Zanubrutinib Plus Venetoclax Yields High Response Rates in Treatment-Naive CLL/SLL

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Zanubrutinib (Brukinsa) plus venetoclax (Venclexta) displayed robust response rates in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to results from the phase 3 SEQUOIA trial (NCT03336333) presented during the 2025 ASCO Annual Meeting.

At a median follow-up of 31.2 months (range, 0.4-58.0), patients in arm D (n = 114) experienced an objective response rate (ORR) of 97.4%. Furthermore, the ORR among patients with 17p deletions and/or TP53 wild-type disease (n = 66) was 98.5%, and among those without 17p deletions and/or TP53-mutant disease (n = 47), it was 95.7%. The complete response (CR)/CR with incomplete hematopoietic recovery rate for the total population was 48.3%, with rates in the groups with 17p deletions and/or TP53 wild-type disease, as well as those without 17p deletions or TP53-mutant disease, of 47.0% vs 48.9%, respectively.

Additional data showed that patients experienced a peripheral blood undetectable minimal residual disease (MRD) rate of 59%, including 60% of patients without TP53 wild-type disease and/or 17p deletions and 59% of those with 17p deletions and/or TP53-mutant disease. The 24-month progression-free survival (PFS) rates in each group, respectively, were 92% (95% CI, 85%-96%), 89% (95% CI, 76%-95%), and 94% (95% CI, 85%-98%).

“Arm D of [the phase 3] SEQUIOA study showed that zanubrutinib plus venetoclax has a robust efficacy and produces deep and durable responses in treatment-naïve CLL regardless of the presence of [17p deletions] or TP53 mutations,” Mazyar Shadman, MD, MPH, associate professor of Clinical Research and medical director of Cellular Immunotherapy at the Fred Hutch Cancer Center in Seattle, Washington, stated during the presentation. “The best [undetected] MRD rate in peripheral blood was 59%...[and] the safety profile was favorable with no new safety signals [identified].”

Unpacking the Study Design

Patients in arm D of the SEQUOIA trial received 160 mg of twice daily zanubrutinib plus venetoclax ramped up to 400 mg once daily from cycle 4 to 28. After cycle 28, zanubrutinib monotherapy was given until disease progression, unacceptable toxicity, or fulfillment of undetectable MRD stopping rules for either agent in peripheral blood and bone marrow on 2 consecutive tests at least 12 weeks apart.

A total of 58% of the patient population had 17p deletions and/or TP53 mutations, with 41% not expressing either. The median age was 67 years (range, 26-87), 56% of patients were males, and 75% had unmutated immunoglobulin heavy chain variable status. A total of 98% of patients had an ECOG performance status of 0 or 1, the median creatinine clearance was 76 mL/min (range, 25-355), and 37% of patients had 17p deletions and TP53 mutations.

The end points for arm D of the trial included investigator-assessed PFS, investigator-assessed ORR, overall survival, undetected MRD rate, and safety.

Safety Data

The most common any-grade treatment-emergent adverse effects (TEAEs) included COVID-19 infection (54%), diarrhea (41%), contusion (32%), and nausea (30%). Additionally, the most common grade 3 or higher TEAEs included neutropenia (17%), hypertension (10%), and diarrhea (6%). A total of 5 patients died due to AEs.

The study was conducted to better ascertain the efficacy of B-cell lymphoma and Bruton tyrosine kinase inhibitors (TKIs) in patients with CLL or SLL with 17p deletions or TP53 mutations. Previous studies found that zanubrutinib monotherapy demonstrated enhanced PFS outcomes in CLL/SLL, being the only Bruton TKI to demonstrate superiority vs ibrutinib (Imbruvica) in phase 3 trials, including for those with high-risk 17p deletions.

Disclosures: Shadman reported being employed by Bristol-Myers Squibb. He also holds consulting or advisory roles for Abbvie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Fate Therapeutics, Genentech, Genmab, Kite, a Gilead company, Lilly, Merck, MorphoSys, Nurix, Pharmacyclics, and Regeneron. He received research funding from Abbvie, Acerta Pharma, BeiGene, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Genmab, Merck, MustangBio, Pharmacyclics, Sunesis Pharmaceuticals, TG Therapeutics, and Vincerx Pharma.

Reference

Shadman M, Munir T, Ma S, et al. Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL/SLL: results in SEQUOIA arm D. J Clin Oncol. 2025;43(suppl 16):7009. doi:10.1200/JCO.2025.43.16_suppl.7009