Cross-Trial Analysis Finds Zanubrutinib Outperforms Other BTKis in R/R CLL

A new cross-trial comparative analysis suggests that zanubrutinib (Brukinsa) is associated with significantly prolonged progression-free survival (PFS) compared with both ibrutinib (Imbruvica) and acalabrutinib (Calquence) in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk features.¹

The study, published recently in the Journal of Medical Economics, addresses a critical evidence gap, as head-to-head clinical trials comparing all available second-generation Bruton tyrosine kinase inhibitors (BTKis) remain limited.

According to the analysis, zanubrutinib demonstrated a 33% reduction in the risk of disease progression or death compared with ibrutinib, equating to a hazard ratio (HR) of 0.67 (95% CI, 0.52-0.87). Furthermore, when compared indirectly to acalabrutinib, zanubrutinib was associated with an even greater reduction (43%) in the risk of progression or death (HR, 0.57; 95% CI, 0.34-0.95).

Notably, zanubrutinib’s PFS advantage was maintained over both agents in the high-risk patient population, defined by the presence of 17p or 11p deletion. Here, zanubrutinib showed a 45% reduction in the risk of progression or death relative to ibrutinib (HR, 0.55) and a 43% risk reduction relative to acalabrutinib (HR, 0.57).

The emergence of second-generation BTKis like zanubrutinib and acalabrutinib was driven by the need for more selective agents with improved safety profiles and efficacy compared with ibrutinib, the first-in-class inhibitor. The finding that zanubrutinib may offer a PFS advantage over acalabrutinib is particularly relevant for sequencing and selection decisions in the R/R setting. The authors primarily attribute zanubrutinib’s superior efficacy to its pharmacokinetic profile, which potentially allows for more complete and sustained BTK inhibition.

“The [analysis] presented in this paper indicates that zanubrutinib offers greater efficacy in terms of PFS compared [with] other BTKis and chemoimmunotherapy in both the general R/R CLL population and the high-risk subgroup with del(17p) and/or del(11q) mutations,” concluded authors Shadman et al.¹ “While all indirect comparisons have inherent limitations, this analysis provides important insights into the comparative efficacy across BTKis and chemoimmunotherapy in R/R CLL, including in high-risk patients.”

Methodology and Data Sources

The researchers utilized multilevel network meta-regression to synthesize evidence from 3 pivotal phase 3 clinical trials: ALPINE (NCT03734016),² ASCEND (NCT02970318),³ and ELEVATE-RR (NCT02477696).⁴ The advanced statistical framework is designed to overcome the limitations of traditional network meta-analyses by accounting for differences in patient baseline characteristics across different trials. This method allows for the integration of individual patient-level data from some trials with aggregate data from others, effectively reducing the bias caused by cross-trial heterogeneity.

In this analysis, patient-level data for zanubrutinib and ibrutinib were sourced from the ALPINE trial (n = 652), which directly compared the 2 agents in R/R CLL. To include acalabrutinib in the comparison, the researchers incorporated aggregate data from the ASCEND trial (acalabrutinib vs investigator’s choice; n = 310) and the ELEVATE-RR trial (acalabrutinib vs ibrutinib; n = 533). The analysis adjusted for several prognostic factors, including 17p deletion status, TP53 mutation, IGHV mutation status, and the number of prior lines of therapy.

REFERENCES

1. Shadman M, Bouwmeester W, Mohseninejad L, et al. Prolonged progression-free survival with zanubrutinib in relapsed/refractory CLL: an indirect treatment comparison versus other BTK inhibitors using multilevel network meta-regression. J Med Econ. 2026;29(1):180-192. doi:10.1080/13696998.2025.2609514

2. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia (ALPINE). ClinicalTrials.gov. Updated March 30, 2025. Accessed February 23, 2026. https://clinicaltrials.gov/study/NCT03734016

3. A study of acalabrutinib vs investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab in R/R CLL. ClinicalTrials.gov. Updated February 6, 2026. Accessed February 23, 2026. https://clinicaltrials.gov/study/NCT02970318

4. A study of acalabrutinib (ACP-196) versus ibrutinib in previously treated participants with high risk chronic lymphocytic leukemia (CLL). ClinicalTrials.gov. Updated November 20, 2025. Accessed February 23, 2026. https://clinicaltrials.gov/study/NCT02477696