FDA Approves Zanubrutinib in Adult Waldenström’s Macroglobulinemia


Zanubrutinib has been approved by the FDA to treat adult patients with Waldenström macroglobulinemia.

Zanubrutinib (Brukinsa) has been approved by the FDA to treat adult patients with Waldenström macroglobulinemia (WM), according to a press release by BeiGene, Ltd.1

The approval was based on data from the phase 3 ASPEN trial (NCT03053440), a global, open-label trial. Results were presented at the 2020 American Society of Hematology Annual Meeting and published in Blood.2 This study demonstrated higher very good partial responses (VGPRs) with zanubrutinib versus ibrutinib (Imbruvica). There were also fewer Bruton’s tyrosine kinase (BTK)–associated toxicities with zanubrutinib compared with ibrutinib.

“The ASPEN trial provided compelling evidence that Brukinsa is a highly active BTK inhibitor in Waldenström’s macroglobulinemia, and compared to the first-generation BTK inhibitor, showed improved tolerability across a number of clinically important side effects. The approval of Brukinsa provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” said Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute and professor of Medicine at Harvard Medical School, in a press release.

“The approval of Brukinsa Waldenström’s macroglobulinemia, which is the second therapy approved specifically for the treatment of this rare type of lymphoma, is positive news for patients. Expanded treatment options offer new hope for those living with this disease and can potentially improve patient experience, especially oral therapies that can be given as a single agent,” said Pete DeNardis, chair of the Board at the International Waldenström’s Macroglobulinemia Foundation, stated in the press release.

In ASPEN, 164 patients with relapsed/refractory disease and 37 with treatment-naïve disease were randomized 1:1 to zanubrutinib at 160 mg twice daily or ibrutinib at 420 mg once daily in 28-day cycles until disease progression or intolerance. A second cohort looked at only zanubrutinib in patients with wild-type MYD88 or undetermined MYD88 mutation status.

VGPR or CR per independent review committee (IRC) assessment was the primary end point of the trial. Secondary end points included major response rate (MRR) assessed by IRC, progression-free survival (PFS), duration of response, reductions in bone marrow and extramedullary tumor burden, and safety. Overall survival and changes in quality of life were investigated as exploratory end points.

The IRC-assessed VGPR rate with zanubrutinib was 28% versus 19% with ibrutinib. This result was not considered to be statistically significant although it was higher with zanubrutinib (2-sided P = .09). The patients who had relapsed/refractory disease had a VGPR rate of 29% and 20% with zanubrutinib and ibrutinib, respectively (P = .12). The treatment-naïve population had a VGPR rate of 26% with zanubrutinib compared with 17% for those receiving ibrutinib (P =.54). The investigators assessment showed a 28% VGPR rate with zanubrutinib versus 17% with ibrutinib (P = .04).

Fifteen percent of the zanubrutinib-treated population progressed on treatment or died after a median follow-up of 18.0 months, and 16% of those given ibrutinib progressed or died after a median 18.5 months. Neither arm was evaluable for median PFS, although both arms had comparable event-free rates of 85% with zanubrutinib and 84% with ibrutinib at 18 months. Patients with relapsed/refractory disease and treatment-naïve disease had 86% and 82% event-free rates at 18 months, respectively.

The most common AEs that occurred in 20% or more of patients with zanubrutinib were neutropenia, upper respiratory infection, and diarrhea. With ibrutinib, the most common were diarrhea, upper respiratory infection, contusion, and muscle spasms. There were 58% who had grade 3 or more AEs in the zanubrutinib group and 63% in the ibrutinib arm. The incidence of grade 3 or more pneumonia and hypertension were ≥5% higher in patients given ibrutinib compared with zanubrutinib. Grade 3 or more neutropenia had a ≥5% higher incidence in those receiving zanubrutinib.

In the zanubrutinib group, serious AEs occurred in 40% of patients compared with 41 in the ibrutinib group. Pneumonia, neutropenia, and febrile neutropenia were the most common serious AEs.

A phase 1/2 trial of zanubrutinib monotherapy in patients with B-cell malignancies led to the ASPEN study after it showed 45% of patients of the 73 patients with WM achieved complete response (CR) or VGPR. After 32.7-month median follow-up, 82% of those patients achieved major response. The safety profile showed that zanubrutinib was well tolerated, with relevant adverse events (AEs) of atrial fibrillation in 5%, major hemorrhage in 4%, and grade 3 or more diarrhea in 3%.

BeiGene, Ltd, announced that zanubrutinib’s supplemental new drug application was accepted by the FDA on February 17, 2021.3 This drug has also been used to treat patients with mantle cell lymphoma (MCL), small lymphocytic leukemia, and chronic lymphocytic leukemia, and has been approved in MCL for adult patients who have received at least 1 prior line of therapy.

“We are delighted by today’s FDA approval for Brukinsa 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, Brukinsa can improve treatment outcomes for these patients and potentially make a positive impact on their lives,” commented Jane Huang, MD, chief medical officer, Hematology at BeiGene, in a press release.


1. U.S. FDA Grants Brukinsa® (zanubrutinib) approval in waldenström’s macroglobulinemia. News release. BeiGene, Ltd. September 1, 2021. Accessed September 1, 2021. https://bwnews.pr/3kOax0v

2. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. doi:10.1182/blood.2020006844

3. BeiGene Announces U.S. 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. https://bit.ly/37oVLaH

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