Page 263 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
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
Zanubrutinib is a next-generation Bruton tyrosine kinase inhib- itor (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 analysis1 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 studies - the randomized phase III trials ALPINE (relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma2,3) and ASPEN cohort 1 (Waldenström macroglobulinemia4). The findings for the pooled zanubrutinib population (N=1,550) were consistent with those of the prior analysis, and the com- parative 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. Identifi- ers: NCT03189524, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, NCT03053440, NCT03336333, NCT03734016, NCT04170283).
Studies were approved by the independent ethics commit- tees/institutional review boards at each participating insti- tution 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 ALPINE3 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, 0.1-90.0 months]), and 56.5% of patients remained on zanubrutinib as of the data cutoff. In the comparative
analysis, median treatment duration was 32.6 months (range, 0.4-68.7 months) for zanubrutinib versus 25.7 months (range, 0.1-59.3 months) for ibrutinib. Relative dose intensity was comparable between treatments, but a greater percentage of patients were on zanubrutinib versus ibrutinib treatment for ≥36 months (29.4% vs. 25.4%; median time to discontin- uation by Kaplan-Meier estimate, 63.3 vs. 42.2 months). In the comparative analysis, zanubrutinib-treated patients were more likely to still be on treatment at data cutoff than those treated with ibrutinib (69.9% vs. 45.0%).
TEAE leading to treatment discontinuation were reported in 13.6% of patients in the total pooled zanubrutinib popu- lation (Online Supplementary Table S2). In the comparative analysis, TEAE leading to treatment discontinuation were less common with zanubrutinib versus ibrutinib (14.1% vs. 22.0%). Infections were the most common TEAE leading to treatment discontinuation in the pooled zanubrutinib and comparative analysis populations (total zanubrutinib, 4.5%; ASPEN/ALPINE zanubrutinib, 5.4%; ASPEN/ALPINE ibrutinib, 6.6%). In the comparative analysis, ibrutinib-treated patients were more likely than zanubrutinib-treated patients to expe- rience cardiac disorder (MedDRA system organ class) TEAE that led to discontinuation (4.3% [N=18; most common, afib, N=7] vs. 0.5% [N=2; cardiomegaly and ventricular extrasys- toles, each N=1]).
Deaths attributed to TEAE occurred in 7.3% of patients in the total pooled zanubrutinib population and 8.7% and 10.2% of patients treated with zanubrutinib and ibrutinib, respectively, in the comparative analysis (Online Supplementary Table S2). Infections were the most common TEAE leading to death (total pooled zanubrutinib, 3.7%; ASPEN/ALPINE zanubrutinib, 5.2%; ASPEN/ALPINE ibrutinib, 6.2%). Cardiac disorder TEAE leading to death occurred in seven patients (1.7%) treated with ibrutinib versus one patient (0.2%) treated with zanubrutinib (see footnotes to Online Supplementary Table S2).
In this pooled analysis, 97.9% of patients who received za- nubrutinib monotherapy had ≥1 TEAE (grade ≥3, 66.9%), and 49.2% had serious TEAE (Online Supplementary Table S2). TEAE considered treatment-related by the investigator were reported in 79.4% of patients (grade ≥3, 35.7%). The most common (any grade in ≥10% of patients; grade ≥3 in ≥5%) non-hematologic TEAE reported are shown in Figure 1A. No grade ≥3 non-hematologic TEAE were reported in ≥10% of patients; the most common were pneumonia (8.4%; treat- ment-related, 4.1%) and hypertension (8.1%; treatment-re-
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