FDA Grants Accelerated Approval to Zanubrutinib for Relapsed/Refractory MZL


Based on response data from the phase 2 MAGNOLIA trial, the FDA has granted accelerated approval to the Bruton tyrosine kinase inhibitor zanubrutinib to treat patients with relapsed/refractory marginal zone lymphoma.

The FDA has granted an accelerated approval to zanubrutinib (Brukinsa) as therapy for patients with relapsed/refractory marginal zone lymphoma (MZL) following prior treatment with at least 1 anti–CD20-based regimen, according to the drug’s manufacturer, BeiGene, Ltd.1

The data supporting the approval are related to overall response rate (ORR) observed in the single-arm, open-label, multicenter, phase 2 MAGNOLIA trial (NCT03846427), which examined the agent in patients with relapsed/refractory MZL. Continued approval may require verification of clinical benefit in a confirmatory trial.

Zanubrutinib is a small molecule inhibitor of Bruton tyrosine kinase, with more selectivity compared with approved agents in its class.

“The MAGNOLIA trial results provided additional evidence that the selective design of Brukinsa can be translated to improved treatment outcomes for these patients,” Jane Huang, MD, chief medical officer of hematology at BeiGene, said in a press release. “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.”

In total, 66 patients with relapsed/refractory MZL and experience with CD20 inhibition were included in the efficacy evaluation, of whom 26 had extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype. The ORR was 56% (95% CI, 43%-68%) per CT assessment, comprised of a complete response (CR) rate of 20%. Per PET-CT assessment, the ORR was 67% (95% CI, 54%-78%) with a CR rate of 26%.

At a median follow-up of 8.3 months, response duration was not reached. The rate of sustained remission at 12 months was 85% (95% CI, 67%-93%), with responses observed across all disease subtypes assessed.

Other supporting data were from the phase 1/2 trial of BGB-3111-AU-003 (NCT02343120), which examined the agent in patients with B-cell malignancies. There were 20 patients with MZL included in this cohort, of whom 9 had extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. ORR by CT assessment was 80% (95% CI, 56%-94%) and the CR rate was 20%. At the median follow-up of 31.4 months, the median duration of response was not reached with 72% (95% CI, 40%-88%) of responding patients maintaining response at 12 months.

In data from MAGNOLIA reported at the 2020 American Society of Hematology Annual Meeting & Exposition,2 treatment-emergent adverse events (TEAEs) of any-grade occurred in 95.6% of the population, with the most common events being diarrhea (20.6%), contusion (19.1%), constipation (13.2%), neutropenia (13.2%), pyrexia (11.8%), upper respiratory tract infection (11.8%), thrombocytopenia (10.3%), and nausea (10.3%). Grade 3 or greater TEAEs occurred in 38.2% of patients, with events of neutropenia (10.3%), diarrhea (2.9%), pyrexia (2.9%), thrombocytopenia (2.9%), anemia (2.9%), and pneumonia (2.9%) all occurring in at least 2 patients. Serious TEAEs were present in 32.4% of the treated population and 2 patients discontinued treatment due to some TEAE considered to be treatment-related, 1 of whom had pre-existing cardiovascular disease and experienced a fatal myocardial infraction.

“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,” Stephen Opat, FRACP, FRCPA, MBBS, director of clinical hematology at Monash Health, department head of Hematology at Monash University, and lead principal investigator of the MAGNOLIA trial, said in a statement.

Prior to the approval, the FDA granted priority review designation to zanubrutinib for this indication. The decision comes slightly ahead of the Prescription Drug User Fee Act (PDUFA) target action date of September 19, 2021.


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://bit.ly/3EjrngK

Opat S, Tedeschi A, Linton K, etal. 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

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