Efficacy of Zanubrutinib Versus Acalabrutinib in the Treatment of Relapsed or Refractory Chronic Lymphocytic
Leukemia (R/R CLL): A Matching-Adjusted Indirect Comparison (MAIC)

Mazyar Shadman*1, Jennifer R. Brown2, Rhys Williams3, Leyla Mohseninejad4, Keri Yang3, Pal Rakonczai5,
Nicole Lamanna6, Sheng Xu7, Aileen Cohen3, Susan O'brien8, Alessandra Tedeschi9, Constantine Tam10
1Fred Hutchinson Cancer Center and University of Washington, Seattle, Washington, United States ofAmerica, 2Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber CancerInstitute and Harvard Medical School, Boston, MA, United States of America, 3BeiGene USA, Inc., SanMateo, CA, United States of America, 4BeiGene Netherlands B.V., Schiphol, The Netherlands, 5Evidera, H1113 Budapest, Hungary, 6Herbert Irving Comprehensive Cancer Center, Columbia University MedicalCenter, New York, United States of America, 7BeiGene (Shanghai) Co., Ltd., Shanghai, China, 8Universityof California, Irvine, CA, United States of America, 9ASST Grande Ospedale Metropolitano Niguarda,Milan, Italy, 10Alfred Hospital and Monash University, Melbourne, Victoria, Australia

Background: Bruton tyrosine kinase inhibitors (BTKis) are widely used in the treatment of CLL. Zanubrutinib is anext-generation covalent BTKi and the only BTKi that provides continuous exposure above its IC50. Zanubrutinib isalso the only BTKi to demonstrate progression-free survival (PFS) superiority vs ibrutinib in R/R CLL in the ALPINE
study. Acalabrutinib is a second-generation BTKi that showed improved PFS vs rituximab-idelalisib/bendamustinein R/R CLL in the ASCEND study but PFS noninferiority to ibrutinib in R/R CLL patients with del(17p) or del(11q) in
ELEVATE-RR.
Aims: As no head-to-head clinical trial of zanubrutinib and acalabrutinib in R/R CLL exists, this study compared theefficacy of zanubrutinib in ALPINE and acalabrutinib in ASCEND using MAIC methodology.
Methods: The MAIC used individual patient-level data (IPD) from ALPINE and matched it against the aggregate
data from ASCEND. An unanchored MAIC was used due to the lack of a common comparator arm between theALPINE and ASCEND trials. The MAIC was conducted using data sets with similar median follow-ups (ALPINE, 39months; ASCEND, 36 months). IPD from the zanubrutinib arm of ALPINE (n=327) were reweighted to match theprofile of acalabrutinib-treated patients in ASCEND (n=155) and adjusted for variables identified as prognostic
factors or predictors of treatment effect. Sensitivity analyses considered the impact of matching for different setsof variables. Pseudo IPD for PFS and overall survival (OS) in the acalabrutinib arm of ASCEND were reconstructedfrom the digitized Kaplan-Meier curves reported in the ASCEND publication. Given the timing of the study withrelation to the COVID-19 pandemic for ASCEND vs ALPINE, adjustments were made to neutralize the impact ofCOVID-19 on ALPINE. A weighted Cox proportional hazard model was used to compare investigator-assessed PFS(PFS-INV) and OS; a weighted logistic regression model was used to compare complete response (CR).
Results: In the unadjusted population, relative treatment effects for zanubrutinib vs acalabrutinib on PFS-INV andOS were 0.77 (95% CI: 0.55-1.07) and 0.60 (95% CI: 0.37-0.97), respectively. After population adjustment, theeffective sample size for zanubrutinib was 184.8. Post-matching, PFS-INV was significantly improved forzanubrutinib (HR= 0.68 [95%CI: 0.46-0.99]; P=0.0448). OS showed potential improvement for zanubrutinib (Table).
The odds ratio (OR) for CR significantly favored zanubrutinib over acalabrutinib in both 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). Results for the sensitivity
analyses were consistent, showing favorable PFS-INV and CR for zanubrutinib.
Summary/Conclusion: This comprehensive MAIC showed a significant PFS and CR advantage, and potentially
improved OS for zanubrutinib compared with acalabrutinib. Results were robust across multiple sensitivity
analyses.

EHA 2024

EHA 2024