Zanubrutinib Receives FDA Approval for Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) in adult patients can be treated with zanubrutinib (Brukinsa, BeiGene), a capsule medicine that received, on August 31, 2021, FDA (US Food and Drug Administration) approval. 

What Is Waldenstrom Macroglobulinemia?

Waldenstrom macroglobulinemia (WM) is a type of non-Hodgkin lymphoma (NHL). The cancer cells produce large amounts of an abnormal protein called macroglobulin. Another name for WM is lymphoplasmacytic lymphoma.

What Is Zanubrutinib’s Mechanism of Action?

Zanubrutinib is an inhibitor developed against the Bruton tyrosine kinase (BTK) enzyme. In B cells, the BTK enzyme is part of the cell signaling pathway’s receptor, which plays an important role in regulating proliferation. Inhibiting the BTK enzyme can prevent uncontrolled B-cell proliferation in B-cell malignancies. Zanubrutinib binds covalently to the BTK enzyme, leading to irreversible inhibition of the enzyme.

Zanubrutinib had previously received accelerated approval on November 14, 2019, for treatment-resistant or relapsed mantle cell lymphoma from the FDA (see the related approval).

The Study Behind Zanubrutinib’s FDA Approval in Waldenstrom Macroglobulinemia

Zanubrutinib was studied in WM patients carrying the MYD88 L265P mutation (MYD88MUT), in a randomized, active-controlled, open-label study comparing zanubrutinib with ibrutinib, called ASPEN.

The 201 patients in the first group were randomized to treatment until disease progression (worsening) or unacceptable toxicity, in a 1:1 ratio, to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily.

The second group included patients without the MYD88 mutation (MYD88WT): 26 patients, or 2 patients whose MYD88 mutation status was unknown. These patients received zanubrutinib 160 mg twice daily.

The main efficacy outcome used to support approval was the response rate, defined as partial response. An additional efficacy outcome measure was duration of response.

Results

• The response rate (complete response + very good partial response + partial response) was 77.5% (95% CI: 68.1.85.1) in the zanubrutinib arm.
• At month 12, the event-free response rate was 94.4% (95% CI: 85.8, 97.9) in the zanubrutinib arm.
• In the second group, the response rate was 50% (13 of 26 response-evaluable patients; 95% CI: 29.9, 70.1).

The most common (≥ %20) adverse reactions reported with zanubrutinib, including laboratory abnormalities, were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia and cough.

The recommended zanubrutinib dose is 160 mg orally twice daily or 320 mg orally once daily.