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. 2025 Sep 13.
doi: 10.1007/s40487-025-00380-0. Online ahead of print.

Indirect Comparisons of the Efficacy and Safety of Zanubrutinib versus Venetoclax plus Obinutuzumab in Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Talha Munir  1   2 , Nicolás Martinez-Calle  3 , Sheng Xu  4 , Keri Yang  5 , Xiaoyun Ge  4 , Ayad K Ali  5 , Leyla Mohseninejad  6 , Balázs Dobi  7 , Pal Rakonczai  7 , Han Ma  5 , Rhys Williams  5 , Wassim Aldairy  5 , Nicole Lamanna  8
Affiliations
Free article

Indirect Comparisons of the Efficacy and Safety of Zanubrutinib versus Venetoclax plus Obinutuzumab in Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Talha Munir et al. Oncol Ther. .
Free article

Abstract

Introduction: Compared with chemoimmunotherapy, both zanubrutinib monotherapy and venetoclax plus obinutuzumab prolong progression-free survival (PFS) in patients with chronic lymphocytic leukemia (CLL). Matching-adjusted indirect comparison (MAIC) can be used to compare the efficacy and safety of different treatment regimens when no head-to-head trial has compared the treatments.

Methods: Patient matching was conducted using unanchored MAIC propensity-score weighting to compare PFS, overall survival (OS), tolerability, and adverse events (AEs) of interest (AEIs; grade 3-4 infections, neutropenia, febrile neutropenia, and/or thrombocytopenia and AEs leading to treatment discontinuation) on the basis of data from patients in SEQUOIA for zanubrutinib and aggregate data from CLL14 for venetoclax plus obinutuzumab. Because SEQUOIA occurred during the pandemic, analyses were also conducted to adjust for coronavirus disease 2019 (COVID-19) infections.

Results: After matching and adjustment, baseline characteristics of the zanubrutinib group in SEQUOIA were well balanced with the CLL14 population (N = 216), with an effective sample size of 163 for the zanubrutinib group. After matching for baseline characteristics, zanubrutinib demonstrated a robust PFS benefit compared with venetoclax plus obinutuzumab (hazard ratio, 0.66 [95% confidence interval, 0.44-0.97]; P = 0.0351) and higher PFS probability at landmark points (60-month landmarks of 73.9% versus 63%, respectively). OS trended in favor of zanubrutinib. Overall, AEs of any grade over time were comparable in the zanubrutinib safety and venetoclax plus obinutuzumab populations. Zanubrutinib was associated with lower rates of selected AEIs compared with venetoclax plus obinutuzumab at all time points, except for grade 3-4 infections after 156 weeks. After adjusting for COVID-19, zanubrutinib was associated with a significantly lower incidence of grade 3-4 infections at 104 weeks but similar incidences of grade 3-4 infections versus venetoclax plus obinutuzumab during the overall follow-up period.

Conclusions: Continuous treatment with zanubrutinib in treatment-naïve patients with CLL/small lymphocytic lymphoma resulted in prolonged PFS and a favorable safety profile compared with fixed-duration venetoclax plus obinutuzumab.

Trial registration no: SEQUOIA (NCT03336333); CLL14 (NCT02242942).

Keywords: Bruton tyrosine kinase (BTK) inhibitor; Matching-adjusted indirect comparison (MAIC); Obinutuzumab; Treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); Venetoclax; Zanubrutinib.

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Conflict of interest statement

Declarations. Conflict of Interest: Talha Munir—honoraria: BeOne Medicines Ltd., AstraZeneca, Sobi, Roche, Janssen, AbbVie, and Lilly; consultant: AbbVie, BeOne Medicines Ltd., Sobi, Alexion, Novartis, Janssen, AstraZeneca, Lilly, and Roche; research grants: Janssen and AbbVie; travel, accommodations, or expenses: Alexion, BeOne Medicines Ltd., AbbVie, Janssen, and AstraZeneca; and advisory board: AbbVie, BeOne Medicines Ltd., AstraZeneca, and Janssen. Nicolás Martinez-Calle—advisory board: AbbVie, AstraZeneca, BeOne Medicines Ltd., Takeda, and CLS Behring; and speaker and honoraria: AbbVie, AstraZeneca, Janssen, and BeOne Medicines Ltd. Sheng Xu, Keri Yang, Xiaoyun Ge, Ayad K. Ali, Leyla Mohseninejad, Han Ma, Rhys Williams, and Wassim Aldairy—employment and may own stock: BeOne Medicines Ltd. Balázs Dobi—research funding: BeOne Medicines Ltd. Pal Rakonczai—current affiliation: AstraZeneca; has nothing to disclose. Nicole Lamanna—consulting or advisory role: AbbVie, AstraZeneca, BeOne Medicines Ltd., Lilly, and Genmab; and research funding: AbbVie, AstraZeneca, BeOne Medicines Ltd., Lilly, Genmab, Genentech, MingSight, Octapharma, and Oncternal. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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