Zanubrutinib sNDA for Waldenström Macroglobulinemia Accepted in China

The China National Medical Products Administration has accepted a supplemental new drug application for zanubrutinib as a treatment for adult patients with Waldenström macroglobulinemia.

The China National Medical Products Administration (NMPA) has accepted a supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) as a treatment for adult patients with Waldenström macroglobulinemia.1

The application is supported by findings from the phase 3 ASPEN trial (BGB-3111-302; NCT03053400), which showed that treatment with zanubrutinib resulted in a combined complete response (CR) and very good partial response (VGPR) rate of 28% (95% CI, 20%-38%) per independent review committee (IRC) assessment in the overall intent-to-treat population vs 19% (95% CI, 12%-28%) with ibrutinib (Imbruvica).

Although this difference was not found to be statistically significant (P = .09), zanubrutinib produced higher VGPR rates and showcased a trend toward increased response quality.

“The sNDA acceptance is welcoming news and following [zanubrutinib’s] recent NMPA approval for patients with Waldenström macroglobulinemia in the relapsed or refractory setting, this represents an opportunity to expand access to more…patients in China, subject to NMPA approval,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, stated in a press release. “As demonstrated in the ASPEN trial, [zanubrutinib] can offer an efficacious treatment option with improved safety in regard to certain cardiovascular events, such as atrial fibrillation, for patients with Waldenström macroglobulinemia.”

The open-label phase 3 trial enrolled patients with relapsed/refractory Waldenström macroglobulinemia following at least 1 prior line of treatment or those with treatment-naïve disease who were not eligible to receive standard chemoimmunotherapy because of certain comorbidities or risk factors. To be eligible for enrollment, patients needed to have measurable disease, acceptable end-organ function, an absolute neutrophil count of 0.75 x 109/L, and a platelet count of 50 x 109/L.

Those who were previously exposed to BTK inhibition, those with disease transformation, active central nervous system lymphoma, significant cardiovascular disease, or who needed warfarin or another vitamin K antagonist, were excluded.

Study participants in cohort 1, who had MYD88L265P disease, were randomized 1:1 to receive ibrutinib at the approved once-daily dose of 420 mg, or zanubrutinib at a twice-daily dose of 160 mg, in 28-day treatment cycles. Treatment was given until disease progression or unacceptable toxicity.

Stratification factors included warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome–like mutation status, as well as number of prior therapies.

Those who had wild-type MYD88 disease or who had undetermined MYD88 mutation status comprised cohort 2, and these patients were given zanubrutinib on a third non-randomized treatment arm.

The primary end point of the trial was the proportion of patients in cohort 1 who achieved either a VFPR or a CR per IRC assessment and in accordance with 6th International Workshop on Waldenström Macroglobulinemia consensus criteria.

Secondary end points comprised major response rate (MRR) per IRC assessment, duration of response (DOR), progression-free survival (PFS), investigator-assessed efficacy outcomes, reductions in bone marrow and extramedullary tumor burden, and safety. Exploratory end points included overall survival (OS) and quality of life (QoL).

The trial enrolled a total of 164 patient with relapsed/refractory disease and 37 patients who were treatment naïve to cohort 1. Two of the patients who had relapsed/refractory disease were never dosed with treatment.

Key baseline characteristics were noted to be generally balanced between the 2 treatment arms, although more patients who received zanubrutinib were older than 75 years vs those who received ibrutinib, at 33% and 22%, respectively. Moreover, more patients who received zanubrutinib (66%) were anemic, with a hemoglobin of 110 g/dL or less, vs those given ibrutinib (54%).

Eleven percent of those on the investigative arm harbored a CXCR4WHIM mutation vs 8% of those on the control arm. Moreover, about 85% of patients were considered to have intermediate or high prognostic risk and 77% had extramedullary disease. More than 90% of patients who had relapsed/refractory disease had received 1 to 3 previous lines of treatment, with a median of 1 line in each treatment arm.

Results indicated that no patients achieved a CR with treatment, but the frequency of VGPRs per IRC assessment proved to be higher with zanubrutinib vs ibrutinib; this trend was observed in those with relapsed/refractory disease, at 29% vs 20%, respectively (P = .12), and in those who were treatment naïve, at 26% and 17%, respectively (P = .54).

Moreover, zanubrutinib resulted in a VGPR rate of 28% per investigator assessment vs 17% with ibrutinib (P = .04). The concordance rates between IRC- and investigator-assessed best responses were 94% and 95% in the investigative and control arms, respectively.

VGPR rates were found to be comparable between the treatment arms regarding key subgroups such as prognostic risk score of intermediate or high, being older than 65 years of age, having a hemoglobin of 110 g/L or less, a platelet count of 100 x 109/L or less, and β-2 microglobulin of 3 mg/dL or higher.

Overall, the MRR with zanubrutinib was 77% vs 78% with ibrutinib. In those with relapsed/refractory disease, the MRRs were 78% and 80%, respectively, and these rates were 74% and 67%, respectively, in those who were treatment naïve.

Regarding safety, zanubrutinib was found to have a more tolerable safety profile vs ibrutinib, with a lower frequency of certain toxicities like atrial fibrillation (2% vs 15%) and major hemorrhage (6% vs 9%).

The most common toxicities reported in those who received zanubrutinib included neutropenia, upper respiratory infection, and diarrhea. In those who were given ibrutinib, the most frequent adverse effects were diarrhea, upper respiratory infection, contusion, and muscle spasms.

Of the 101 patients who received zanubrutinib, 4% discontinued because of toxicities; 14% of patients required dose reductions because of toxicity.

In June 2021, the China NMPA granted a conditional approval to zanubrutinib for adult patients with Waldenström macroglobulinemia who previously received 1 therapy. The decision was based on data from a single-arm phase 2 trial (NCT03332173).3 At a median follow-up of 14.9 months, the BTK inhibitor elicited a MRR of 72.1% (95% CI, 56.3%-84.7%) per IRC assessment in Chinese patients with relapsed/refractory disease.

In March 2021, Health Canada approved zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia based on data from ASPEN.4 In September 2021, the FDA also approved zanubrutinib for adult patients with Waldenström macroglobulinemia, also based on ASPEN findings.5


  1. BeiGene announces acceptance of a supplemental new drug application in China for BRUKINSA (zanubrutinib) in Waldenström’s macroglobulinemia. News release. BeiGene, Ltd.; January 20, 2022. Accessed January 21, 2022.
  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 China NMPA approval of BRUKINSA (zanubrutinib) for the treatment of patients with relapsed or refractory Waldenström’s macroglobulinemia. News release. BeiGene, Ltd.; June 18, 2021. Accessed January 21, 2022.
  4. Health Canada approves BRUKINSA (zanubrutinib) for the treatment of Waldenström macroglobulinemia. News release. BeiGene, Ltd; March 2, 2021. Accessed Accessed January 21, 2022.
  5. US FDA grants BRUKINSA (zanubrutinib) approval in Waldenström’s Macroglobulinemia. News release. BeiGene, Ltd.; September 1, 2021. Accessed Accessed January 21, 2022.