FDA Accepts Application for Zanubrutinib in Waldenström Macroglobulinemia

February 17, 2021 — The FDA has accepted a supplemental new drug application of zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia.

The FDA has accepted a supplemental new drug application (sNDA) of zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström macroglobulinemia, according to an announcement from BeiGene, Ltd, the drug developer.1

The application comprises information collected from 351 patients with the disease; it was primarily based on safety and efficacy findings yielded from the pivotal phase 3 ASPEN trial (NCT03053440), with supportive data gleaned from a phase 2 trial (NCT03332173) of the agent that was done in Chinese patients with relapsed/refractory disease, and findings from a global phase 1/2 trial (NCT02343120) that examined zanubrutinib in those with B-cell malignancies.

Safety findings from a total of 779 patients who were enrolled across 6 trials examining zanubrutinib were also included in the submission.

The target action date for the application under the Prescription Drug User Fee Act is October 18, 2021.

“We are pleased that the FDA has accepted the sNDA for [zanubrutinib] in Waldenström macroglobulinemia, a rare disease with significant morbidity. BTK inhibitors have transformed the treatment of Waldenström macroglobulinemia in recent years, but discrepancies in response exist in patients with different subtypes, and toxicity can remain an issue,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, stated in a press release. “We look forward to continuing our communications with the FDA in the coming months and hope that [zanubrutinib] will become a new treatment option for patients with Waldenström macroglobulinemia in the United States.”

Results from the phase 3 ASPEN trial presented during the 2020 ASCO Virtual Scientific Program showed that the BTK inhibitor was associated with a higher complete response or very good partial response (CR+VGPR) rate of 28.4% versus 19.2% with ibrutinib (Imbruvica; P = .0921).2 However, this did not meet the primary study hypothesis, which was superiority with CR+VGPR in the zanubrutinib arm per an independent review committee.

Moreover, the best overall response rate per investigator assessment in the zanubrutinib and ibrutinib arms at the time of the August 2019 data cutoff, were 28.4% versus 17.2%, respectively (P = .0437); at the time of the January 2020 data cutoff, these rates were 30.4% versus 18.2%, respectively (P = .0302).

In the trial, 201 patients with Waldenström macroglobulinemia and a MYD88 mutation were randomized 1:1 to receive either 160 mg of zanubrutinib twice daily (n = 102) or 420 mg of ibrutinib once daily (n = 99). Patients were stratified based on CXCR4 mutational status (CXCR4WHIM vs CXCR4WT vs missing) and how many previous therapies were received (0 vs 1 to 3 vs 3 or more). Another cohort of 28 patients who did not harbor MYD88 mutations were given 160 mg of zanubrutinib daily.

The primary objective of the trial was to compare the efficacy of zanubrutinib with ibrutinib. The primary end point was CR+VGPR rate in patients with activating mutations. Key secondary objectives included further comparing the efficacy, clinical benefit, and anti-lymphoma effects of zanubrutinib versus ibrutinib and to explore the safety and tolerability of the 2 agents. Exploratory objectives comprised characterization of the pharmacokinetics of zanubrutinib in this patient population and to compare quality of life by EORTC QLQ-C30 and EQ-5D.

One-third, or 33.3% of patients who received zanubrutinib were over 75 years compared with 22.2% of those given ibrutinib. Moreover, patients on the zanubrutinib arm had higher rates of anemia than those on the ibrutinib arm, at 65.7% versus 53.5%, respectively. The majority of patients across the treatment arms received 1 to 3 previous therapies.

Regarding safety, those who had zanubrutinib experienced lower rates of atrial fibrillation compared with ibrutinib (2.0% vs 15.3%, respectively), as well hypertension (10.9% vs 17.3%), major bleeding (5.9% vs 9.2%), grade 3 or higher toxicities (58.4% vs 63.3%), adverse effects resulting in treatment discontinuation (4.0% vs 9.2%), and toxicity-related death (1.0% vs 4.1%). 

Although rates of grade 3 or higher infections were comparable between the investigational and control arms, at 17.8% and 19.4%, respectively, zanubrutinib proved to have a higher rate of neutropenia versus ibrutinib, at 29.7% versus 13.3%, respectively.

Zanubrutinib is also under regulatory review for this indication in the European Union, Canada, Australia, China, Taiwan, and South Korea.

Previously, in November 2019, zanubrutinib was granted an accelerated approval from the FDA for use in patients with mantle cell lymphoma who had received at least 1 previous therapy. In June 2020, zanubrutinib was granted a conditional approval in China for use in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who had received at least 1 previous therapy; it was also indicated for patients with MCL who had received at least 1 prior therapy.


  1. BeiGene announces US FDA acceptance of supplemental new drug application for BRUKINSA (zanubrutinib) in Waldenström’s macroglobulinemia. News release. BeiGene, Ltd. February 17, 2021. Accessed February 17, 2021. http://bit.ly/37m8RFV.
  2. Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). J Clin Oncol. 2020;38(suppl 15):8007. doi:10.1200/JCO.2020.38.15_suppl.8007