FDA Approves Zanubrutinib for Relapsed or Refractory Marginal Zone Lymphoma


The FDA has granted an accelerated approval to zanubrutinib for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least 1 anti–CD20-based regimen.



The FDA has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least 1 anti–CD20-based regimen.1

The regulatory decision is based on efficacy data yielded from 2 single-arm clinical trials, with overall response rates (ORRs) as evaluated by independent review committee (IRC) per 2014 Lugano Classification as the primary end point: the phase 2 MAGNOLIA trial (NCT03846427) and the phase 1/2 trial BGB-3111-AU-003 (trial NCT02343120).

Results from MAGNOLIA indicated that zanubrutinib elicited an ORR of 56% (95% CI, 43-68) with a complete response (CR) rate of 20%, based on assessment using CT scan. The ORR with the agent was even higher when based on assessment prioritizing PET-CT scan, at 67% (95% CI, 54-78) with a CR rate of 26%. Moreover, at the median follow-up time of 8.3 months, the median duration of response (DOR) had not yet been reached, and 85% of responders were still in remission at 12 months (95% CI, 67-93). Notably, responses to zanubrutinib were noted in all MZL subtypes examined.

Data from BGB-3111-AU-003 indicated that zanubrutinib elicited an ORR of 80% (95% CI, 56-94) based on assessment using CT scan, with a CR rate of 20%. In this trial, the median DOR was also not reached at the median follow-up of 31.4 months. Seventy-two percent of responders were still in remission at 12 months (95% CI, 40-88).

“We are excited about the FDA’s approval for [zanubrutinib] in patients with previously treated marginal zone lymphoma, a significant milestone that was made possible by the diligent BeiGene team, the dedicated investigators, and the participating patients and their families," Jane Huang, MD, chief medical officer, Hematology at BeiGene, stated in a press release. "The MAGNOLIA trial results provided additional evidence that the selective design of [zanubrutinib] can be translated to improved treatment outcomes for these patients."

A total of 66 patients with relapsed/refractory MZL were evaluated on the single-arm, open-label, multicenter MAGNOLIA trial; this included 26 patients with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype. To be eligible for participation, patients must have received at least 1 anti–CD20-based regimen.

Zanubrutinib was given at a twice-daily dose of 160 mg until patients experienced progressive disease or intolerable toxicity. Notably, long-term treatment with antiplatelet and anticoagulation agents was permitted.

The primary end point of the trial was ORR per IRC and Lugano classification, and secondary end points comprised ORR per investigator assessment, DOR, progression-free survival (PFS), and safety.

Earlier data on 68 patients enrolled to the trial showed that the median age of the participants was 70 years (range, 37-95), with 28% of patients being 75 years or older.2 Patients received a median of 2 prior lines of therapies (range, 1-6). Notably, 35% of patients had disease that proved to be refractory to their last treatment.

Earlier data presented during the 2020 ASH Annual Meeting showed that at a data cutoff of August 14, 2020, 66 patients were evaluable for efficacy. At a median follow-up of 10.7 months, the investigator-assessed IRR was 74.2% (95% CI, 62.0-84.2) with zanubrutinib, which included a 24.2% CR rate and a 50.0% partial response rate.

In high risk subgroups such as those aged 75 years or older (n = 18), those who received at least 3 lines of prior therapy (n = 17), those with refractory disease (n = 21), and those with nodal MZL, the ORRs were 88.9% (95% CI, 65.3%-98.6%), 64.7% (95% CI, 38.3%-85.8%), 71.0% (95% CI, 47.8%-88.7%), and 84.0% (95% CI, 63.9%-95.5%), respectively.

The median follow-up time for PFS was 9.13 months, and the 6-month PFS rate was 80.0%; the 9-month PFS rate was 67.0%. Notably, 79.0% of responders maintained their response at 6 months. The 12-month overall survival rate was 94.0% with zanubrutinib.

Regarding safety, the most common adverse effects, including laboratory abnormalities, reported in the pooled safety population of 847 patients included decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain.

“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 MZL subtypes," 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, stated in the press release. "In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions. We are optimistic that BRUKINSA will bring clinically meaningful benefit to patients with relapsed or refractory marginal zone lymphoma."

Continued approval for the new indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.


  1. 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://bit.ly/3zbzB6X
  2. BeiGene announces data on BRUKINSA (zanubrutinib) from phase 2 trial in marginal zone lymphoma and phase 3 trial in chronic lymphocytic leukemia or small lymphocytic lymphoma at the 62nd ASH Annual Meeting. News release. BeiGene, Ltd. December 6, 2020. Accessed September 15, 2021. https://bwnews.pr/3hCRyp1
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