FDA Approves Zanubrutinib for Anti-CD20 Pretreated Marginal Zone Lymphoma


An accelerated approval has been granted by the FDA to zanubrutinib, for the treatment of marginal zone lymphoma in patients who have received 1 prior anti-CD20-based therapy.

The FDA has granted accelerated approval to the Bruton’s tyrosine kinase (BTK) inhibitor, zanubrutinib (Brukinsa), for the treatment of marginal zone lymphoma (MZL) in patients who have received 1 prior anti-CD20-based therapy, according to a press release issued by BeiGene Ltd.1

The accelerated approval is based on results of phase 2 MAGNOLIA Trial (NCT03846427) with supporting data from a global phase 1/2 BGB-3111-AU-00 trial (NCT02343120) of the agent in B-cell malignancies in general. Additionally, 847 patients were included in a pooled analysis from 7 separate trials were also included in the initial supplemental new drug application submission.2

“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. 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,” 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.

A total of 68 patients were enrolled in the MAGNOLIA trial and assessed for the primary end point of overall response rate (ORR) up to 3 years. Secondary end points included time to response (TTR), patient-reported outcomes, progression-free survival, and safety. Zanubrutinib was administered the participants at 160 mg twice daily.3

There were multiple subtypes of MZL identified in the study subjects including extranodal disease in 58% of patients, nodal in 64%, splenic in 58%, and 50% had unknown subtypes.

The median age of patients enrolled in the MAGNOLIA study was 70 years (range, 37-95). The median number of prior therapies was 2 (range, 1-6). The median follow-up was 6.8 months. The ORR for this population was 56% (95% CI: 43, 68) which consisted of completed responses (CRs) in 20% of patients across all MZL subtype. Median DOR was not reached at a median follow-up of 8.3 months, however 85% of patients who responded were still in remission at 12 months (95% CI67-93). PFS was not reached.

The agent was also fairly well tolerated. Of the initial 68 patients, 21 had discontented treatment, mainly due to disease progression (23.5%). Additional reasons for treatment discontinuation included, 1 withdrew consent, and 2 patients required prohibited mediation. An additional 2 withdrew due to AEs, 1 from pyrexia and 1 from myocardial infraction. The most common AEs reported were diarrhea (19.1%), bruising (17.6%), and constipation (13.2%).

The phase 1/2 supportive data study utilized a single-arm study and dose-levels were escalated following a modified 3+3 dose escalation scheme. In total, 397 participants were enrolled. T he primary outcome of the study was the number of participants with AEs. Secondary outcomes included area under the plasma concentration-time curve from o to the time of the last measurable concentration, maximum plasma concertation, time to reach maximum plasma concentration, terminal elimination, BTK inhibition activity, and tumor response.2,4

In the 20 patients evaluated, 9 had extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. The ORR observed with zanubrutinib treatment was 80% (95% CI, 56-94) with a CR rate of 20%. Median DOR was not yet reached in the study but at a median follow-up of 31.4 months, 72% of patients who responded were still in remission (95% CI, 40-88).

In order to participate, patients must have histologically confirmed MZL, have ≥1 lines of prior therapy including at least 1 CD20-directed therapy, have a current need for systemic MZL therapy, have measurable disease a life expectancy of ≥6 months and adequate organ function. Patients with prior BTK inhibitor treatment or allogeneic stem cell transplantation were not eligible to participate. In order to participate, patients must have a confirmed B-lymphoid malignancy, have relapsed or refractory disease, and an ECOG score of 0-2.

In addition to MZL, zanubrutinib holds indications in mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenströms macroglobulinemia. It is designed to optimize selectivity, bioavailability, and half-life.

"We are excited about the FDA’s approval for Brukinsa 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. 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 at BeiGene.


1. U.S. 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://bwnews.pr/2YTnVsZ

2. BeiGene announces U.S. FDA acceptance and priority review of supplemental new drug application for BRUKINSA® (Zanubrutinib) in marginal zone lymphoma. News release. BeiGene. May 19, 2021. Accessed May 19, 2021. https://bit.ly/3hDIj92.

3. Opat S, Tedeschi A, Linton K, et al. Efficacy and safety of zanubrutinib in patients with relapsed/Rrfractory marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) trial. Blood 2020; 136 (Supplement 1): 28–30. doi: https://doi.org/10.1182/blood-2020-134611

4. Study of the safety and pharmacokinetics of bgb-3111 in subjects with b-cell lymphoid malignancies. Clinicatrials.gov. Accessed September 15, 2021.

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