Five-year follow-up data from the phase 3 SEQUOIA study provide compelling evidence for zanubrutinib's sustained efficacy in treating treatment-naive chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients, particularly those with high-risk del(17p) mutations. The findings, presented at the 2025 American Society of Clinical Oncology Annual Meeting, demonstrate significant improvements in both progression-free survival and overall survival outcomes.
Study Design and Patient Population
The SEQUOIA trial (NCT03336333) is a global, open-label, randomized phase 3 study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL/SLL. The study's arm C represents the largest cohort of uniformly treated patients with del(17p), consisting of 111 patients with a median age of 71 years (range: 42-87 years) who received zanubrutinib monotherapy between February 2018 and March 2019.
The patient population in arm C was characterized by high-risk features: 47 patients (42%) had both del(17p) and TP53 mutations, 79 (71%) were male, and 67 (60%) had IGHV unmutated status. Patients received oral zanubrutinib as two 80-mg capsules twice daily (160 mg total).
Efficacy Outcomes
At a median follow-up of 65.8 months, the study demonstrated robust long-term efficacy. Although the median progression-free survival was not reached, the estimated 60-month PFS was 72.2% (95% CI: 62.4%-79.8%), or 73.0% (95% CI: 63.3%-80.6%) when adjusted for COVID-19 impact. Similarly, the median overall survival was not met, with investigators reporting a 60-month OS estimate of 85.1%, or 87% when adjusted for COVID-19.
The study achieved a clinically meaningful overall response rate of 97.3%, with a complete response/complete response with incomplete hematologic recovery rate of 18.2%. These results underscore zanubrutinib's therapeutic potential in this challenging patient population.
Treatment Persistence and Safety Profile
Treatment with zanubrutinib was ongoing in 62.2% of patients at the time of analysis. Treatment discontinuation occurred primarily due to adverse events (17.1%) and progressive disease (15.3%). The safety profile remained consistent with previous reports, with no new safety signals identified during the extended follow-up period.
Specific adverse events of interest included any-grade infection (82%), bleeding (60%), neutropenia (19%), hypertension (18%), anemia (9%), thrombocytopenia (8%), and atrial fibrillation/flutter (7%). Grade 3-5 adverse events comprised infection (33%), neutropenia (16%), hypertension (8%), bleeding (6%), atrial fibrillation/flutter (5%), and thrombocytopenia (2%).
Clinical Significance
Zanubrutinib, a potent Bruton kinase (BTK) inhibitor, binds to BTK proteins with greater precision for longer durations and persists at high concentrations during treatment. The FDA approved zanubrutinib in 2019 for CLL/SLL based on initial SEQUOIA trial data showing superior progression-free survival and high overall response rates in patients with or without del(17p).
According to the study authors, "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." The long-term data provide crucial insights into the durability of response and confirm zanubrutinib's role as an effective therapeutic option for this patient population.
