Zanubrutinib Shows Potential Efficacy Edge in High-Risk R/R CLL, Analysis Finds

The analysis included patients treated in the phase 3 ALPINE, ELEVATE-RR, and ASCEND trials.

Zanubrutinib (Brukinsa) may provide greater efficacy than acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with high-risk, relapsed/refractory chronic lymphocytic leukemia (CLL), according to findings from a network meta-analysis comparing outcomes with BTK inhibitors in this population.

The NMA, which was published in Blood, included patients with high-risk, relapsed/refractory ALL who were treated in the phase 3 ALPINE (NCT03734016), ELEVATE-RR (NCT02477696), and ASCEND (NCT02970318) studies.

The analysis incorporated investigator-assessed progression-free survival (PFS) and response outcomes from patients treated with zanubrutinib, ibrutinib, acalabrutinib, bendamustine plus rituximab (Rituxan; BR), or idelalisib plus rituximab (IR). High-risk subgroups were defined by the presence of del(17p) and/or TP53 mutations del(17p) for those enrolled in the ALPINE (n = 150) and ASCEND (n = 86) studies, and del(17p) and/or del(11q) in ELEVATE-RR (n = 533). Network comparisons were performed using both COVID-19–adjusted and unadjusted data from the ALPINE trial to evaluate the robustness of outcomes.

In the COVID-19–adjusted analysis, zanubrutinib reduced the risk of disease progression or death compared with ibrutinib (HR, 0.49; 95% credible interval [CrI], 0.31-0.78), acalabrutinib (HR, 0.55; 95% CrI, 0.32-0.94), and BR/IR (HR, 0.12; 95% CrI, 0.05-0.26).. Similar findings were observed in the unadjusted analysis for zanubrutinib vs ibrutinib (HR, 0.52; 95% CrI, 0.33-0.82), vs acalabrutinib (HR, 0.58; 95% CrI, 0.34-0.99), and vs BR/IR (HR, 0.13; 95% CrI, 0.06-0.28).

Overall survival (OS) outcomes showed a numerical benefit with zanubrutinib compared with ibrutinib (HR, 0.59; 95% CrI, 0.31-1.11; probability better, 94.8%), acalabrutinib (HR, 0.72; 95% CrI, 0.35-1.50; probability better, 81.5%), and BR/IR (HR, 0.65; 95% CrI, 0.23-1.75; probability better, 80.0%), although these findings did not reach statistical significance.

“The ALPINE and ELEVATE-RR trials have been critical in demonstrating the efficacy of the next-generation BTKis for treatment of R/R CLL. However, ELEVATE-RR did not show the same sustained superior benefit over ibrutinib in high-risk patients when compared to the ALPINE trial,” lead study author Mazyar Shadman, MD, MPH, and colleagues, wrote in a publication of the data. “Findings from this NMA highlight this difference, along with the magnitude of relative benefit for zanubrutinib versus acalabrutinib in patients with high-risk mutations.”

Shadman is an associate professor in the Clinical Research Division, medical director of Cellular Immunotherapy, and endowed chair of the Innovators Network Fred Hutch Cancer Center in Seattle, Washington.

NMA Design

A systematic literature review (SLR) and NMA were conducted to compare clinical outcomes associated with approved and recommended BTK inhibitors in patients with relapsed/refractory CLL. The SLR was performed according to the PRISMA guidelines, with systematic searches conducted on January 17, 2023. Eligible studies included randomized controlled trials reporting OS, PFS, and response outcomes.

“While the most important end point for evaluation of response to BTK inhibitors is an important open question, in particular given the high overall response rate observed and clinical benefits observed beyond response outcomes, our NMA aimed to maximize the reported subgroup data available for high-risk patients,” Shadman and colleagues explained.

Patients from ALPINE, ELEVATE-RR, and ASCEND who met inclusion criteria were selected for feasibility assessment and inclusion in the NMA. All trials evaluated at least one BTK inhibitor and were considered sufficiently comparable in terms of design, population, geographic scope, and primary endpoints.

Given that the ALPINE trial data were collected during the COVID-19 pandemic, a post hoc adjustment was made to account for COVID-19–related deaths. The adjusted dataset served as the base case for the NMA, with a sensitivity analysis conducted using unadjusted data.

Baseline Information

Median patient age was similar across trials, ranging from 66 years in ELEVATE-RR to 67 years in both ALPINE and ASCEND. The proportion of male patients ranged from 67% in ASCEND to 71% in ELEVATE-RR. Most patients had an ECOG performance status of 0 to 1, reported in 97% of the ALPINE population, 92% of ELEVATE-RR population, and 87% of ASCEND population.

Disease staging at baseline showed that Rai stage III to IV disease was reported in 50% of ELEVATE-RR and 42% of ASCEND participants; these data were not reported in ALPINE. Binet stage distribution was similar between ALPINE and ELEVATE-RR.

The prevalence of del(11q) varied: 64% in ELEVATE-RR compared with 27% in both ALPINE and ASCEND. Del(17p) was reported in 46% of patients in ELEVATE-RR, 16% of patients in ASCEND, and 15% of those in ALPINE. The proportion of patients with TP53 mutations mirrored del(17p) frequencies, with ELEVATE-RR enrolling a notably higher proportion of patients with TP53 alterations (40%) compared with ALPINE (15%) and ASCEND (24%). When considering combined del(17p) and/or TP53 alterations, the distribution was 51% in ELEVATE-RR, 28% in ASCEND, and 23% in ALPINE.

Unmutated IGHV was present in the majority of patients across trials: 86% in ELEVATE-RR, 74% in ASCEND, and 73% in ALPINE.

In terms of prior treatment, the median number of prior lines ranged from 1 in ALPINE (range, 1-8) to 2 in both ELEVATE-RR (range, 1-12) and ASCEND (range, 1–10). The proportion of patients with 3 or more prior lines was 10% in ALPINE, 13% in ASCEND, and not explicitly separated in ELEVATE-RR, which grouped 1 to 3 lines together (88%). Prior exposure to anti-CD20 antibodies was common across studies, ranging from 80% in ASCEND to 86% in ELEVATE-RR.

Reference

Shadman M, Brown JR, Mohseninejad L, et al. Comparative efficacy of Bruton tyrosine kinase inhibitors in high-risk relapsed/refractory CLL: a network meta-analysis. Blood Adv. 2025;9(7):2024014523. doi:10.1182/bloodadvances.2024014523