FDA Grants Priority Review to Zanubrutinib for Marginal Zone Lymphoma

The FDA has granted priority review to a supplemental new drug application for zanubrutinib as a treatment option for adult patients with marginal zone lymphoma who have previously received at least 1 anti-CD20–based therapy.

The FDA has granted priority review to a supplemental new drug application (sNDA) for zanubrutinib (Brukinska) as a treatment option for adult patients with marginal zone lymphoma who have previously received at least 1 anti-CD20–based therapy.1

The application includes data from the phase 2 MAGNOLIA trial (BGB-3111-214; NCT03846427), which were presented during the 2020 ASH Annual Meeting, and showed that the second-generation BTK inhibitor elicited an objective response rate (ORR) of 60% in 67 evaluable patients with relapsed/refractory marginal zone lymphoma; this comprised a complete response (CR) rate of 15% and a partial response rate of 45%.2 Twenty-seven percent of patients achieved stable disease.

Data from a global phase 1/2 trial (NCT02343120), which examined zanubrutinib in patients with B-cell malignancies, and pooled safety findings from 847 patients with B-cell malignancies who received the BTK inhibitor in 7 clinical trials, were also used to support the sNDA.

Under the Prescription Drug User Fee Act, the regulatory agency is expected to make a decision on the application by September 19, 2021.

“This is our first regulatory submission on marginal zone lymphoma, a serious disease diagnosed in more than 2,000 patients every year in the United States, with no clear standard of care. In clinical trials, [zanubrutinib] has demonstrated promising efficacy and tolerability in marginal zone lymphoma and presents a potential new option for [these] patients,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, Ltd., stated in a press release. “We look forward to continuing our communications with the FDA in the coming months as we work on advancing the broad global development program for our potentially best-in-class BTK inhibitor.”

Zanubrutinib is a potent, highly specific, and irreversible next-generation BTK inhibitor that was developed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, which are believed to be associated with atrial fibrillation, thrombocytopenia, and bleeding events.

Previous data from the BGB-3111-AU-003 trial, which examined zanubrutinib in a total of 20 patients with relapsed/refractory marginal zone lymphoma, showed that the BTK inhibitor induced an ORR of 80% at a median follow-up of 27.1 months.3

In the multicenter, single-arm phase 2 MAGNOLIA trial, investigators set out to examine zanubrutinib in adult patients requiring systemic treatment for relapsed/refractory marginal zone lymphoma who had received 1 or more lines of prior therapy, including at least 1 CD20-directed regimen.

A total of 68 study participants received zanubrutinib at a twice-daily dose of 160 mg until they experienced progressive disease or intolerable toxicity. Notably, the use of long-term antiplatelet and anticoagulation agents was allowed.

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

The median age of the participants was 70 years (range, 37-95), with 28% of patients being 75 years or older. Thirty-eight percent of patients had extranodal disease, 38% had nodal disease, 18% had splenic disease, and the disease subtype was unknown in 6%. 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.

Additional data from the trial that read out during the meeting showed that zanubrutinib induced ORRs of 58%, 64%, 58%, and 50% in patients with extranodal, nodal, splenic, and unknown subtypes, respectively. The CR rates experienced by those with extranodal disease, nodal disease, and those with unknown disease subtype were 23%, 12%, and 50%, respectively. Those who had splenic disease did not experience a CR. At a median follow-up of 6.8 months, the median DOR and PFS had not yet been reached.

Regarding safety, the most frequently reported treatment-emergent toxicities included diarrhea (19.1%), bruising (17.6%), constipation (13.2%), pyrexia (10.3%), upper respiratory tract infection (10.3%), and nausea (10.3%). However, most of the toxicities were noted to be low grade. The most commonly experienced grade 3 or higher toxicity was neutropenia, which was reported in 7.3% of patients.

Serious adverse effects determined to be associated with zanubrutinib included atrial flutter (n = 1), pyrexia (n = 1), pneumonia (n = 1), and thrombocytopenia (n = 1). One patient had pre-existing coronary artery disease and died from myocardial infarction; this was not determined to be related to the BTK inhibitor.

Moreover, all-grade toxicities of interest were neutropenia (10.3%), thrombocytopenia (10.3%), and atrial flutter (1.5%).

A total of 21 patients (30.9%) discontinued treatment with zanubrutinib; 16 patients did so because of progressive disease, 1 withdrew consent, 2 needed prohibited medications, and 2 did so because of toxicities (pyrexia, n = 1; myocardial infarction, n = 1).

In November 2019, zanubrutinib was FDA approved for the treatment of patients with mantle cell lymphoma (MCL) who have previously received at least 1 therapy. The following year, in June 2020, the BTK inhibitor was given the green light in China for the same indication in MCL and for those with chronic lymphocytic leukemia or small lymphocytic lymphoma who had previously received 1 therapy. Moreover, in February 2021, zanubrutinib was approved in the United Arab Emirates for the treatment of patients with relapsed or refractory MCL.

Most recently, in March 2021, the BTK was approved in Canada for the treatment of patients with Waldenström macroglobulinemia. In February 2021, the FDA accepted a sNDA for zanubrutinib as a treatment for adult patients with Waldenström macroglobulinemia based on data from the pivotal phase 3 ASPEN trial (NCT03053440), supportive data from a phase 2 trial (NCT03332173) done in Chinese patients with relapsed/refractory disease, and the aforementioned global phase 1/2 trial.


  1. BeiGene announces US FDA acceptance and priority review of supplemental new drug application for BRUKINSA (zanubrutinib) in marginal zone lymphoma. News release. BeiGene, Ltd. May 19, 2021. Accessed May 19, 2021. https://bit.ly/2SUcy0Y
  2. 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
  3. 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