Zanubrutinib Approaches EU Approval for Waldenström Macroglobulinemia


The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion regarding the use of zanubrutinib in adult patients with Waldenström macroglobulinemia who have previously received at least 1 therapy or in the frontline treatment of patients who are not eligible for chemoimmunotherapy.

Professor Christian Buske, MD

Professor Christian Buske, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion regarding the use of zanubrutinib (Brukinsa) in adult patients with Waldenström macroglobulinemia who have previously received at least 1 therapy or in the frontline treatment of patients who are not eligible for chemoimmunotherapy.1

The recommendation is based on data from the phase 3 ASPEN trial (NCT03053440), which showed that the agent elicited a combined complete response/very good partial response (CR+VGPR) rate of 28.4% (95% CI, 20%-38%) vs 19.2% (95% CI, 12%-28%) with ibrutinib (Imbruvica) in the overall intention-to-treat (ITT) population comprised of 201 patients (P = .0921).2

Although the difference was not determined to be statistically significant, numerically higher VGPR rates were reported with zanubrutinib and trended toward increased response quality vs ibrutinib, according to BeiGene.

“BTK inhibitors have emerged as a promising treatment for Waldenström macroglobulinemia, yet treatment discontinuation due to lack of response or adverse effects remains a concern,” Professor Christian Buske, MD, trial investigator and medical director at the University Hospital Ulm, stated in a press release. “The ASPEN trial demonstrated that [zanubrutinib] provided deep and durable responses and offered substantial improvements in safety and tolerability over standard therapy. Patients in Europe with Waldenström macroglobulinemia may soon have a new treatment option that can offer improved outcomes.”

The ASPEN trial enrolled patients with a histologic diagnosis of Waldenström macroglobulinemia who had a MYD88 mutation and did not receive prior BTK inhibitors. Cohort 1 of the trial was comprised of those with MYD88-mutated disease (n = 201) and cohort 2 enrolled patients with MYD88 wild-type disease (n = 28).

Participants in cohort 1 were randomized 1:1 to receive zanubrutinib at a once-daily dose of 160 mg (n = 102) or ibrutinib at a once-daily dose of 420 mg (n = 99). Treatment was administered until disease progression. Those in cohort 2 just received zanubrutinib at a once-daily dose of 160 mg until disease progression.

Stratification factors included CXCR4 status (CXCR4WHIM vs CXCR4WT vs missing) and number of prior liens of therapy (0 vs 1 to 3 vs 3 or more).

The primary objective was to compare the efficacy of the 2 agents, with a focus on CR+VGPR in patients whose tumors harbored activating MYD88 mutations. Investigators also sought to compare the efficacy, clinical benefit, and anti-lymphoma effects of zanubrutinib vs ibrutinib, and to assess the safety and tolerability of the 2 agents. Exploratory objectives comprised pharmacokinetics and quality of life.

At a median follow-up of 19.4 months, 98 patients received ibrutinib and 101 patients received zanubrutinib. Moreover, 77.8% and 79.4% of patients, respectively, were still on study treatment. Twenty patients on the zanubrutinib arm discontinued treatment, with 7 doing so due to disease progression, 4 due to toxicities, 5 because of patient decision, 2 because of investigator decision, and 2 for another reason; 21 patients on the ibrutinib arm discontinued.

The median age of patients spanning the study arms was 70 years (range, 38-90), with 70.7% of patients on the ibrutinib arm over 65 years of age and 33.3% of those on zanubrutinib older than 75 years. Moreover, 66.7% of patients were male, 74.6% received 1 to 3 prior therapies, and 45.3% had high-risk disease per the International Prognostic Scoring System for Waldenström Macroglobulinemia. In the zanubrutinib arm, 65.7% of patients had hemoglobin of 110 g/L or higher.

Additional results indicated that at an August 2019 data cutoff, the CR+VGPRs for zanubrutinib and ibrutinib were 28.4% and 17.2%, respectively (P = .0437). At the January 2020 data cutoff, these rates were 30.4% and 18.2%, respectively (P = .0302). The area under the curve for IgM reduction over time was noted to be significantly greater for zanubrutinib vs ibrutinib (P = .037).

Moreover, in the ITT population, the estimated 12-month PFS rates with zanubrutinib and ibrutinib were 89.7% and 87.2%, respectively. The estimated 12-month OS rate with zanubrutinib was 97.0% vs 93.9% with ibrutinib.

Regarding safety, zanubrutinib was found to have a better profile than ibrutinib, with lower frequency of certain toxicities such as atrial fibrillation or flutter (2.0% vs 15.3%, respectively), minor bleeding (48.5% vs 59.2%), and major hemorrhage (5.9% vs 9.2%).

Additionally, 9.2% of patients on ibrutinib discontinued treatment because of a toxicity vs 4.0% of those on zanubrutinib. AEs resulted in a dose reduction in 23.5% of those on control arm vs 13.9% of those on the investigational arm; toxicities resulted in dose interruptions in 56.1% and 46.5% of patients, respectively.

“The positive CHMP opinion reflects [zanubrutinib’s] potential role in the Waldenström macroglobulinemia therapeutic landscape as a selective inhibitor designed to deliver sustained and continuous inhibition of BTK, offering patients the potential for reduced frequency of certain cardiovascular events like atrial fibrillation compared to ibrutinib, and underscores our bold approach to R&D,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, stated in a press release. “We are committed to advancing the global registration of [zanubrutinib] and, if approved, believe it will become the preferred BTK inhibitor for patients with Waldenström macroglobulinemia.”

A final decision on the marketing application is anticipated within 67 days of the receipt of the CHMP opinion and the decision will be applied to all 27 member states in the European Union plus Iceland and Norway.

In September 2021, the FDA approved zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia based on data from ASPEN.3


  1. BeiGene receives positive CHMP opinion for BRUKINSA (zanubrutinib) for the treatment of adults with Waldenström’s macroglobulinemia. News release. BeiGene. September 17, 2021. Accessed September 17, 2021.
  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. J Clin Oncol. 2020;38(suppl 15):8007. doi:10.1200/JCO.2020.38.15_suppl.8007
  3. US FDA grants BRUKINSA (zanubrutinib) approval in Waldenström’s Macroglobulinemia. News release. BeiGene. September 1, 2021. Accessed September 17, 2021.
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