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. 2025 Jul 8:17:17588359251340554.
doi: 10.1177/17588359251340554. eCollection 2025.

Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC)

Mazyar Shadman  1 , Jennifer R Brown  2 , Rhys Williams  3 , Leyla Mohseninejad  4 , Keri Yang  3 , Pal Rakonczai  5 , Nicole Lamanna  6 , Sheng Xu  7 , Aileen Cleary Cohen  3 , Susan M O'Brien  8 , Alessandra Tedeschi  9 , Constantine S Tam  10
Affiliations

Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC)

Mazyar Shadman et al. Ther Adv Med Oncol. .

Abstract

Background: There are no head-to-head studies comparing the efficacy of the Bruton tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, in relapsed or refractory chronic lymphocytic leukemia (R/R CLL).

Objective: To compare the relative efficacy of zanubrutinib and acalabrutinib in R/R CLL using indirect treatment comparison.

Design: An unanchored matching-adjusted indirect comparison (MAIC) was performed.

Methods: Individual patient-level data from ALPINE (zanubrutinib) were reweighted using prognostic/effect-modifying variables to match aggregate data from ASCEND (acalabrutinib). MAIC outcomes included investigator-assessed progression-free survival (PFS-INV), overall survival (OS), and complete response (CR).

Results: Post-matching, PFS-INV was improved significantly for zanubrutinib versus acalabrutinib (hazard ratio (HR) = 0.68 (95% confidence interval (CI): 0.46-0.99); p = 0.0448) and OS showed a trend toward improvement for zanubrutinib (HR = 0.60; 95% CI: 0.35-1.02, p = 0.0575). CR was significantly higher for zanubrutinib versus acalabrutinib (odds ratio = 2.90 (95% CI: 1.13-7.43); p = 0.0270).

Conclusion: Zanubrutinib was associated with a significant PFS-INV and CR advantage over acalabrutinib, with a trend toward improvement in OS.

Keywords: Bruton tyrosine kinase inhibitor (BTKi); chronic lymphocytic leukemia; comparative efficacy.

Plain language summary

A study testing the effects of two medicines used to treat patients with a type of blood cancer called chronic lymphocytic leukemia: how do zanubrutinib and acalabrutinib compare? Medications that block Bruton tyrosine kinase (BTK) are important treatments for patients with chronic lymphocytic leukemia (CLL). There are several BTK blockers available, but they have not all been directly compared in clinical trials. It is ideal to directly test two medications head-to-head in the same clinical trial; however, certain indirect study methods can be used to compare the treatment effects of medications that have only been tested in different trials. In this study, we indirectly compared the effects of two BTK-blocking medications, zanubrutinib and acalabrutinib, which are used to treat patients with CLL whose cancer is no longer responding to previous therapy. We used a statistical method to “match” patients from two different trials, which allowed us to compare outcomes in patient populations with similar characteristics. These outcomes included progression-free survival, overall survival, and complete response. We found that zanubrutinib significantly improved progression-free survival by 32% compared with acalabrutinib. Zanubrutinib also improved overall survival by 40% compared with acalabrutinib, but this was a trend and not statistically significant. The odds of having a complete response to treatment were almost 3 times as high with zanubrutinib compared with acalabrutinib. The findings from this study help us better understand how zanubrutinib and acalabrutinib compare for the treatment of patients with CLL. This is important information, but it should be noted that testing two medications in the same clinical trial remains the best way to compare their effects.

