Zanubrutinib Emerges as Leading cBTKi for Relapsed/Refractory CLL

In a groundbreaking study published in *Blood Advances*, researchers have identified zanubrutinib (Brukinsa; BeOne Medicines) as the most effective covalent Bruton tyrosine kinase inhibitor (cBTKi) for treating relapsed or refractory chronic lymphocytic leukemia (CLL). This indirect comparative analysis marks the first of its kind to assess the relative efficacy of approved cBTKis in the absence of direct head-to-head trials.

The study, conducted by a team led by Dr. Muhammad Shadman, Assistant Professor at the University of Washington and a hematologist at the Fred Hutchinson Cancer Research Center, involved a meta-analysis of data from pivotal trials involving three cBTKis—zanubrutinib, acalabrutinib (Calquence; AstraZeneca), and ibrutinib (Imbruvica; Pharmacyclics and Johnson & Johnson). The findings indicate that zanubrutinib significantly reduces the risk of disease progression or death compared to its counterparts.

According to the study published on July 5, 2025, zanubrutinib demonstrated a 51% reduction in the risk of disease progression or death when compared with ibrutinib (HR, 0.49; 95% CrI, 0.31-0.78) and a 45% reduction compared to acalabrutinib (HR, 0.55; 95% CrI, 0.32-0.94) among high-risk patients. These results reveal a significant improvement in progression-free survival (PFS) and favorable response rates, suggesting that zanubrutinib may provide enhanced clinical benefits for CLL patients, particularly those with high-risk factors such as del(17p) or TP53 mutations.

The researchers noted that these findings are particularly relevant for specific patient subgroups, where treatment options often remain uncertain. Dr. Shadman stated, "The results provide insights that cannot be derived directly from assessment of individual trial outcomes."

The analysis included data from three pivotal randomized controlled trials: ALPINE, which compared zanubrutinib with ibrutinib in patients with TP53 mutations and/or del(17p); ELEVATE-RR, which assessed acalabrutinib against ibrutinib in similar patient groups; and ASCEND, which evaluated acalabrutinib versus bendamustine + rituximab (BR/IR). Follow-up durations in these trials ranged from 39 to 46.5 months, underlining the importance of long-term efficacy data in assessing treatment options for CLL patients.

While the study provides a comprehensive comparison, the authors urge caution in interpreting the results due to the indirect nature of the comparisons. Dr. Shadman cautioned, "When interpreting the results of the present study, the structure of the network must be considered. Indirect evidence may impact the observed relative effects that rely on those chains, thereby making results less reliable."

The analysis also highlighted numerical improvements in overall survival rates associated with zanubrutinib compared to both acalabrutinib and ibrutinib, though these findings did not reach statistical significance. The overall response rate (ORR) for zanubrutinib was also notably higher, revealing a potential advantage in clinical response among patients treated with this cBTKi.

The findings of this study may reshape treatment paradigms for CLL, emphasizing the need for oncologists to consider zanubrutinib as a first-line treatment option, particularly for high-risk patient populations. As the field continues to evolve, these insights will be vital in guiding clinical decisions and improving patient outcomes in CLL management.

In conclusion, the comparative analysis underscores zanubrutinib's promising position within the therapeutic landscape for relapsed or refractory CLL. Ongoing research and clinical trials will further elucidate its long-term efficacy and safety in diverse patient populations, paving the way for enhanced treatment strategies in hematologic malignancies.