Zanubrutinib Shows Similar Efficacy but Better Safety Than VEN–I in Frontline CLL

In the absence of head-to-head trials of first-line treatments for chronic lymphocytic leukemia (CLL), a newly published matching-adjusted indirect comparison (MAIC) provides the clearest evidence to date on how continuous zanubrutinib (Brukinsa; BeiGene) and fixed-duration venetoclax (Venclexta; AbbVie and Genentech) plus ibrutinib (Imbruvica; Pharmacyclics) (V+I) stack up against each other.

While progression-free survival outcomes are broadly similar between zanubrutinib and venetoclax, the BTKi demonstrates a notably more favorable safety profile. | Image credit: laszlo-stock.adobe.com

The new analysis, appearing in British Journal of Haematology, suggests that while progression-free survival (PFS) outcomes are broadly similar, zanubrutinib demonstrates a notably more favorable safety profile, even when accounting for differences in trial populations and treatment duration.

The research team used patient-level data from the SEQUOIA trial—479 treatment-naïve patients with CLL without del(17p) and 111 with del(17p)—all treated with zanubrutinib. These data were matched to aggregated baseline characteristics from 2 major V+I studies: GLOW, a phase 3 trial in older patients with comorbidities, and CAPTIVATE, a phase 2 trial in younger, fitter patients. V+I is currently approved in Europe and Canada but not in the United States.2,3

The studies differed substantially in patient characteristics and treatment duration: median zanubrutinib exposure exceeded 43 months, whereas V+I exposure was 13.8 months in both comparator studies due to its fixed-duration design. To address these imbalances, the team applied MAIC methodology following NICE Decision Support Unit standards. This involved reweighting zanubrutinib patients so that the distribution of key prognostic factors aligned with each V+I population, then estimating relative outcomes using weighted Cox regression.

Across both comparator studies, zanubrutinib demonstrated PFS, with a numerical but non-significant trend favoring the BTKi. Against GLOW, the hazard ratio (HR) for investigator-assessed PFS shifted from 0.71 pre-matching to 0.84 post-matching, both supporting broadly similar outcomes. Against CAPTIVATE, the HR shifted from 1.00 to 0.69, indicating a potential PFS advantage but still within wide confidence intervals due to limited sample size.

These estimates remained consistent across multiple sensitivity analyses, including alternative matching variables and adjustments for comorbidities such as Cumulative Illness Rating Scale scores.

In contrast to the uncertain differences in PFS, the safety comparison showed robust and consistent advantages for zanubrutinib despite the much longer treatment duration for zanubrutinib.

The Bruton’s tyrosine kinase inhibitor (BTKi) had lower rates of numerous grade ≥3 treatment-emergent adverse events compared with V+I, including diarrhea (OR, 0.19 vs GLOW; OR, 0.12 vs CAPTIVATE), neutropenia (OR, 0.58 vs GLOW; OR, 0.31 vs CAPTIVATE), nausea (OR, 0.49 vs GLOW; 0.18 vs CAPTIVATE), and anemia (OR, 0.34 vs GLOW; 0.50 vs CAPTIVATE).

For most events, the upper bound of the 95% confidence interval remained below 1, emphasizing a statistically supported reduction in risk with zanubrutinib, noted the researchers. Only cough appeared slightly more frequent with zanubrutinib, but the wide confidence interval suggested this was not a reliable finding.

“Although no quality-of-life outcomes were available for comparison, we anticipate a positive impact from zanubrutinib based on safety results, an aspect that may influence treatment decisions of clinicians and patients for [treatment-naïve] CLL,” wrote the researchers.

The authors emphasized that the MAIC methodology cannot fully replace direct randomized comparisons, particularly given population imbalances and small comparator-arm sample sizes. However, the consistency of safety results and the fact that side effect reporting in CAPTIVATE was limited to rates above prespecified thresholds suggest the tolerability advantage of zanubrutinib may be even more pronounced in real-world practice.

The researchers also note that while PFS differences were not statistically significant, the numerical separation in favor of zanubrutinib beyond 3 years in the CAPTIVATE comparison indicates the possibility of long-term benefit that warrants future investigation.

References

1. Munir T, Mohseninejad L, Rakonczai P, et al. Matching-adjusted indirect comparisons of efficacy and safety for zanubrutinib versus the combination of fixed-duration venetoclax and ibrutinib in patients with treatment-naïve chronic lymphocytic leukaemia. Br J Haem. Published online November 11, 2025. doi:10.1111/bjh.70241

2. European Commission approves Imbruvica (ibrutinib) in a fixed-duration combination regimen for adult patients with previously untreated chronic lymphocytic leukaemia (CLL). News release. Johnson & Johnson. Published online August 4, 2022. Accessed November 20, 2025. https://www.jnj.com/media-center/press-releases/european-commission-approves-imbruvica-ibrutinib-in-a-fixed-duration-combination-regimen-for-adult-patients-with-previously-untreated-chronic-lymphocytic-leukaemia-cll

3. Ryan C. Fixed-duration ibrutinib plus venetoclax earns approval in Canada for previously untreated CLL. OncLive. Published online March 28, 2023. Accessed November 20, 2025. https://www.onclive.com/view/fixed-duration-ibrutinib-plus-venetoclax-earns-approval-in-canada-for-previously-untreated-cll