FDA Approves Zanubrutinib To Treat Patient With Marginal Zone Lymphoma


Zanubrutinib received an accelerated approval for the indication of adults with marginal zone lymphoma with at least 1 prior treatment with an anti-CD20-based therapy.

The FDA approved zanubrutinib (Brukinsa) for the treatment of patients with marginal zone lymphoma (MZL) who had with at least 1 prior treatment with an anti-CD20-based therapy.

Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor that was designed to maximize BTK occupancy, and therefore minimize off-target inhabitation of TEC- and EGFR-family kinases. These kinase families are believed to induce atrial fibrillation, thrombocytopenia, and bleeding events, according to a press release.1

The regulatory decision was based on findings from 2 single arm trials.

The multicenter, single-arm phase 2 MAGNOLIA (NCT03846427) trial assessed zanubrutinib’s efficacy and safety in 68 adult patients with relapsed/refractory MZL who had received 1 or more lines of prior therapy, including at least 1 CD20-directed therapy.2

Zanubrutinib was administered twice a day at a dose of 160mg, until either the disease progressed, or intolerable toxicity was presented. Importantly, the study permitted long-term antiplatelet and anticoagulation agents.

Investigator assessment determined secondary end points, which comprised overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety.

An independent review committee and Lugano classification determined ORR for the primary end point of the trial. ORR was 56% (95% CI, 43%-68%) and the complete response (CR) rate was 20%. At 8.3 months, the median DOR had not yet been reached, though 85% of responders were still in remission at 12 months (95% CI, 67-93).

"BTK plays a critical role in B-cell receptor signaling, a driver in the development of marginal zone lymphoma. In the MAGNOLIA trial, Brukinsa demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, FRACP, FRCPA, MBBS, director of clinical hematology at Monash Health, Head of Department of Hematology at Monash University, and lead principal investigator of the MAGNOLIA trial. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

Notable adverse events (AEs) included decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain.

The most common toxicities associated with treatment in the MAGNOLIA trial were reported to be low grade and consisted of diarrhea (19.1%), bruising (17.6), constipation (13.2%), pyrexia (10.3%), upper respiratory tract infection (10.3%), and nausea (10.3%).

Serious AEs presented themselves as thus: 1 case of atrial flutter, 1 case of pyrexia, 1 case of pneumonia, and 1 case of thrombocytopenia. In addition, 1 patient with pre-existing coronary artery disease died due to a myocardial infarction but this is not believed to be associated to the zanubrutinib treatment.

Less serious grade AEs included neutropenia (10.3%, thrombocytopenia (10.3%) and atrial flutter (1.5%).

Throughout the trial, 21 patients discontinued their treatment. Sixteen patients stopped because their disease progressed, 1 withdrew their consent, 2 required prohibited medication, and 2 stopped as a result of their treatment-related AEs.

Previous data from the BGB-3111-AU-003 trial, which examined zanubrutinib in a total of 20 patients with relapsed/refractory MZL, 9 of whom had extranodal subtype, 5 had a nodal subtype, and 6 had s splenic subtype, showed that the BTK inhibitor induced an ORR of 80% at (95% CI, 56%-94%) and the CR rate was 20%. Similarly, the median DOR was not reached. Median follow-up time was 31.4 months, and 72% of responders were in remission at 12 months (95% CI, 40-88).3

“The MAGNOLIA trial results provided additional evidence that the selective design of Brukinsa can be translated to improved treatment outcomes for these patients," said Jane Huang, MD, chief medical officer, hematology, BeiGene. "The ongoing evaluation of Brukinsa in its broad global clinical program will enable us to further understand this potentially best-in-class BTK inhibitor and its impact on patients.”

The FDA already approved zanubrutinib for the treatment of patients with mantle cell lymphoma (MCL) who have previously received at least 1 therapy. It received the same indication in China the following year, and was also approved to treat chronic lymphocytic leukemia or small lymphocytic lymphoma in patients who had already received 1 line of therapy. In February 2021, the Unites Arab Emirates approved zunubrutinib to treat relapsed or refractory MCL.

Zanubrutinib should be administered at either 160 mg twice a day or 320 mg daily, with or without food. Dosage may be adjusted in response to AEs or certain drug interactions.


US FDA grants BRUKINSA (zanubrutinib) accelerated approval in relapsed or refractory marginal zone lymphoma. News release. BeiGene, Ltd. September 15, 2021. Accessed September 15, 2021. https://ir.beigene.com/news-details/?id=0d5b56bb-d6cd-4606-a9bd-f49e85bb113b.

  1. Opat S, Tedeschi A, Linton K, et al. Efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) trial. Blood. 2020;136(suppl 1):28-30. doi:10.1182/blood-2020-134611
  2. Tedeschi A, Trotman J, Tam C, et al. Phase 1/2 study of single-agent zanubrutinib in patients with relapsed/refractory marginal zone lymphoma. Presented at: 2020 EHA Annual Congress; June 11-21, 2020; Virtual. Abstract EP1165. https://bit.ly/2S7P3RI

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