FDA Approves Zanubrutinib for Waldenström Macroglobulinemia

On September 1, 2021, The Food and Drug Administration (FDA) approved zanubrutinib for the treatment of Waldenström macroglobulinemia (WM).

In an interview with Journal of Clinical Pathways, Constantine Tam, MD, MBBS, Peter MacCallum Cancer Centre, Melbourne, Australia, discusses the clinical results from the phase 3 ASPEN trial that led to the approval of zanubrutinib for the treatment of adult patients with WM in the United States.

What is zanubrutinib? 

Dr Tam: Zanubrutinib is a next-generation small molecule inhibitor of Bruton’s tyrosine kinase (BTK), currently being evaluated in a broad clinical program to treat various B-cell malignancies, including Waldenström macroglobulinemia (WM), chronic lymphocytic leukemia, mantle cell lymphoma, and marginal zone lymphoma.

BTK is a key component of the B-cell receptor (BCR) signaling pathway and is an important regulator of cell proliferation and cell survival in various B-cell malignancies. When cancer forms in B cells, they often rely on BTK to survive and grow. Zanubrutinib was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity.

What data led to the approval of zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia (WM)?

Dr Tam: The approval of zanubrutinib for the treatment of adult patients with WM in the United States is primarily supported by clinical results from the phase 3 ASPEN trial, a randomized global study comparing zanubrutinib vs ibrutinib in patients with relapsed or refractory (R/R) or treatment-naïve (TN) WM. A total of 201 patients with a MYD88 mutation (MYD88MUT) were randomized and enrolled in Cohort 1, with 102 receiving zanubrutinib 160 mg twice daily, and 99 receiving ibrutinib 420 mg once daily.

The primary efficacy endpoint of the ASPEN trial was very good partial response (VGPR) rate in the overall intention-to-treat (ITT) population as assessed by independent review committee (IRC). Based on the modified Sixth International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) response criteria (Treon 2015), the VGPR rate was 28% with zanubrutinib, and 19% with ibrutinib. Importantly, zanubrutinib was associated with less frequent occurrence of side-effects, including atrial fibrillation and hypertension, compared to ibrutinib.

Although the trial did not achieve statistical superiority, the results reinforced that zanubrutinib is a highly effective BTK inhibitor with clinically meaningful improvements in safety and tolerability compared to ibrutinib. 

What is the current treatment landscape for WM? How does zanubrutinib fit into the treatment paradigm?

Dr Tam: There are several treatment options available for patients with WM, including chemotherapy, stem cell transplants, radiation, immunotherapies, and targeted therapies. Treatment plans vary among patients based on disease stage, age, and overall health. In most parts of the world, chemotherapy is still the standard of care for WM treatment, but targeted therapies, such as BTK inhibitors, have been transforming the treatment landscape in various B-cell malignancies, including WM. 

Based on the results from the ASPEN trial, compared to the first-generation BTK inhibitor, zanubrutinib can provide clinical benefits and meaningful improvements in safety for patients with WM.

What is the safety profile of zanubrutinib?

Dr Tam: In the ASPEN trial, zanubrutinib was well-tolerated and demonstrated fewer adverse events leading to treatment discontinuation, as well as a lower frequency of atrial fibrillation/flutter or major bleeding, compared to ibrutinib. 

Based on the pooled safety population of 779 patients, the most common (≥20%) adverse reactions of zanubrutinib were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.

Will this approval have an immediate impact in real-world practice? What advice do you have for practicing oncologists interested in zanubrutinib their patients with WM?

Dr Tam: In countries where zanubrutinib has been approved as a treatment for WM, I hope the ASPEN trial results along with data in zanubrutinib’s broad clinical program can provide physicians with assurance in prescribing. Zanubrutinib has also been included as a category 1 preferred treatment option for patients with frontline and previously treated WM in the National Comprehensive Cancer Network (NCCN) guidelines. I would encourage oncologists to review existing literature and clinical results on zanubrutinib, and, based on their patients’ unique characteristics, including mutations and age, assess whether this could be the right treatment for them.

What value does zanubrutinib offer in comparison to other treatments for WM?

Dr Tam: BTK inhibitors are increasingly replacing chemotherapy-based treatment for B-cell malignancies, including WM. ASPEN trial results demonstrated that zanubrutinib could bring clinical benefits to patients with WM, and provide an improved safety profile compared to first-generation BTK inhibitor.

Among the leading BTK inhibitors, zanubrutinib is the only one capable of 100% potent, sustained inhibition in both peripheral blood mononuclear cells (PBMCs) and lymph nodes, when dosed at 160mg BID. Zanubrutinib has higher affinity to BTK and can maintain therapeutic concentrations for over 24 hours. Zanubrutinib can be co-administered with gastric acid-reducing agents, such as proton pump inhibitors (PPIs).