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

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).