Zanubrutinib Surpasses Acalabrutinib and Venetoclax in CLL PFS Rates

Zanubrutinib, marketed as Brukinsa, has demonstrated a significant advantage in progression-free survival (PFS) over the combination treatment of acalabrutinib (Calquence) and venetoclax (Venclexta) in patients with chronic lymphocytic leukemia (CLL). This finding emerged from a recent analysis presented at the 2025 European Hematology Association (EHA) Congress held from June 12-15 in Milan, Italy.

The study utilized a matching-adjusted indirect comparison (MAIC) approach to evaluate the efficacy of zanubrutinib against acalabrutinib plus venetoclax in treatment-naive CLL patients. The analysis revealed that patients treated with zanubrutinib experienced a PFS hazard ratio (HR) of 0.47 (95% confidence interval [CI], 0.28-0.77; P = .003) in comparison to the combination therapy, marking a statistically significant improvement. Additionally, the population-adjusted INV-PFS demonstrated a hazard ratio of 0.26 (95% CI, 0.13-0.54; P = .0003), further solidifying the efficacy of zanubrutinib in this patient cohort.

Dr. Talha Munir, MBChB, PhD, a consultant hematologist at Leeds Teaching Hospitals NHS Trust and deputy chair of the UK National Cancer Research Institute Chronic Lymphocytic Leukemia Study Group, led the research. "In the absence of head-to-head comparative trials, the indirect comparison statistical analyses were applied to compare the efficacy of zanubrutinib vs AV," Munir stated. "Results should be interpreted with considerations of inherent limitations of indirect comparison, such as MAIC model assumptions."

The SEQUOIA trial, which assessed zanubrutinib's efficacy, involved treatment-naive CLL patients randomized to receive either zanubrutinib or bendamustine plus rituximab (BR). Meanwhile, the AMPLIFY trial compared acalabrutinib plus venetoclax against traditional chemoimmunotherapy approaches. The MAIC employed individual patient data from the SEQUOIA trial (n = 479) and aggregate data from the AMPLIFY trial (n = 581).

A detailed look at baseline patient characteristics revealed that the AMPLIFY trial had 26.8% of participants aged 65 years or older, with a majority being male (64.5%). In contrast, the SEQUOIA trial's baseline data showed that 78.7% of its low-risk patients were aged 65 or older, emphasizing a significant disparity in participant demographics between the two trials.

Further outcomes demonstrated that the PFS rates for zanubrutinib at 12, 24, 36, and 48 months were 97%, 94.2%, 88.5%, and 86.7%, respectively. In comparison, the AMPLIFY trial reported PFS rates of 96%, 91%, 79%, and 67% for the acalabrutinib plus venetoclax arm at the same intervals. This data underscores the potential of zanubrutinib as a more effective treatment option for patients with CLL, particularly those lacking the 17p deletion or TP53 mutation.

The implications of these findings are significant, as they may influence treatment guidelines and clinical decision-making for CLL management. The increased PFS associated with zanubrutinib could lead to improved long-term outcomes for patients, underscoring the need for healthcare providers to stay informed about emerging therapies in the rapidly evolving landscape of CLL treatment.

Future research will be critical to confirm these findings and to explore the long-term efficacy and safety of zanubrutinib in diverse patient populations. As the field of hematology continues to advance, the importance of well-structured clinical trials and comparative effectiveness research remains paramount in defining optimal treatment strategies for CLL and other malignancies.