On September 15, zanubrutinib (Brukinsa), a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one anti–CD20-based regimen.
This accelerated approval is based on overall response rate; continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
“BTK plays a critical role in B-cell receptor signaling, a driver in the development of marginal zone lymphoma. In the MAGNOLIA trial, zanubrutinib demonstrated impressive overall response and complete remission rates, with responses observed in all marginal zone lymphoma subtypes. In addition, this next-generation BTK inhibitor was well tolerated in these patients, with a low rate of discontinuation due to adverse reactions. We are optimistic that zanubrutinib will bring clinically meaningful benefit to patients with relapsed or refractory marginal zone lymphoma,” said Stephen Opat, FRACP, FRCPA, MBBS, Director of Clinical Hematology at Monash Health, Head of the Department of Hematology at Monash University, and lead principal investigator of the MAGNOLIA trial.
MAGNOLIA and BGB-3111-AU-003 Trials
The FDA approval of zanubrutinib is based on efficacy results from two single-arm clinical trials, with overall response rate as assessed by independent review committee (IRC) per 2014 Lugano Classification as the primary endpoint.
The multicenter, pivotal phase II MAGNOLIA trial (ClinicalTrials.gov identifier: NCT03846427) evaluated patients with relapsed or refractory marginal zone lymphoma who received at least one anti–CD20-based regimen; a total of 66 patients were evaluated, including 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype. Based on assessment using computed tomography (CT), the overall response rate was 56% (95% confidence interval [CI] = 43%–68%), with a complete response rate of 20%; based on assessment prioritizing positron-emission tomography (PET)/CT scan, the overall response rate was 67% (95% CI = 54%–78%) with a complete response rate of 26%. The median duration of response was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months (95% CI = 67–93). Responses were observed in all marginal zone lymphoma subtypes.
In the global phase I/II trial of BGB-3111-AU-003 (ClinicalTrials.gov: NCT02343120), a total of 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on assessment using CT scan, the overall response rate was 80% (95% CI = 56%–94%), with a complete response rate of 20%. The median duration of response was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months (95% CI = 40–88).
The most common ( ≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain.