 82% of patients on the U2 regimen and 66% of those on chlorambucil-obinutuzumab, with the most common being diarrhea (12% vs 3%, respectively) and neutropenia (31% vs 36%). In the U2 group, high-grade diarrhea occurred slightly more frequently in the upfront setting (13.8% vs 10.0%), while high-grade neutropenia was more common in the previously treated group (40.0% vs 24.1%).

Serious AEs occurred in 46.1% of those on the U2 regimen versus 23.5% of patients on chlorambucil-obinutuzumab, with deaths due to toxicity in 3.9% and 2.5%, respectively.

UNITY-CLL enrolled 421 patients with treatment naive (n=240) or previously treated (n=181) CLL who were randomized 1:1 to combination treatment with either oral umbralisib plus intravenous ublituximab or oral chlorambucil plus intravenous obinutuzumab.

Treatment arms were well balanced, with median ages of 67-68, presence of del(17p) in 9%-11%, and unmutated IGHV in 54%-55%. Patients needed to have adequate organ function and an Eastern Cooperative Oncology Group performance status of 0-2 to enroll.

Stratification factors included presence of del(17p) and prior treatment status. In the pretreated group, patients in the U2 arm had a higher median number of prior therapies (two vs versus). Between 81%-91% in both groups had received a prior anti-CD20 agent, 13%-15% had received a BTK inhibitor, and 86%-89% had received prior chemoimmunotherapy.

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