Zanubrutinib in combination with Gazyva (obinutuzumab) leads to clinically meaningful responses and is well-tolerated by patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma, a Phase 1b trial shows.

The findings were announced at an oral presentation titled, “ Zanubrutinib Plus Obinutuzumab in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Relapsed/Refractory (R/R) Follicular Lymphoma (FL) ,” at the 15th International Conference on Malignant Lymphoma (ICML), June 18-22 in Lugano, Switzerland.

Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK), an enzyme that plays an important role in the development of immune B cells and is currently being explored as a therapeutic target to treat different types of B-cell cancers. The compound is being developed by BeiGene.

Gazyva is a monoclonal antibody designed to bind to CD20, a protein found on the surface of certain types of B cells, including malignant CLL or SLL cells, destroying them. In the U.S., Gazyva is part of a collaboration between Genentech, a subsidiary of Roche, and Biogen.

The safety and efficacy of the combination therapy of zanubrutinib and Gazyva in patients with different types of B-cell malignancies are currently being assessed in an open-label Phase 1b trial (NCT02569476) taking place in the U.S., Australia, and South Korea.

The trial is divided into two phases:

An initial dose-escalation phase to determine the optimal doses and treatment regimens, in which patients will receive 28 cycles of zanubrutinib (320 mg once a day, or 160mg twice a day) in combination with Gazyva that will be administered in line with standard CLL dosing (three loading doses of 1,000 mg once a week, followed by 1,000 mg on day one of cycles 2–6);

A dose-expansion phase, in which patients will be divided in disease-specific groups and will receive 28 cycles of zanubrutinib (160 mg twice a day) in combination with Gazyva.

The primary endpoint of the trial will be to assess the overall response rate and duration of response among study participants with different types of B-cell malignancies.

At the time of the analysis (Feb. 28, 2019), 81 people had already enrolled in the trial, 45 CLL/SLL patients — either treatment-naïve or who had failed prior treatments — and 36 follicular lymphoma patients who had failed prior lines of therapy.

At this point, more than half the patients (62.9%) were still receiving treatment, including 73.3% with CLL/SLL and 50% with follicular lymphoma. Patients with CLL/SLL were followed for a median 28.9 months and follicular lymphoma patients for 20.1 months.

Key findings presented at the conference showed that:

Among the 20 previously untreated CLL/SLL patients, 100% responded to treatment, including 30% who achieved a complete response (complete tumor eradication);

Among the 25 CLL/SLL patients who had failed prior therapies, 92% achieved a response, including 28% complete responses;

Of the 36 follicular lymphoma patients, responses were observed in 72.2%, with 38.9% of the patients attaining a complete response;

Of the six CLL/SLL patients with complete responses who were tested, half were negative for minimal residual disease (MRD, had less than one malignant cancer cell found among 10,000 white blood cells);

Progression-free survival (PFS, the time patients lived without their disease worsening) had not been reached for either group of CLL/SLL patients, with 73.3% of the patients remaining on treatment;

PFS lasted 24.9 months among patients with follicular lymphoma, and half of the patients were still receiving treatment;

Most treatment-emergent adverse events were either mild or moderate (grade 1 or 2). One patient with CLL/SLL experienced a treatment-emergent adverse event that resulted in death.

“These data demonstrated that zanubrutinib, in combination with the anti-CD20 monoclonal antibody obinutuzumab, was generally well-tolerated, with the majority of adverse events being grade 1 or 2. In addition, the early finding of peripheral blood MRD negativity in three out of six patients with CLL/SLL merits further investigation,” Constantine S. Tam, MD, who presented the findings of the trial at the conference, said in a press release.

Tam is the disease group lead for low-grade lymphoma and chronic lymphocytic leukemia at the Peter MacCallum Cancer Center and director of hematology at St. Vincent’s Hospital, Australia.

“These updated data provide further evidence for the rational combination of zanubrutinib and obinutuzumab, and build upon the foundation supporting our global pivotal Phase 2 trial comparing obinutuzumab plus zanubrutinib to obinutuzumab alone as a treatment for patients with [relapsed or refractory] follicular lymphoma. It is our hope that we will continue to see deep and durable responses for these patients,” said Jane Huang, MD, chief medical officer at BeiGene.