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Conflict of interest statement

M.S. reports receiving funding from BeOne paid to Fred Hutchinson Cancer Research Center and the University of Washington (Seattle, WA, USA), with regard to the submitted work; research funding from Pharmacyclics (Inst), Acerta Pharma (Inst), Merck (Inst), TG Therapeutics (Inst), BeOne (Inst), Celgene (Inst), Genentech (Inst), MustangBio (Inst), AbbVie (Inst), Sunesis Pharmaceuticals (Inst), Bristol Myers Squibb/Celgene, Genmab (Inst), and Vincerx Pharma (Inst); and consulting or advisory roles with AbbVie, Genentech, AstraZeneca, Sound Biologics, Cellectar, Pharmacyclics, BeOne, Bristol Myers Squibb/Celgene, MorphoSys, Innate Pharma, Kite, a Gilead Company, Adaptive Biotechnologies, Epizyme, Fate Therapeutics, Lilly, Regeneron, Adaptimmune, MustangBio, TG Therapeutics, and MEI Pharma, outside the submitted work. J.R.B. reports receiving research funding from BeOne (Inst), Gilead Sciences (Inst), Loxo/Lilly (Inst), MEI Pharma (Inst), Secura Bio (Inst), Sun Pharma (Inst), and TG Therapeutics (Inst); and consulting or advisory roles with AbbVie, Acerta/Astra-Zeneca, BeOne, Bristol Myers Squibb/Celgene/Juno, Catapult Therapeutics, Lilly, Genentech/Roche, HUTCHMED, iOnctura, Janssen, MEI Pharma, MorphoSys, Novartis, and Pharmacyclics, outside of the submitted work. R.W., L.M., K.Y., and S.X. are employees of BeOne, with regard to the submitted work, and report stocks or stock options, or both, from BeOne, outside the submitted work. A.C.C. was an employee of BeOne at the time of this study, with regard to the submitted work, and report stocks or stock options, or both, from BeOne, outside the submitted work. P.R.—no conflict. N.L. reports receiving consulting or advisory roles with Celgene, Genentech, AbbVie, ProNAi, Pharmacyclics, Juno Therapeutics, Roche, Janssen, AstraZeneca, Gilead Sciences, BeOne, and Loxo/Lilly Research; and funding from Genentech/AbbVie (Inst), Infinity Pharmaceuticals (Inst), Gilead Sciences (Inst), ProNAi (Inst), BeOne (Inst), Verastem (Inst), Juno Therapeutics (Inst), TG Therapeutics (Inst), Acerta Pharma/AstraZeneca (Inst), Loxo (Inst), Oncternal Therapeutics, Inc. (Inst), MingSight (Inst), and Octapharm (Inst), outside the submitted work. S.M.O. reports employment with University of California, Irvine; honoraria from Celgene, Janssen, Pharmacyclics, Gilead Sciences, Pfizer, Amgen, Astellas Pharma, GlaxoSmithKline, Aptose Biosciences, Vaniam Group, AbbVie, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Eisai, TG Therapeutics, and NOVA Research Company; consulting or advisory roles with Amgen, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie/Genentech, Alexion Pharmaceuticals, Astellas Pharma, Gilead Sciences, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis Pharmaceuticals; receiving research funding from Acerta Pharma (Inst), Regeneron (Inst), Gilead Sciences (Inst), Pfizer (Inst), TG Therapeutics (Inst), Pharmacyclics (Inst), Kite, a Gilead Company (Inst), Sunesis Pharmaceuticals (Inst), Lilly (Inst), and Caribou Biosciences (Inst); and travel, accommodations, expenses from Celgene, Janssen, Gilead Sciences, Regeneron, and Janssen Oncology. A.T. reports receiving consulting fees from AbbVie, AstraZeneca, BeOne, and Janssen; and honoraria from AbbVie, AstraZeneca, BeOne, and Janssen, outside the submitted work. C.S.T. reports receiving funding from Janssen-Cilag (Inst), AbbVie (Inst), BeOne (Inst); consulting or advisory roles with Janssen, Loxo, Roche, BeOne, and AbbVie; and honoraria from Janssen-Cilag, AbbVie, Novartis, BeOne, Pharmacyclics, Roche/Genentech, and Loxo/Lilly, outside the submitted work.

Figures

Figure 1.
Figure 1.
Unadjusted and base-case adjusted clinical outcomes comparing zanubrutinib and acalabrutinib. (a) PFS-INV. (b) OS. CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; PFS-INV, investigator-assessed progression-free survival.
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