FDA Green Lights Zanubrutinib for Adults with Waldenström Macroglobulinemia


Zanubrutinib (Brukinsa) is now FDA approved for the treatment of adults with Waldenström Macroglobulinemia.

FDA Green Lights Zanubrutinib for Adults with Waldenström Macroglobulinemia

FDA Green Lights Zanubrutinib for Adults with Waldenström Macroglobulinemia

Zanubrutinib (Brukinsa) is now FDA approved for the treatment of adults with Waldenström Macroglobulinemia.1

“We are delighted by today’s FDA approval for [zanubrutinib] in its second indication, offering a new treatment option with demonstrated efficacy and safety benefits for patients with Waldenström’s macroglobulinemia. As shown in the ASPEN trial [NCT03053440], [zanubrutinib] can improve treatment outcomes for these patients and potentially make a positive impact on their lives,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, said in a press release.

The regulatory decision was primarily based on data from the multicenter, open-label, phase 3 ASPEN trial, which compared zanubrutinib with ibrutinib (Imbruvica) in patients with Waldenström macroglobulinemia.

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% vs 19.2% with ibrutinib (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% vs 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 vs 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% vs 53.5%, respectively. Most 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 vs ibrutinib, at 29.7% vs 13.3%, respectively.


  1. U.S. FDA Grants BRUKINSA® (zanubrutinib) approval in Waldenström’s Macroglobulinemia. News release. BeiGene. September 1, 2021. Accessed September 1, 2021. https://bwnews.pr/38vGDZx
  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
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