Zanubrutinib Approved in China for Relapsed/Refractory Waldenström Macroglobulinemia

The China National Medical Products Administration has granted a conditional approval to zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia who have previously received at least 1 therapy.

The China National Medical Products Administration (NMPA) has granted a conditional approval to zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström macroglobulinemia who have previously received at least 1 therapy.1

The regulatory decision is supported by data from a single-arm phase 2 trial (NCT03332173), which showed that at a median follow-up of 14.9 months, the agent elicited a major response rate (MRR) of 72.1% (95% CI, 56.3%-84.7%) per independent review committee (IRC) assessment in Chinese patients with relapsed/refractory disease.

“With NMPA approval of [zanubrutinib], our next-generation BTK inhibitor, we are proud to be able to offer patients, their families, and physicians a new option for treating Waldenström macroglobulinemia an incurable disease that can cause significant morbidities,” Xiaobin Wu, PhD, general manager of China and president of BeiGene, stated in a press release. “This marks [zanubrutinib]’s third approval for the treatment of B-cell malignancies in China, and we believe it may serve an important role in addressing unmet needs for patients with blood cancers around the world.”

Findings from the phase 3 ASPEN trial (BGB-3111-302; NCT03053440) demonstrated that IRC-assessed very good partial responses (VGPR) were higher with zanubrutinib vs ibrutinib (Imbruvica) in patients with symptomatic Waldenström macroglobulinemia, at 28% and 19%, respectively (2-sided P = .09).2 No CRs were experienced with the treatment.

Concordance rates between IRC- and investigator-assessed best responses achieved with zanubrutinib and ibrutinib proved to be 94% and 95%, respectively. Moreover, IRC-evaluated best responses based on reductions in serum IgM alone and those based on the 6th International Workshop on Waldenström Macroglobulinemia consensus guidelines were concordant in 92% and 95% of patients, respectively.

Additionally, zanubrutinib elicited an MRR of 77% vs 78% with ibrutinib in all patients (n = 201); these rates were 78% and 80%, respectively, in patients with relapsed/refractory disease (n = 164), and 74% and 67%, respectively, in treatment-naïve patients (n = 37).

In the open-label phase 3 study, investigators compared the safety and efficacy of zanubrutinib vs ibrutinib in patients with Waldenström macroglobulinemia who required treatment based on consensus criteria.

To be eligible for inclusion, patients needed to have relapsed/refractory disease following at least 1 previous line of therapy or have treatment-naïve disease and were not able to receive standard chemoimmunotherapy based on the presence of documented comorbidities or risk factors. Patients also 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.

Patients could not participate if they had previously received a BTK inhibitor, had disease transformation, active central nervous system lymphoma, clinically significant cardiovascular disease, or if they needed warfarin or another vitamin K antagonist.

Patients with MYD88L265P disease were enrolled to cohort 1. These patients were randomized 1:1 to receive either ibrutinib at a once-daily dose of 420 mg or zanubrutinib at a twice-daily dose of 160 mg in 28-day treatment cycles until disease progression or unacceptable toxicity.

Patients were stratified based on warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome–like mutation status, and number of previous lines of therapy.

The primary end point of the trial was proportion of patients in cohort 1 who experienced a VGPR or CR per IRC assessment based on the 6th International Workshop on Waldenström Macroglobulinemia consensus criteria. Secondary end points comprised IRC-assessed MRR, duration of response (DOR), and progression-free survival (PFS).

Investigators also looked at reductions in bone marrow and extramedullary tumor burden, safety, and other investigator-assessed efficacy outcomes. Overall survival (OS) and quality of life served as exploratory end points.

At a median follow-up of 19.4 months, 79% of patients continued to receive study treatment and 89% remained on the study.

Additional data showed that 1 patient in each arm who harbored a CXCR4WHIM mutation experienced a VGPR. Moreover, 20% vs 31% of those who received zanubrutinib or ibrutinib, respectively, and had CXCR4WT disease achieved a VGPR. In these 2 subsets, zanubrutinib elicited MRRs of 63% and 80%, respectively; ibrutinib induced MRRs of 64% and 79%, respectively.

The median times to achieve a VGPR were skewed in favor of zanubrutinib, which investigators concluded owed to the large difference observed for patients with treatment-naïve disease, at 5.6 months vs 22.1 months with zanubrutinib and ibrutinib, respectively (P = .35). Among patients with relapsed/refractory disease, the times to achieve a VGPR were comparable, at 4.7 months and 5.1 months, respectively (P = .17).

Moreover, the median time to major response for both treatment arms was 2.8 months, and little difference was observed in the relapsed/refractory and treatment-naïve patient subgroups, or among those with CXCR4WT disease. Among the subgroup of patients with CXCR4WHIM disease, the median times to major response with zanubrutinib or ibrutinib were 6.6 months and 3.1 months, respectively. The median DOR had not been reached in either arm.

After a median follow-up for PFS of 18.0 months and 18.5 months, respectively, 15% of patients who received zanubrutinib died vs 16% of those who were given ibrutinib. The median PFS had not yet been reached in either treatment arm.

Additionally, the 18-month event-free rates in the investigative and control arms were 85% and 84%, respectively; in the relapsed/refractory subset, these rates were 86% and 82%, respectively. Six patients who received zanubrutinib (3 relapsed/refractory, 3 treatment naïve) and 8 patients given ibrutinib (all relapsed/refractory) died. The estimated 18-month OS rates with zanubrutinib and ibrutinib were 97% and 93%, respectively.

Regarding safety, the most frequent adverse effects (AEs) reported with zanubrutinib included neutropenia, upper respiratory infection, and diarrhea; the most common AEs with ibrutinib comprised diarrhea, upper respiratory infection, contusion, and muscle spasms.

Moreover, atrial fibrillation, diarrhea, contusion, muscle spasms, peripheral edema, and pneumonia were all experienced at 10% or higher incidence with ibrutinib vs zanubrutinib. Neutropenia was reported in 10% or higher incidence among those who were given zanubrutinib.

Sixty-three percent vs 58% of those in the investigative and control arms, respectively, experienced AEs that were grade 3 or higher in severity.

“[Zanubrutinib] was specifically designed by BeiGene scientists to limit off-target effects seen with first-generation BTK inhibitors and we have built a broad clinical development program to assess clinical benefit, including the head-to-head ASPEN trial,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, added in the press release.


  1. BeiGene announces China NMPA approval of BRUKINSA (zanubrutinib) for the treatment of patients with relapsed or refractory Waldenström’s macroglobulinemia. News release. BeiGene. June 18, 2021. Accessed June 21, 2021.
  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