Five-Year Follow-Up Data Show Zanubrutinib Improves Progression-Free Survival, Overall Survival in CLL/SLL

Zanubrutinib demonstrates statistically significant efficacy for the treatment of treatment-naive high-risk patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) with deletion of the short arm of chromosome 17 (del[17p]). The 5-year follow-up data from the SEQUOIA study (NCT03336333) are to be presented at the 2025 American Society of Clinical Oncology Annual Meeting.¹

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Zanabrutinib is a potent Bruton kinase (BTK) inhibitor that binds to BTK proteins with greater precision for longer durations and persists at high concentrations during treatment. It was approved by the FDA in 2019 for CLL/SLL based on initial data from the SEQUOIA trial, which showed superior progression-free survival (PFS) and high overall response rates (ORR) in patients with or without del(17p).²

SEQUOIA is a global, open-label, randomized phase 3 trial of zanubrutinib compared with bendamustine (Bendeka; Teva Pharmaceuticals) plus rituximab (Rituxan; Biogen, Genentech) in participants with previously untreated CLL/SLL with or without del(17p). The trial consists of 3 arms. Patients in arm A received oral zanubrutinib as two 80-mg capsules by mouth twice a day (160 mg total). In arm B, patients received bendamustine (intravenously [IV] 90 mg/m²/day on the first 2 days of each cycle for 6 cycles) plus rituximab (IV 375 mg/m² on day 0 of cycle 1; 500 mg/m² on day 1 of cycles 2 to 6).²

Arm C is a non-randomized cohort consisting of 111 patients with del(17p) (median age: 71; range: 42-87 years) who received zanubrutinib monotherapy (two 80-mg capsules twice daily [160 mg total]) between February 2018 and March 2019. Forty-seven patients (42%) had both a del(17p) and a TP53 mutation, 79 (71%) were male, and 67 (60%) were IGHV unmutated.²

Although the PFS was not met at the median follow-up of 65.8 months, the estimated 60-month PFS was 72.2% (62.4%-79.8%), or 73.0% (63.3%-80.6%) when adjusted for COVID-19. The median OS was also not met, but investigators report a 60-month estimate of 85.1% or 87% when adjusted for COVID-19. There was a clinically meaningful ORR of 97.3%, and a complete response/complete response with incomplete hematologic recovery rate was 18.2%.²

Of the population, treatment with zanubrutinib was ongoing in 62.2% of patients. Treatment discontinuation was primarily a result of adverse events (AEs; 17.1%) and progressive disease (15.3%). Specific AEs of interest (AEIs) consisted of any-grade infection (82%), bleeding (60%), neutropenia (19%), hypertension (18%), anemia (9%), thrombocytopenia (8%), and atrial fibrillation/flutter (7%). Additional AEs that were grades 3 through 5 included infection (33%), neutropenia (16%), hypertension (8%), bleeding (6%), atrial fibrillation/flutter (5%), and thrombocytopenia (2%).²

“Additionally, with longer-term follow-up, no new safety signals were identified,” the authors wrote in the abstract. “This update, in the largest cohort of uniformly treated patients with del(17p), suggests that zanubrutinib remains a valuable frontline treatment option for patients with or without del(17p) CLL/SLL.”²

REFERENCES

1. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). Updated March 7, 2025. Accessed May 27, 2025. https://clinicaltrials.gov/study/NCT03336333#study-plan

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.