Five-Year Data Show Sustained Efficacy of Zanubrutinib in CLL With High Response Rates

Zanubrutinib (Brukinsa; BeiGene, Ltd) demonstrated sustained efficacy in an analysis of 5-year follow-up data from the SEQUOIA study (NCT03336333) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL; CLL/SLL) harboring del(17p) mutations. The data were presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago.¹

Blood smears showing increased counts of lymphocytes | Image Credit: © DigitalDruid - stock.adobe.com

Treatment for CLL/SLL has greatly improved over the past decades, but gaps remain. The introduction of Bruton kinase (BTK) inhibitors changed the therapeutic landscape, yielding improved responses and overall outcomes for patients. Zanubrutinib is a BTK inhibitor with multiple FDA approvals, including treatment of CLL/SLL, mantle cell lymphoma, follicular lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma. It received approval for CLL/SLL in 2023 based on data from the SEQUOIA trial, which showed superior progression-free survival (PFS) and overall response rate (ORR) in patients harboring del(17p) mutations.^2-4

“Zanubrutinib is a highly potent and selective next-generation BTK inhibitor that was designed to provide complete and sustained target inhibition supported by the PK data,” said Catherine Callaghan Coombs, MD, from the University of California, Irvine. “It's the only BTK inhibitor to demonstrate superiority over ibrutinib in a head-to-head phase 3 trial that included patients with high-risk disease with del(17p).”²

SEQUOIA is a global phase 3, open-label, randomized (1:1) study comparing zanubrutinib and bendamustine plus rituximab in participants with previously untreated chronic CLL/SLL with del(17p) (n = 111; 71% male). The study included 3 arms. Arm A was a randomized group in which patients received either zanubrutinib or bendamustine plus rituximab. Arms B and C were nonrandomized: patients in arm B received zanubrutinib, whereas those in arm C were treated with a combination of zanubrutinib and venetoclax. The key end points of the study were PFS, ORR, overall survival (OS), and safety.^1,2

PFS was not reached at a median follow-up of 65.8 months; however, the estimated 60-month PFS rate was 72.2% (95% CI, 62.4%-79.8%), or 73.0% (95% CI, 63.3%-80.6%) when adjusted for COVID-19. Median OS was also not reached, with an estimated 60-month OS rate of 85.1% (95% CI, 76.9%-90.6%), or 87.0% (95% CI, 79.0%-92.1%) with COVID-19 adjustment. The investigators reported an ORR of 97.3%, with a complete response/complete response with incomplete hematologic recovery rate of 18.2%.²

“Arm C of the SEQUOIA study showed that zanubrutinib and venetoclax have a robust efficacy and produce deep and durable responses in treatment-naive CLL, regardless of the presence of del(17p) P53 mutation,” concluded Coombs.²

The most common adverse effects (AEs) included any-grade infection (82%), bleeding (60%), neutropenia (19%), hypertension (18%), anemia (9%), thrombocytopenia (8%), and atrial fibrillation/flutter (7%). Grade 3 or higher AEs of interest were infection (33%), neutropenia (16%), hypertension (8%), bleeding (6%), atrial fibrillation/flutter (5%), and thrombocytopenia (2%). Zanubrutinib treatment was ongoing in 62.2% of patients at the time of analysis, and the most common reasons for treatment discontinuation were AEs (17.1%) and disease progression (15.3%).²

The data from the 5-year analysis of arm C validate and support the efficacy and safety of zanabrutinib for treatment-naïve patients with CLL/SLL harboring del(17p). Continued monitoring and study are needed to further solidify zanabrutinib’s role in the CLL treatment landscape, but these initial data are promising.

REFERENCES

1. A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL (SEQUOIA). Updated March 7, 2025. Accessed June 13, 2025. https://clinicaltrials.gov/study/NCT03336333

2. Tam C, Ghia P, Shadman M, et al. SEQUOIA 5-year follow-up in arm C: Frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). 2025 ASCO Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL. Abstract 7011

3. Brukinsa FDA approval history. Drugs.com. March 8, 2024. Accessed June 13, 2025. https://www.drugs.com/history/brukinsa.html

4. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed June 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma