An ML-NMR analysis associated zanubrutinib with PFS improvements vs ibrutinib or acalabrutinib in relapsed/refractory chronic lymphocytic leukemia.
Data from a multilevel network metaregression (ML-NMR) analysis demonstrated that zanubrutinib (Brukinsa) was associated with improved progression-free survival (PFS) compared with acalabrutinib (Calquence) or ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL).1
The analysis included patients treated with the respective Bruton tyrosine kinase (BTK) inhibitors during the phase 3 ALPINE (NCT03734016; n = 652), ELEVATE-RR (NCT02477696; n = 533), and ASCEND (NCT02970318; n = 310) trials. Findings published in the Journal of Medical Economics showed that in an R/R CLL population similar to that enrolled in the ALPINE trial, zanubrutinib reduced the risk of disease progression or death by 33% compared with ibrutinib (HR, 0.67; 95% credible interval [Crl], 0.52-0.87) and by 43% compared with acalabrutinib (HR, 0.57; 95% Crl, 0.34-0.95). Zanubrutinib was also associated with improved PFS vs idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine (Treanda) plus rituximab (IR/BR; HR, 0.15; 95% CI, 0.08-0.28). Notably, ibrutinib (HR, 0.23; 95% Crl, 0.13-0.39) and acalabrutinib (HR, 0.27; 95% Crl, 0.19-0.37) were also associated with PFS improvements compared with IR/BR.
Overall survival (OS) outcomes trended in favor of zanubrutinib vs ibrutinib (HR, 0.67; 95% Crl, 0.40-1.07), compared with acalabrutinib (HR, 0.77; 95% Crl, 0.36-1.65) and IR/BR (HR, 0.48; 95% CI, 0.19-1.19). However, the study authors noted that these uncertain OS findings with wide Crls could be attributed to data attributed to limited follow-up and immature data.
“The greater efficacy with zanubrutinib compared to other BTK inhibitors can be attributed to different factors,” lead study author Mazyar Shadman, MD, MPH, and colleagues wrote in the publication. “[The] next-generation covalent BTK inhibitor zanubrutinib and second-generation BTK inhibitor acalabrutinib demonstrate higher specificity for BTK [than] ibrutinib. However, the key advantage of zanubrutinib lies in its distinct pharmacokinetic profile. Unlike ibrutinib and acalabrutinib, zanubrutinib remains present in the bloodstream throughout the entire dosing interval. This persistent presence allows zanubrutinib to inhibit newly generated BTK molecules continuously, potentially leading to more complete and sustained BTK inhibition.”
Shadman is a professor in the clinical research division, medical director of cellular immunotherapy, and the Innovators Network Endowed Chair at Fred Hutch Cancer Center in Seattle, Washington.
Zanubrutinib, acalabrutinib, and ibrutinib are all approved by the FDA for the treatment of patients with CLL or small lymphocytic leukemia, with zanubrutinib earning the most recent
With no head-to-head studies comparing the efficacy and safety of all 3 BTK inhibitors, the ML-NMR was designed to estimate the treatment effect of zanubrutinib vs other BTK inhibitors in patients with R/R CLL with a patient profile similar to those treated in the ALPINE trial, which evaluated zanubrutinib vs ibrutinib.1
ALPINE, ELEVATE-RR (acalabrutinib vs ibrutinib), and ASCEND (acalabrutinib vs IR/BR) had similar inclusion criteria, including patients aged at least 18 years who had received at least 1 prior treatment for CLL and had an ECOG performance status of 0 to 2. Notably, ALPINE included patients with CLL or small lymphocytic lymphoma, whereas ELEVATE-RR and ASCEND included only patients with CLL. In ELEVATE-RR, patients were also required to harbor 17p or 11q deletions.
The ML-NMR analysis was intended to explore the treatment effects of these regimens after adjusting for patient-related treatment effect modifiers across the studies.
Shadman and colleagues also analyzed outcomes for patients with 17p or 11q deletions, mirroring the enrollment criteria for ELEVATE-RR. Findings showed that zanubrutinib improved PFS compared with ibrutinib (HR, 0.55; 95% Crl, 0.36-0.83) and acalabrutinib (HR, 0.57; 95% Crl, 0.34-0.95).
OS outcomes in the high-risk population were similar to those of the overall ALPINE population for zanubrutinib vs ibrutinib (HR, 0.55; 95% Crl, 0.27-1.09) and vs acalabrutinib (HR, 0.77; 95% Crl, 0.36-1.65).
“Since we had to assume that the impact of covariates on the HRs of zanubrutinib vs ibrutinib, acalabrutinib vs ibrutinib, and BR/IR vs ibrutinib are of the same magnitude…the HRs between zanubrutinib, acalabrutinib, and IR/BR are unaffected by the effect modifiers and therefore the same for the high-risk population and the ALPINE ITT [intention-to-treat] population,” Shadman and colleagues wrote.
