FDA Accepts sNDA for Zanubrutinib in Adult Waldenström Macroglobulinemia


The FDA has accepted a supplemental New Drug Application for zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia.

The FDA has accepted a supplemental New Drug Application (sNDA) for zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström macroglobulinemia (WM). The application will undergo a traditional review process and has a Prescription Drug User Fee Act target action date of October 18, 2021, announced BeiGene, Ltd, in a press release.1

“We are pleased that the FDA has accepted the sNDA for BRUKINSA in WM, a rare disease with significant morbidity. BTK inhibitors have transformed the treatment of WM in recent years, but discrepancies in response exist in patients with different subtypes, and toxicity can remain an issue,” said Jane Huang, MD, chief medical officer, Hematology, BeiGene, Ltd, in a statement.

Several clinical trials support the sNDA for zanubrutinib, including the global phase 3 ASPEN trial, which compared zanubrutinib to ibrutinib (Imbruvica) as treatment of WM (NCT03053440), a pivotal phase 2 trial Chinese study of zanubrutinib as treatment of patients with relapsed or refractory WM (NCT0333217), as well as a global phase 1/2 trial of zanubrutinib in patients with B-cell malignancies (NCT02343120), inclusive of WM. The application also references safety data from 6 clinical trials that include a total of 779 patients with WM treated with zanubrutinib.

Results from the ASPEN trial were presented during the 2020 American Society of Hematology (ASH) Annual Meeting and subsequently published in Blood.2 In the study, zanubrutinib achieved higher rates of very good partial responses (VGPRs) compared with ibrutinib. Zanubrutinib also led to fewer Bruton’s tyrosine kinase (BTK)–associated toxicities compared with ibrutinib.

Execution of the ASPEN study was rationalized by data from the phase 1/2 study of zanubrutinib monotherapy in patients with B-cell malignancies, which showed that 45% of patients in the 73-patient WM cohort achieved either a complete response (CR) or VGPR. It was also shown that 82% achieved a major response after a median follow-up of 32.7 months. In terms of safety, the phase 1/2 data demonstrated a well-tolerated safety profile with the relevant toxicities being atrial fibrillation (5%), major hemorrhage (4%), and grade ≥3 diarrhea (3%).

For the purposes of the ASPEN study, 164 patients with relapsed/refractory disease and 37 patients who were treatment naïve from 58 sites were enrolled. Patients were randomized 1:1 to receive ibrutinib at the FDA-approved dose of 420 mg once daily or zanubrutinib, at a dose of 160 mg twice daily, in 28-day cycles until progression or intolerance. In a second cohort, patients were nonrandomized and received zanubrutinib. Unlike cohort 1, patients in cohort 2 were positive for either wild-type MYD88 or had an undetermined MYD88 mutation status.

The primary end point of the study was VGPR or CR, assessed per an independent review committee (IRC). The secondary end point included IRC-assessed major response rate (MRR), duration of response (DOR), and progression-free survival (PFS), investigator-assessed efficacy outcomes, reductions in bone marrow and extramedullary tumor burden, and safety. As exploratory end points, the study assessed overall survival and changes in quality of life.

Zanubrutinib led to a VGPR rate of 28% compared with 19% in the ibrutinib arm, as assessed by the IRC. Although higher with zanubrutinib, the result was not considered to be statistically significant (2-sided P = .09). Looking by disease setting, the VGPR rate observed with zanubrutinib in the relapsed/refractory population was 29% versus 20% with ibrutinib (P = .12). In patients who were treatment naïve, the VGPR rate was 26% with zanubrutinib versus 17% with ibrutinib (P = .54). According to the investigators’ assessment, the VGPR rate was 28% with zanubrutinib compared with 17% in the ibrutinib-treated population (P = .04).

The MRR observed in the overall study population of patients treated with zanubrutinib was 77%. In relapsed/refractory patients, the MRR was 78%, and in treatment-naïve patients, the MRR was also 78%. Noninferiority of zanubrutinib compared with ibrutinib was not tested in this study.

After a median follow-up for PFS of 18.0 months in the zanubrutinib arm and 18.5 months in the ibrutinib arm, 15% and 16% of patients, respectively, progressed on treatment or died. The median PFS was not evaluable for either arm. Both patients in the zanubrutinib arm and those who were in the ibrutinib arm had comparable event-free rates of 85% and 84%, respectively, at 18 months. In addition, those who were previously treated had compared event-free rates of 86% and 82% in the zanubrutinib and ibrutinib arms, respectively, at 18 months.

In terms of safety, the most common AEs among zanubrutinib-treated patients were neutropenia, upper respiratory infection, and diarrhea, which occurred in >20% of patients. In patients treated with ibrutinib, the most common AEs were diarrhea, upper respiratory infection, contusion, and muscle spasms. Grade ≥3 AEs were reported in 58% of the zanubrutinib arm versus 63% of the ibrutinib arm. Also, grade ≥3 hypertension and pneumonia had a ≥5% higher incidence in patients who received ibrutinib compared with those who received zanubrutinib, and the incidence rate of grade ≥3 neutropenia was ≥5% higher among patients treated with zanubrutinib.

Serious AEs occurred in 40% of the zanubrutinib arm versus 41% of the ibrutinib arm. The most common serious AEs were pneumonia, neutropenia, and febrile neutropenia.

Regarding the FDA’s review of the sNDA for zanubrutinib, Huang stated in the press release: “We look forward to continuing our communications with the FDA in the coming months and hope that Brukinsa will become a new treatment option for patients with WM in the United States.”

In addition to WM, zanubrutinib is used to treat patients with mantle cell lymphoma (MCL), small lymphocytic leukemia (SLL), and chronic lymphocytic leukemia (CLL). The agent is FDA approved for the treatment of MCL in adult patients who have received at least one prior therapy.

For the treatment of WM, zanubrutinib has applications submitted for regulatory approval in the European Union, Canada, Australia, China, Taiwan, and South Korea. There are also over 20 marketing applications for zanubrutinib submitted across 45 countries.


1. 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

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

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