Comparative Analysis Suggests Zanubrutinib as Most Effective cBTKi in R/R CLL

Zanubrutinib (Brukinsa; BeOne Medicines) outperforms other covalent Bruton tyrosine kinase inhibitors (BTKis) in relapsed or refractory chronic lymphocytic leukemia (CLL), suggest findings of a new comparative analysis.1

Compared with its competitors, zanubrutinib showed an edge in reducing the risk of disease progression or death, researchers found in analyzing data from pivotal trials of covalent BTKis. In the absence of head-to-head trials, the study, published in Blood Advances, is the first to offer indirect comparisons between the treatments, which the researchers say is particularly important for certain patient subgroups.

“The results provide insights that cannot be derived directly from assessment of the individual trial outcomes and were not previously known,” explained the group. For example, while there is consensus on optimaltreatment for patients with certain high-risk factors, including del(17p) or TP53 mutations, uncertainty remains around the best course of action for patients with del(11q) or IGHV mutational status.

The meta-analysis assessed data on the 3 covalent BTKis approved in CLL—zanubrutinib, acalabrutinib (Calquence; AstraZeneca), and an earlier generation counterpart ibrutinib (Imbruvica; Pharmacyclics and Johnson & Johnson)—as well as bendamustine + rituximab (Rituxan; Genentech and Biogen) and idelalisib (Zydelig; Gilead) + rituximab (BR/IR). The analysis did not take into account data on the noncovalent BTKi pirtobrutinib (Jaypirca; Eli Lilly).

The indirect comparative analysis is the first of its kind to assess the relative efficacy of approved covalent Bruton tyrosine kinase inhibitors to treat CLL in the absence of head-to-head trials.

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Data came from the 3 pivotal randomized controlled trials for the BTKis—ALPINE (comparing zanubrutinib vs ibrutinib in patients with TP53 mutations and/or del[17p]),2 ELEVATE-RR (comparing acalabrutinib vs ibrutinib among patients with del[17p] and/or del[11q]),3 and ASCEND (comparing acalabrutinib vs BR/IR among patients with TP53 mutations and/or del[17p]).4 Follow-up within the trials ranged from 39 months to 46.5 months.

Compared with other BTKis and BR/IR, zanubrutinib showed significant improvements in progression-free survival (PFS), and while not statistically significant, numerical improvements in overall survival against acalabrutinib (HR, 0.72; 95% credible interval [CrI], 0.35-1.50) and ibrutinib (HR, 0.59; 95% CrI, 0.31-1.11), as well as against BR/IR (HR, 0.65; 95% CI, 0.23-1.75)

The analysis showed a 51% reduced risk of disease progression or death against ibrutinib (HR, 0.49; 95% CrI, 0.31-0.78) and a 45% reduced risk against acalabrutinib (HR, 0.55; 95% CrI, 0.32-0.94) among high-risk patients. PFS improvements associated with zanubrutinib were more pronounced against BR/IR (HR, 0.12; 95% CrI, 0.05-0.26).

This benefit, explained the researchers, remained even when adjusting data from the ALPINE trial for deaths related to COVID-19.

The group also looked at differences in response rates, observing similar findings coming from the ALPINE study, with more favorable overall (ORR) (OR, 3.09; 95% CrI, 1.40-7.26) and complete response (CR) (OR, 1.96; 95% CrI, 0.55-8.14) rates for zanubrutinib against ibrutinib. Numerical improvements in ORR (OR, 1.91; 95% CrI, 0.75-5.00) and CR (OR, 2.07; 95% CrI, 0.50-9.67) for zanubrutinib versus acalabrutinib were also documented.

The researchers noted that due to limited sample sizes provided in the data, they were unable todetermine clear long-term survival outcomes. The group also emphasized caution in takeaways of their findings based on the indirect comparisons made.

“When interpreting the results of the present study, the structure of the network must be considered; specifically for comparisons of zanubrutinib versus BR/IR which rely on indirect evidence (via ibrutinib), thereby decreasing the certainty of relative effect estimates,” wrote the researchers. “When estimates are informed by a single study per node along a chain, differences in effect modifiers across studies within the chain may impact the observed relative effects that rely on those chains, thereby making results less reliable.”

References

1. Shadman M, Brown J, 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(12):2863-2870. doi:10.1182/bloodadvances.2024014523
2. Brown J, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388:319-332. doi:10.1056/NEJMoa2211582
3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized Phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210.
4. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25). doi:10.1200/JCO.19.03355