Zanubrutinib Outlasting Acalabrutinib in CLL

New real-world data show patients with chronic lymphocytic leukemia (CLL) stayed on zanubrutinib (Brukinsa; BeOne Medicines) significantly longer than acalabrutinib (Calquence; AstraZeneca) as first-line therapy, according to a retrospective analysis published in Future Oncology.¹ The findings add community-practice evidence to a comparison that has so far relied on trial-matched indirect analyses, since acalabrutinib and zanubrutinib have never been studied against each other in a head-to-head randomized trial.

Acalabrutinib and zanubrutinib are second-generation covalent Bruton tyrosine kinase (BTK) inhibitors and are listed as category 1 preferred regimens for treatment-naive CLL under National Comprehensive Cancer Network guidelines.² Both were developed to improve on the selectivity of first-generation ibrutinib and reduce the cardiovascular toxicity that has limited its use.³ But because acalabrutinib and zanubrutinib have never been compared directly in a randomized trial, clinicians and payers have had limited data to weigh one against the other in routine practice.¹

Zanubrutinib Showed Longer Treatment Persistence

Using the IntegraConnect PrecisionQ de-identified electronic health record database, which spans more than 3 million patients with cancer treated across over 500 US sites, investigators identified 473 patients who initiated first-line covalent BTK inhibitor monotherapy between January 2020 and November 2023: 289 on acalabrutinib and 184 on zanubrutinib. Baseline demographics were similar between groups:

• Median age of 76 years
• At least 62% of patients were male patients
• White patients comprised 83.7% of patients on acalabrutinib monotherapy and 82.1% on zanubrutinib monotherapy
• African American patients comprised 5.9% and 7.1%, respectively
• 71.6% and 66.8% were not of Hispanic ethnicity
• 82.4% and 76.6% had Medicare/Medicaid coverage

Median time to treatment discontinuation was 29.5 months for acalabrutinib but was not reached for zanubrutinib, translating to a significantly longer duration of treatment (adjusted HR [aHR], 0.50; 95% CI, 0.32-0.74; P < .01). At 12 months, 83.3% of patients remained on zanubrutinib compared with 69.5% on acalabrutinib. Toxicity was the most-cited reason for discontinuation in both arms, but it occurred about twice as often with acalabrutinib (10.7%) as with zanubrutinib (5.4%). Other top reasons were patient choice (8.3%), death or hospice (3.8%), and disease progression (2.4%) for acalabrutinib, and unknown (2.7%); patient choice, death, or hospitalization (1.6% each); and hospice (1.1%) for zanubrutinib.

Time to next treatment numerically favored zanubrutinib (not reached vs 42.5 months for acalabrutinib), and 12-month survival probability was numerically higher with zanubrutinib (92.3% vs 89.3%). Still, neither difference reached statistical significance after adjustment for age, sex, Eastern Cooperative Oncology Group performance status, and biomarkers including TP53 and del(17p).

What Comes Next for BTK Inhibitor Selection?

Earlier real-world modeling using claims data has similarly pointed to lower downstream medical spending when patients remain on therapy longer and progress less often, reinforcing that treatment durability has cost implications that extend well past the drug’s list price.⁴

The authors were candid about the limitations of this research. Follow-up time differed substantially between groups—a median of 15.8 months (range, 1.3-49.8) for acalabrutinib vs 11.1 months (range, 2.3-32.2) for zanubrutinib—reflecting zanubrutinib’s later 2023 FDA approval for CLL relative to acalabrutinib’s 2019 approval.^5,6 There was also a relatively modest sample size and low rates of biomarker testing for key covariates like TP53, which limited generalization.¹ The study also overlapped with the COVID-19 pandemic, another potential confounder for treatment discontinuation patterns.

Longer-term follow-up is needed to confirm whether zanubrutinib’s early persistence advantage holds up. The authors noted that the increasingly complex CLL treatment landscape—including combinations with anti-CD20 agents and BCL2 inhibitors—will require continued real-world study to guide sequencing decisions to “provide clinically relevant real-world insights into treatment durability and tolerability that demonstrate zanubrutinib’s clinical benefit in real-world outcomes in routine practice.”

References

1. Hou JZ, Choksi R, Maglinte GA, et al. Real-world comparative effectiveness of first-line BTK inhibitors in chronic lymphocytic leukemia. Future Oncol. 2026;22(17):2081-2088. doi:10.1080/14796694.2026.2691254
2. NCCN clinical practice guidelines in oncology: chronic lymphocytic leukemia/small lymphocytic lymphoma (version 2.2026). National Comprehensive Cancer Network. December 22, 2025. Accessed August 13, 2026. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
3. Quartermaine C, Ghazi SM, Yasin A, et al. Cardiovascular toxicities of BTK Inhibitors in chronic lymphocytic leukemia: JACC: CardioOncology state-of-the-art review. JACC CardioOncol. 2023;5(5):570-590. doi:10.1016/j.jaccao.2023.09.002
4. Kaltwasser J. Efficacy and cost savings of zanubrutinib in high-risk R/R CLL. AJMC^®. February 18, 2026. Accessed August 13, 2026. https://www.ajmc.com/view/efficacy-and-cost-savings-of-zanubrutinib-in-high-risk-r-r-cll
5. Caffrey M. FDA gives zanubrutinib approval for first-line, R/R CLL/SLL. AJMC. January 19, 2023. Accessed August 13, 2026. https://www.ajmc.com/view/fda-gives-zanubrutinib-approval-for-first-line-r-r-cll-sll
6. Calquence approved in the US for adult patients with chronic lymphocytic leukemia. News release. AstraZeneca. November 21, 2019. Accessed August 13, 2026. https://www.astrazeneca.com/media-centre/press-releases/2019/calquence-approved-in-the-us-for-adult-patients-with-chronic-lymphocytic-leukaemia-21112019.html#