Zanubrutinib—a next-generation Bruton’s tyrosine kinase (BTK) inhibitor—achieved high response rates and durable disease control with a low incidence of cardiac effects in patients with relapsed or refractory marginal zone lymphoma, according to updated findings from the final analysis of the phase II MAGNOLIA trial reported at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

“B-cell receptor signaling mediated through BTK is a critical pathway in marginal zone lymphoma pathogenesis,” said study author Stephen Opat, MBBS, Director of Clinical Haematology at Monash Health and Head of the Department of Haematology, School of Clinical Sciences at Monash Health, Monash University, Australia.

Preliminary findings from MAGNOLIA led to the U.S. Food and Drug Administration (FDA) approval of zanubrutinib in the treatment of marginal zone lymphoma in 2021.

Stephen Opat, MBBS

Marginal zone lymphoma is a rare, heterogeneous, indolent subtype of non-Hodgkin lymphoma. It has been difficult to identify optimal therapeutic strategies for this hematologic malignancy. Like other indolent non-Hodgkin lymphomas, advanced-stage disease is generally incurable, and most patients experience a pattern of relapse and remission. The disease is mediated by B-cell receptor signaling, suggesting a role for B-cell receptor pathway targeting via inhibition of BTK. Ibrutinib is approved by the FDA to treat relapsed or refractory marginal zone lymphoma.

Zanubrutinib is a highly specific and irreversible next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC and EGFR family kinases. These kinases are thought to be related to cardiac events such as atrial fibrillation, thrombocytopenia, and bleeding events.

Study Details and Key Findings

MAGNOLIA is a phase II, multicenter, single-arm study of adults requiring systemic treatment of relapsed or refractory marginal zone lymphoma. All patients had previously received one or more lines of therapy including at least one CD20-directed regimen and were treated with zanubrutinib at 160 mg twice daily until disease progression or unacceptable toxicity. 

Data presented by Dr. Opat were based on a median follow-up of 28 months and a median treatment duration of 24.2 months. In 66 patients with relapsed or refractory marginal zone lymphoma, the overall response rate assessed by the independent review committee was 68.2% (n = 45), with a 25.8% (n = 17) complete response rate. Among subgroups with extranodal, nodal, splenic, and unknown subtypes, overall response rates were 64.0%, 76.0%, 66.7%, and 50.0%, respectively. Complete response rates for extranodal, nodal, splenic, and unknown subtypes were 40.0%, 20.0%, 8.3%, and 25.0%, respectively.

Dr. Opat said that responses were seen quickly, with a median of 2.8 months. He noted that responses were observed “regardless of age, subtype … disease stage, presence or absence of bone marrow involvement, and whether relapsed or refractory disease.”

By independent review, at 24 months, 72.9% of patients were still responding to treatment, and the rate of progression-free survival was 70.9%. The rate of overall survival was 85.9% at 24 months.

Overall Toxicity and Cardiac Adverse Events

A total of 35.3% of patients (n = 24) discontinued treatment with zanubrutinib due to investigator-assessed disease progression; five patients stopped treatment due to adverse events; two required prohibited medications; and one withdrew consent. All patients experienced at least one adverse event, but no new safety signals for zanubrutinib emerged in the phase II trial.

The most common treatment-emergent adverse events occurring in more than 10% of patients included bruising (23.5%), diarrhea (22.1%), constipation (17.6%), arthralgia (14.7%), pyrexia (14.7%), upper respiratory tract infection (13.2%), and pain (abdominal and back, each 11.8%). Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common grade 3 or higher adverse events. There were five patient deaths (7.4%) due to unrelated adverse events.

The rate of cardiac adverse events was low, and none of these events led to treatment discontinuation. Three patients (4.4%) experienced hypertension, and one patient each (each 1.5%) experienced atrial fibrillation and atrial flutter. One patient (1.5%) experienced grade 3 gastrointestinal hemorrhage while receiving rivaroxaban for pulmonary embolism. This patient fully recovered and continued onto the long-term extension study. 

DISCLOSURE: Dr. Opat reported financial relationships with BeiGene, Merck, AstraZeneca, Janssen, F. Hoffmann–LaRoche, AbbVie, Amgen, Epizyme, Mundipharma, and Gilead Sciences.

REFERENCE

1. Opat S, Tedeschi A, Hu B, et al: Long-term efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma. 2022 ASH Annual Meeting and Exposition. Abstract 234. Presented December 10, 2022.