What question did this study set out to answer?

This analysis aimed to compare the efficacy of zanubrutinib, ibrutinib, and acalabrutinib in treatment-naive chronic lymphocytic leukemia.

June 13, 2026Open Access

Indirect Comparison of the Efficacy of Zanubrutinib vs Ibrutinib and Acalabrutinib in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-Up

Key Points

This analysis aimed to compare the efficacy of zanubrutinib, ibrutinib, and acalabrutinib in treatment-naive chronic lymphocytic leukemia.
Conducted indirect comparisons of zanubrutinib vs ibrutinib and zanubrutinib vs acalabrutinib using data from phase 3 trials, SEQUOIA, ELEVATE-TN, and RESONATE-2.
Eligibility criteria were aligned for cross-trial comparability, focusing on treatment-naive CLL patients without del(17p) and/or TP53 mutations.
Included median follow-up periods of 73.4 months for zanubrutinib vs ibrutinib and 73.6 months for zanubrutinib vs acalabrutinib.
Zanubrutinib significantly prolonged PFS-INV (HR 0.65, 95% CI 0.44-0.97, P=0.0330) and showed a trend toward improved OS (HR 0.60, 95% CI 0.36-1.01, P=0.0532) compared to ibrutinib.
At 72 months, PFS-INV rates were significantly higher with zanubrutinib vs ibrutinib (risk difference 15.3%, 95% CI 8.3-22.2%).
Compared to acalabrutinib, zanubrutinib trended toward improved PFS-INV (HR 0.76, 95% CI 0.52-1.11, P=0.1553) and OS (HR 0.66, 95% CI 0.41-1.06, P=0.0836).

Abstract

INTRODUCTION: Zanubrutinib, acalabrutinib, and ibrutinib each demonstrated improved investigator-assessed progression-free survival (PFS-INV) and overall survival (OS) versus chemotherapy-based regimens in treatment-naive chronic lymphocytic leukemia (CLL) in the phase 3 trials SEQUOIA (NCT03336333), ELEVATE-TN (NCT02475681), and RESONATE-2 (NCT01722487), respectively. In the absence of head-to-head studies, this analysis compared the efficacy of zanubrutinib vs ibrutinib and vs acalabrutinib in treatment-naive CLL via indirect naive comparisons. METHODS: Eligibility criteria were aligned to improve cross-trial comparability. The zanubrutinib vs ibrutinib comparison included COVID-19-adjusted PFS-INV and OS in arm A of SEQUOIA (n = 241; median follow-up, 73.4 months) and the ibrutinib arm of RESONATE-2 (n = 136; median follow-up, 88.5 months). The zanubrutinib vs acalabrutinib comparison included PFS-INV and OS in subgroups of patients without del(17p) and/or TP53 mutations from arm A of SEQUOIA (n = 215; median follow-up, 73.6 months) and the acalabrutinib arm of ELEVATE-TN (n = 156; median follow-up, 74.5 months). RESULTS: Baseline characteristics were similar for each comparison. Zanubrutinib significantly prolonged PFS-INV (hazard ratio HR, 0.65; 95% CI, 0.44-0.97; P = 0.0330) and showed a trend toward improved OS (HR, 0.60; 95% CI, 0.36-1.01; P = 0.0532) vs ibrutinib. At the 72-month landmark, PFS-INV and OS rates were significantly higher with zanubrutinib vs ibrutinib, with a risk difference of 15.3% (95% CI, 8.3-22.2%) for PFS and 9.9% (95% CI, 3.0-16.7%) for OS. Compared with acalabrutinib, zanubrutinib trended toward improved PFS-INV (HR, 0.76; 95% CI, 0.52-1.11; P = 0.1553) and OS (HR, 0.66; 95% CI, 0.41-1.06; P = 0.0836). The 72-month landmark PFS-INV and OS rates were significantly higher with zanubrutinib vs acalabrutinib, with a risk difference of 9.9% (95% CI, 3.0-16.9%) for PFS-INV and 8.8% (95% CI, 2.0-15.5%) for OS. CONCLUSION: These findings inform the long-term comparative efficacy of Bruton tyrosine kinase inhibitors and suggest that zanubrutinib may confer sustained PFS and OS benefits compared with ibrutinib and acalabrutinib in similar treatment-naive CLL populations. Graphical abstract and video available for this article. Overview of the Comparative Efficacy of Covalent BTK Inhibitors in Treatment-Naïve CLL/SLL With Six-Year Follow-Up (MP4 345006 kb).

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