Zanubrutinib is a potent and highly selective small molecule inhibitor of Bruton’s tyrosine kinase (BTK), with demonstrated near complete BTK occupancy in peripheral blood mononuclear cells (PBMCs).¹ It has exposure coverage above its IC₅₀ during the entire dose interval for both BID and QD dosing schedules.²

Zanubrutinib is currently being evaluated in over 35 trials across 29 countries. In head-to-head clinical trials, zanubrutinib demonstrated a more favorable safety profile with fewer cardiovascular toxicities than ibrutinib.  Zanubrutinib’s non-cardiac safety profile is consistent with that reported for other BTKis.^3,4 Zanubrutinib is the only BTKi with proven superiority of PFS vs ibrutinib in the ALPINE trial, which included high-risk relapsed/refractory chronic lymphocytic leukemia (CLL) patients with del(17p)/TP53 and uIGHV.³

Zanubrutinib combination studies include sonrotoclax (BCL2 inhibitor), tislelizumab (anti-PD-1 mAb), BGB-10188 (PI3Kδ inhibitor), obinutuzumab (anti-CD-20 mAb), rituximab (anti-CD-20 mAb), lenalidomide + rituximab, and venetoclax (BCL2 inhibitor).

References

1. Tam, C. S. et al.Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019;134:851–859.
2. Tam, C. S., Ou, Y. C., Trotman, J. & Opat, S. Clinical pharmacology and PK/PD translation of the second-generation Bruton’s tyrosine kinase inhibitor, zanubrutinib. Expert Rev. Clin. Pharmacol 2021;14(11):1329-1344.
3. Brown, J. R. et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: Final comparative analysis of ALPINE. Blood 2024; 2024024667.
4. Dimopoulos, M. A, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: Final analysis from the randomized phase III ASPEN study. Clin. Oncol. 2023;41(33):5099-5106.

Bruton’s tyrosine kinase (BTK) is a 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 including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström’s macroglobulinemia (WM) and marginal zone lymphoma (MZL). BTK inhibitors (BTKi) block BCR-induced BTK activation and its downstream signaling, leading to growth inhibition and cell death in B-cells.¹

Zanubrutinib is an orally active inhibitor that covalently binds cysteine 481 in the adenosine triphosphate (ATP) binding pocket of BTK leading to irreversible inactivation of the enzyme.² Zanubrutinib was designed to minimize off-target inhibition of TEC and EGFR family kinases. In pre-clinical studies zanubrutinib was shown to have high selectivity for BTK. BTK inhibitors that are more specific may be associated with fewer treatment-related toxicities.²

References

1. Pal Singh, S., Dammeijer, F. & Hendriks, R. W. Role of Bruton’s tyrosine kinase in B cells and malignancies.  Cancer2018;17:57.
2. Tam, C. S. et al.Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019;134:851–859.

Zanubrutinib is indicated for the treatment of adult patients with:

• Waldenström’s macroglobulinemia (WM) after at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy.
• Marginal zone lymphoma (MZL) after at least one prior anti-CD20-based therapy.
• Chronic lymphocytic leukemia (CLL).
• Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after at least two prior systemic therapies.

Please see the Summary of Product Characteristics for important information on approved uses.

For a complete list of zanubrutinib monotherapy and combination clinical trials, view the pipeline.