Umbralisib plus Ublituximab Regimen Superior to Chemoimmunotherapy in CLL

TOP - March 2021 Vol 14, No 2 - ASH 2020 Highlights

The combination of 2 investigational 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 PI3Kδ compared with the alpha and beta isoform, and is more than 200-fold more selective for PI3Kδ relative to the xxx isoform, resulting in lower rates of immune-mediated adverse events compared with older generations of PI3Kδ 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.

Adverse Events

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.

FDA Updates

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, on February 5, 2021, the FDA approved umbralisib for the treatment of marginal-zone lymphoma and follicular lymphoma (see here).

Related Items
New NCCN Guidelines for CLL/SLL Include Second-Generation BTK Inhibitors
William King
TOP - May 2023 Vol 16, No 3 published on May 5, 2023 in NCCN 2023 Conference Highlights, Lymphoma, Leukemia
Optimal Systemic Therapy for Renal Cell Carcinoma Is Still Evolving
William King
TOP - May 2023 Vol 16, No 3 published on May 5, 2023 in NCCN 2023 Conference Highlights, Renal-Cell Carcinoma, Kidney Cancer, Urothelial Cancer
Molecular Characteristics Increasingly Define Adult Gliomas
William King
Online First published on May 5, 2023 in NCCN 2023 Conference Highlights
Addressing Health Equity in Bladder Cancer Care
William King
TOP - May 2023 Vol 16, No 3 published on May 1, 2023 in Healthcare Equity, Bladder Cancer, Urothelial Carcinoma
What Will It Take to End Cancer As We Know It?
William King
TOP - March 2023 Vol 16, No 2 published on March 14, 2023 in ASCO GU 2023 Highlights
First-Line Ribociclib plus Endocrine Therapy Beats Chemotherapy for Advanced Breast Cancer
William King
TOP - January 2023 Vol 16, No 1 published on January 10, 2023 in SABCS
AVBCC Panel Discusses Current and Future State of Value-Based Agreements
William King
TOP - January 2023 Vol 16, No 1 published on January 10, 2023 in Value-Based Care, AVBCC Summit Highlights
CTC-Driven Treatment Choice May Improve Long-Term Outcomes in Patients with Metastatic Breast Cancer
William King
TOP - January 2023 Vol 16, No 1 published on January 10, 2023 in SABCS
Capivasertib plus Fulvestrant Yields PFS Improvement in Patients with HR-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer
William King
TOP - January 2023 Vol 16, No 1 published on January 10, 2023 in SABCS
Adding Pembrolizumab to Chemotherapy Extends Survival in Women with Cervical Cancer Across Several Key Subgroups
William King
TOP - November 2022 Vol 15, No 6 published on November 9, 2022 in Cervical Cancer
Last modified: July 22, 2021