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.
“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.