Zanubrutinib Shows Superior Efficacy and Persistence Over Other BTK Inhibitors in CLL and B-Cell Lymphomas

Treatment with zanubrutinib (Brukinsa; BeOne Medicines) was linked to more improved overall response (ORR) and complete response (CR) rates compared with acalabrutinib (Calquence; AstraZeneca) and ibrutinib (Imbruvica; Janssen) across multiple B-cell lymphoma indications, according to a meta-analysis. The study, led by researchers at the University of Bologna, was funded by BeOne Medicines.

The meta-analysis compared the efficacy of these 3 FDA-approved Bruton tyrosine kinase (BTK) inhibitors across 4 indications: chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM), at both the treatment-naïve (TN) and relapsed/refractory (R/R) stages. The researchers drew on 22 clinical trials encompassing 3599 patients.

Across all indications, the pooled OR for CR was 1.80 (95% CI, 1.03-3.13), favoring zanubrutinib over acalabrutinib, and 2.85 (95% CI, 1.16-7.04), favoring zanubrutinib over ibrutinib. For ORR, pooled ORs were 1.59 (95% CI, 1.00-2.53) and 2.25 (95% CI, 1.40-3.61) against acalabrutinib and ibrutinib, respectively.

Results in R/R mantle cell lymphoma were among the most striking. Zanubrutinib demonstrated statistically superior CR compared with both acalabrutinib (OR 3.33; 95% CI, 1.91-5.81) and ibrutinib (OR 9.53; 95% CI, 5.45-16.66). Zanubrutinib also showed significantly better ORR versus ibrutinib in R/R MCL (OR 2.23; 95% CI, 1.21-4.12). In R/R MZL, zanubrutinib outperformed ibrutinib on both CR (OR 3.32) and ORR (OR 2.39). In TN CLL, zanubrutinib showed higher ORR than both comparators and higher CR versus acalabrutinib.

Because most data came from single-arm rather than head-to-head trials, the team used a 2-step statistical approach: pooling response rates within each indication, then performing a meta-analysis to produce naïve odds ratios (ORs) across each indication, using a random effects model.

In a separate retrospective study of older patients with CLL, zanubrutinib was associated with a longer time to discontinuation (TTD) and lower healthcare resource utilization (HCRU) compared to other BTKis. The study in patients 65 years and older found that zanubrutinib resulted in an estimated median TTD of 22.8 months, which was significantly longer than acalabrutinib (17.4 months; P =.0009) and ibrutinib (14.3 months; P <.0001). Zanubrutinib's 24-month discontinuation rate was significantly lower (51.1%) than both ibrutinib (61.4%; P <.0001) and acalabrutinib (57.7%; P <.0001).

HCRU was also significantly lower in patients receiving zanubrutinib. Outpatient visits per patient per year (PPPY) while receiving treatment were only 9.7 (standard deviation [SD], 9.7) compared to 10.9 (SD, 14.2; P =.047) for acalabrutinib and 11.5 (SD, 14.2; P =.0007) for ibrutinib. Zanubrutinib treatment also resulted in significantly lower average number of inpatient visits PPPY (0.8; SD, 3.4) than ibrutinib (1.2; SD, 4.0; P =.0046) and acalabrutinib (1.0; SD, 3.7; P =.0497). The study included a total of 5344 patients with CLL who initiated BTKi treatment during the index period of January 2022 to November 2024 and were aged 65 years or older.

An economic analysis examining zanubrutinib versus acalabrutinib in patients with R/R CLL found that using zanubrutinib instead of acalabrutinib avoided one R/R CLL progression for every 10 patients (for a number needed to treat [NNT] of 10). The NNT to avoid one death was 15. Among high-risk patients, the NNT to avoid one progression was 6, and the NNT to avoid one death was 18. Patients were classified as high-risk if they had a detectable deletion of chromosomes 17p or 11q, mutations in the TP53 gene, or an unmutated immunoglobulin heavy-chain variable region gene.

In terms of healthcare spending, the per-patient cost savings associated with using zanubrutinib instead of acalabrutinib were $7335 over the course of 24 months in the general R/R CLL group and $11,533 among high-risk patients. The cost savings were driven by lower subsequent treatment and disease management costs associated with disease progression.

Zanubrutinib "was designed for greater BTK specificity, sustained occupancy, and increased potency compared with ibrutinib and acalabrutinib," according to the economic analysis, which was funded by BeOne Medicines. The meta-analysis noted that the ELEVATE-RR trial, which involved patients with R/R CLL, did show that acalabrutinib had similar efficacy compared with ibrutinib, but otherwise there are few data sets for clinicians to use to directly compare therapies.