Zanubrutinib Shows Enhanced Efficacy vs Approved BTKis in R/R CLL

Overall survival numerically favored zanubrutinib vs ibrutinib, bendamustine/rituximab or idelalisib/rituximab, and acalabrutinib, but these findings did not reach statistical significance.

Zanubrutinib (Brukinsa) demonstrated a reduced risk of progression or death in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) compared with other approved and recommended Bruton tyrosine kinase inhibitors (BTKis), including ibrutinib (Imbruvica), acalabrutinib (Calquence), and bendamustine or idelalisib (Zydelig)/rituximab (Rituxan), suggesting that it may be the most efficacious treatment for this patient population, according to a network meta-analysis (NMA) of the phase 3 ALPINE trial (NCT03734016), the phase 3 ASCEND trial (NCT02970318), and the phase 3 ELEVATE-RR trial (NCT02477696) published in Blood Advances.

Results from the NMA using COVID-19 adjusted data from the ALPINE trial revealed that among patients with relapsed/refractory CLL, zanubrutinib conferred greater efficacy than ibrutinib (HR, 0.49; 95% CI, 0.31-0.78). Additional efficacy benefit was observed with zanubrutinib vs acalabrutinib (HR, 0.55; 95% CI, 0.32-0.94) and bendamustine/rituximab or idelalisib/rituximab (HR, 0.12; 95% CI, 0.05-0.26), in the ELEVATE-RR and ASCEND trials, respectively. A reduction in the risk of death or progression by 51%, 45%, and 88% was observed with zanubrutinib vs ibrutinib/acalabrutinib, and bendamustine/rituximab or idelalisib/rituximab, respectively.

Furthermore, among those with 17p deletions, a benefit was also observed with zanubrutinib, with respective HRs of 0.49 (95% CI, 0.27-0.89), 0.49 (95% CI, 0.25-0.98), and 0.06 (95% CI, 0.02-0.18) among the ibrutinib, acalabrutinib, and bendamustine/rituximab or idelalisib/rituximab, respectively. Additionally, the respective HRs among those with TP53 mutations were 0.49 (95% CI, 0.28-0.85), 0.52 (95% CI, 0.27-1.00), 0.13 (95% CI, 0.05-0.31).

Furthermore, overall survival (OS) numerically favored zanubrutinib vs ibrutinib (HR, 0.59; 95% CI, 0.31-1.11), bendamustine/rituximab or idelalisib/rituximab (HR, 0.65; 95% CI, 0.23-1.75), and acalabrutinib (HR, 0.72; 95% CI, 0.35-1.50), but these findings did not reach statistical significance. Additionally, investigator-assessed progression-free survival (PFS) which favored zanubrutinib: respective HRs were 0.22 (95% CI, 0.12-0.40) vs acalabrutinib, 0.49 (95% CI, 0.31-0.78) vs ibrutinib, and 0.90 (95% CI, 0.70-1.16) vs ), bendamustine/rituximab or idelalisib/rituximab.

“The findings suggest that zanubrutinib provides benefits over other approved covalent BTKis (acalabrutinib and ibrutinib) and [bendamustine/rituximab or idelalisib/rituximab] in terms of PFS, and over ibrutinib in terms of response. Furthermore, while results were not statistically significant, there was a numeric trend in favor of zanubrutinib over other BTKis and [bendamustine/rituximab or idelalisib/rituximab] in terms of OS,” lead investigator, Mayzar Shadman, MD, MPH, associate professor, of Clinical Research, medical director of Cellular Immunotherapy, and Innovators Network Endowed Chair of the Fred Hutch Cancer Center, wrote in the publication with study coinvestigators. “[T]his is the first NMA to compare the efficacy of zanubrutinib vs approved and recommended BTKis in high-risk patients with R/R CLL. Findings suggest that zanubrutinib is likely to be the most efficacious BTKi for patients with genetic high-risk features such as the presence of TP53 mutations and/or [17p deletions].”

The trials included in the study were found following a systematic literature review. These searches were conducted on January 17, 2023, and they sought to identify randomized controlled trials reporting OS, PFS, and response outcomes among patients treated with BTKis for relapsed/refractory CLL.

Studies identified in the systematic literature review were required to report HRs or Kaplan-Meier curves for either OS, PFS, or objective response/complete response rates for an approved or recommended BTKi vs an approved comparator. NMAs were additionally performed using available mutation status-based subgroup data across trials. Data from the ALPINE trial, which collected data during the COVID-19 pandemic, included adjusted data for COVID-19–related deaths and unadjusted data.

Assessment of differences in potential effect modifiers found the trials were sufficiently similar. Across trials, similarities were observed in median patient age (range, 66-67), ECOG status (more than 87% had an ECOG status of 0 or 1), and Rai stage (stages III to IV range, 42%-50%).

Reference

Shadman M, Brown J, Mohseninejed L, et al. Comparative efficacy of Bruton tyrosine kinase inhibitors in high-risk relapsed/refractory CLL: a network meta-analysis. Blood Adv. Published online April 9, 2025. doi:10.1182/bloodadvances.2024014523