Zanubrutinib Outperforms Acalabrutinib in Adjusted Head-to-Head Analysis

In a head-to-head study, zanubrutinib (Brukinsa; BeiGene, Ltd) demonstrated superior investigator-assessed progression-free survival (PFS-INV) and complete response (CR) to acalabrutinib (Calquence; AstraZeneca Pharmaceuticals LP), with a trend toward improvement in overall survival (OS), in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL). The findings from the unanchored matching-adjusted indirect comparison (MAIC) were published in Therapeutic Advances in Medical Oncology.¹

Box of zanubrutinib capsules | Image Credit: © luchschenF - stock.adobe.com

Treatment for CLL has advanced significantly in recent decades, yet therapeutic gaps persist. The emergence of Bruton tyrosine kinase (BTK) inhibitors reshaped the treatment landscape, offering improved response rates and long-term outcomes. Zanubrutinib, a next-generation covalent BTK inhibitor, has received multiple FDA approvals—including for CLL/small lymphocytic leukemia (SLL), mantle cell lymphoma, follicular lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma. Its 2023 approval for CLL/SLL was based on results from the SEQUOIA trial (NCT03336333), which demonstrated significantly improved PFS and overall response rate (ORR), particularly in patients with the high-risk del(17p) mutation.^2,3

“Zanubrutinib represents an appropriate BTK [inhibitor] for patients with [RR CLL] due to its high affinity and inhibition potency for BTK, and because it is the only BTK [inhibitor] that maintains plasma levels above IC50 for 24 hours,” the authors wrote. “Zanubrutinib is the only BTK [inhibitor] to demonstrate [PFS] superiority versus ibrutinib in [RR CLL] in ALPINE [NCT03734016], which was sustained with an extended follow-up of 39 months.”^1,4

Until this study, there were no head-to-head studies of zanubrutinib and acalabrutinib. The researchers performed an unanchored MAIC using individual patient-level data from the ALPINE and ASCEND (NCT02970318) trials. Data from the ALPINE trial were reweighted using prognostic and effect-modifying variables to align with the aggregate patient population characteristics from the ASCEND trial. The primary end point was overall response, with key secondary end points including PFS-INV, independent review committee-assessed PFS (PFS-IRC), and OS.^1,5

The ALPINE trial population for zanubrutinib was narrowed to patients with complete data on key baseline characteristics, reducing the sample from 327 to 308. After adjusting the population to match ASCEND, the effective sample size dropped to 185 (60% of the filtered group). Before adjustment, there were differences between the zanubrutinib and acalabrutinib groups in IGHV mutation status, TP53 status, and geographic region. After matching, these differences were eliminated.¹

In the unadjusted group, zanubrutinib showed a trend toward superior PFS-INV compared with acalabrutinib, with a hazard ratio (HR) of 0.77 (95% CI: 0.55–1.07; P = .1213). After matching, zanubrutinib demonstrated significantly improved PFS-INV (HR = 0.68; 95% CI: 0.46–0.99; P = .0448) and a trend toward better OS (HR = 0.60; 95% CI: 0.35–1.02; P = .0575).¹

The odds of achieving a CR were significantly higher with zanubrutinib in both the unadjusted (OR = 2.88; 95% CI: 1.18–7.02; P = .0198) and adjusted analyses (OR = 2.90; 95% CI: 1.13–7.43; P = .0270). Sensitivity analyses confirmed these results, showing consistent benefits in PFS-INV and CR for zanubrutinib.¹

“The findings from this study help us better understand how zanubrutinib and acalabrutinib compare for the treatment of patients with CLL,” the authors wrote. “This is important information, but it should be noted that testing 2 medications in the same clinical trial remains the best way to compare their effects.”¹

REFERENCES

1. Shadman M, Brown J, Tam C, et al. Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC). Therapeutic Advances in Medical Oncology. July 8, 2025. Accessed July 15, 2025. https://journals.sagepub.com/doi/10.1177/17588359251340554?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

2. Gerlach A. Five-year data show sustained efficacy of zanubrutinib in CLL with high response rates. Pharmacy Times. June 13, 2025. Accessed July 15, 2025. https://www.pharmacytimes.com/view/five-year-data-show-sustained-efficacy-of-zanubrutinib-in-cll-with-high-response-rates

3. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). Updated March 7, 2025. Accessed July 15, 2025. https://clinicaltrials.gov/study/NCT03336333

4. A Study of acalabrutinib vs investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab in R/​R CLL. Updated February 19, 2025. Accessed July 15, 2025. https://clinicaltrials.gov/study/NCT02970318

5. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/​refractory chronic lymphocytic leukemia (ALPINE). Updated March 30, 2025. Accessed July 15, 2025. https://clinicaltrials.gov/study/NCT03734016