Characterization of zanubrutinib safety and tolerability profile and comparison with ibrutinib safety profile in patients with B-cell malignancies: post-hoc analysis of a large clinical trial safety database

Characterization of zanubrutinib safety and tolerability profile and comparison with ibrutinib safety profile in patients with B-cell malignancies: post hoc analysis of a large clinical trial safety databaseZanubrutinib is a next-generation Bruton tyrosine kinase inhibitor (BTKi) designed to minimize off-target effects associated with toxicities that have limited long-term treatment with ibrutinib, a first-generation BTKi.A previous pooled safety analysis of zanubrutinib monotherapy using data from six clinical trials (N=779) found that treatment was generally well tolerated, 1 with infections, hemorrhage, and neutropenia the most commonly reported categories of treatment-emergent adverse events (TEAE) of special interest (AESI).Rates of cardiovascular toxicities with zanubrutinib, including atrial fibrillation (afib)/flutter and hypertension, were considerably lower than those observed previously with ibrutinib.Here, we expanded on these findings and combined updated data from six studies examined in a prior pooled analysis 1 with data from four additional studies (Online Supplementary Table S1).A comparative analysis of zanubrutinib versus ibrutinib was also conducted using data from two of these ten studiesthe randomized phase III trials ALPINE (relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma 2,3 ) and ASPEN cohort 1 (Waldenström macroglobulinemia 4 ).The findings for the pooled zanubrutinib population (N=1,550) were consistent with those of the prior analysis, and the comparative analysis demonstrated the favorable safety profile of zanubrutinib 160 mg twice daily (N=425) compared with ibrutinib 420 mg once daily (N=422) (clinicaltrials gov.Identifiers: NCT03189524, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, NCT03053440, NCT03336333, NCT03734016, NCT04170283).Studies were approved by the independent ethics committees/institutional review boards at each participating institution and conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.All patients provided written informed consent.The median age of the pooled zanubrutinib population was 66.2 years, and the majority of patients were male (66.3%) (Table 1).Most patients had chronic lymphocytic leukemia/small lymphocytic lymphoma (60.5%), and approximately two-thirds had relapsed/refractory disease (68.9%).In the comparative analysis using data from ALPINE 3 and ASPEN (cohort 1), 5 baseline characteristics were generally similar between zanubrutinib-and ibrutinib-treated patients.In the total pooled zanubrutinib population, 45.0% of patients received zanubrutinib for ≥36 months (median, 34.4 months [range, 0.1-90.0months]), and 56.5% of patients remained on zanubrutinib as of the data cutoff.In the comparative