Zanubrutinib Extends PFS vs Acalabrutinib Plus Venetoclax in Untreated, Low-Risk CLL

Zanubrutinib (Brukinsa) produced a significant improvement in median progression-free survival (PFS) compared with fixed-duration acalabrutinib(Calquence) plus venetoclax (Venclexta) in patients with treatment-naive, low-risk chronic lymphocytic leukemia (CLL), according to data from a network meta-analysis presented during the 2025 SOHO Annual Meeting.1

Findings from the analysis revealed that patients who received zanubrutinib (n = 199) experienced a reduction in the risk of disease progression or death of 54% compared with those who received acalabrutinib plus venetoclax (n = 291), per investigator assessment (HR, 0.46; 95% CI, 0.28-0.76). The 36-month PFS rates were 85.6% and 78.9%, respectively.

“In the absence of head-to-head trials, [we] conducted a network meta-analysis to estimate the relative efficacy of continuous zanubrutinib vs fixed-duration acalabrutinib plus venetoclax in low-risk, treatment-naive patients with CLL,” lead study author Mazyar Shadman, MD, MPH, and his coauthors wrote in a poster presentation of the findings. “[Data from] the network meta-analysis found a statistically significant improvement in PFS for zanubrutinib over acalabrutinib plus venetoclax in patients with low-risk, treatment-naive CLL.”

Shadman is a professor in the Clinical Research Division, the medical director of Cellular Immunotherapy, and the Innovators Network Endowed Chair at Fred Hutchinson Cancer Center in Seattle, Washington, where he is also the medical director of the Bezos Family Immunotherapy Clinic, a member of the Immunotherapy Integrated Research Center, and an affiliate investigator in the Translational Science and Therapeutics Division. He is also a professor in the Department of Hematology and Oncology at the University of Washington School of Medicine.

In January 2023, zanubrutinib was approved by the FDA for the treatment of patients with CLL/small lymphocytic lymphoma.2 The approval was supported by data from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.

In July 2025, a supplemental new drug application (sNDA) seeking the approval of fixed-duration duration acalabrutinib plus venetoclax in patients with treatment-naive CLL was submitted to the FDA.3 The sNDA was supported by data from the phase 3 AMPLIFY trial (NCT03836261).

What were the methods of the meta-analysis evaluating zanubrutinib in previously untreated, low-risk CLL?

To conduct their analysis, the study authors performed a systematic literature review to identify phase 3 randomized controlled trials that included patients with low-risk CLL.1 Low-risk patients were defined based on prespecified trial definitions and included those without 17p deletions or TP53 mutations. The primary analysis consisted of investigator-assessed PFS outcomes from SEQUOIA and AMPLIFY. A subgroup analysis per IGHV mutational status was also conducted.

The SEQUOIA trial data inputs used in the analysis included a PFS benefit per investigator assessment with zanubrutinib (n = 199) vs BR (n = 199; HR, 0.27; 95% CI, 0.18-0.40). The median follow-up for SEQUOIA was 43.7 months. The AMPLIFY trial data inputs included an investigator-assessed PFS benefit with acalabrutinib plus venetoclax (n = 291) vs FCR/BR (n = 290; HR, 0.58; 95% CI, 0.43-0.78) and an IRC-assessed PFS advantage also favoring the acalabrutinib/venetoclax arm (HR, 0.65; 95% CI, 0.49-0.87). The median follow-up for AMPLIFY was 41.0 months.

The study authors noted that at the time of the SOHO abstract submission, the network meta-analysis was conducted based on data availability from the interim analysis of AMPLIFY, which reported only independent review committee (IRC)–assessed PFS in the common control arm of fludarabine plus cyclophosphamide and rituximab (Rituxan).

What were the additional efficacy findings with zanubrutinib in low-risk CLL?

Additional data from the network meta-analysis showed that patients with low-risk, IGHV-unmutated disease who received zanubrutinib achieved a significant PFS benefit vs those who were treated with acalabrutinib plus venetoclax (HR, 0.30; 95% CI, 0.16-0.57). Moreover, patients with IGHV-mutated disease also experienced a PFS benefit in favor of zanubrutinib (HR, 0.49; 95% CI, 0.21-1.13).

Data from the sensitivity analysis of investigator-assessed PFS and IRC-assessed PFS demonstrated consistent results with a HR of 0.42 (95% CI, 0.25-0.71) in favor of zanubrutinib. The results were also consistent when adjusted for COVID-19, with an HR of 0.28 (95% CI, 0.16-0.49) in favor of zanubrutinib.

“While the network meta-analysis is an indirect comparison method that preserves trial randomization, the study results should be interpreted under the inherent limitations and assumptions of [a] network meta-analysis,” Shadman and his coauthors wrote in conclusion.

Disclosures: Shadman reported being employed by Bristol-Myers Squibb. He also reported consulting or advisory roles with AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeOne, Bristol-Myers Squibb, Celgene, Morphosys, Kite, Fate Therapeutics, Lilly, Genmab, Merck, Nurix, and ADC Therapeutics. He also reported receiving research funding from Pharmacyclics, Acerta Pharma, Merck, TG Therapeutics, Celgene, Genentech, Mustang Bio, AbbVie, Sunesis Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genmab, and Vincerx Pharma. He also reported owning stock options in Koi Biotherapeutics.

References

1. Shadman M, Yang K, Xu S, Williams R, Munir T. A network meta-analysis of efficacy of zanubrutinib vs fixed-duration acalabrutinib plus venetoclax in treatment-naive chronic lymphocytic leukemia. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Abstract CLL-1029.
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed September 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. AbbVie submits for U.S. FDA approval of combination treatment of Venclexta (venetoclax) and acalabrutinib for previously untreated patients with chronic lymphocytic leukemia (CLL). News release. AbbVie. July 29, 2025. Accessed September 4, 2025. https://news.abbvie.com/2025-07-29-AbbVie-Submits-for-U-S-FDA-Approval-of-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-with-Chronic-Lymphocytic-Leukemia-CLL