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 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 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 lymphoma^2,3) 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 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 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 discontinuation 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 population (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 experience 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 extrasystoles, 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 zanubrutinib 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%; treatment-related, 4.1%) and hypertension (8.1%; treatment-related, 3.4%). Pneumonia (8.2%) was the only serious TEAE in ≥5% of patients. In summary, these findings were consistent with those for the prior pooled safety analysis,¹ even with a median treatment duration ≈9 months longer.

Table 1.Demographics and baseline characteristics.

Select TEAE preferred terms were grouped as AESI (“opportunistic infections” included preferred terms under the narrow standardized MedDRA query “opportunistic infections”; for all other AESI preferred terms, see Tam et al.¹). In order to account for differing treatment exposures across the trials, exposure-adjusted incidence rates (EAIR) of these AESI were determined for the total pooled zanubrutinib population (Figure 1B; see legend for EAIR calculation and assumption) and comparative analysis populations (Figure 1C).

Infections, hemorrhage, and neutropenia were the most frequently reported AESI in the total pooled zanubrutinib population, even after adjusting for dose exposure (Figure 1B). Despite a longer median treatment duration, the EAIR of the cardiovascular AESI were comparable to those of the earlier analysis (hypertension, 6.81 in the present analysis vs. 6.87 persons per 100 person-years [PY] in Tam et al.;¹ afib/flutter, 1.74 vs. 1.45 persons per 100 PY, respectively). ALPINE had a greater hypertension EAIR than SEQUOIA and ASPEN; exclusion of data from ALPINE decreased the hypertension EAIR to 5.73 persons per 100 PY. In ALPINE, the hypertension rate was similar between the zanubrutinib and ibrutinib arms; however, the incidence of cardiac disorders such as afib/flutter was higher in the ibrutinib arm,³ whereas incidence in the zanubrutinib arm remained low and comparable to that observed in SEQUOIA and ASPEN.

Figure 1.Incidence of any-grade non-hematologic treatment-emergent adverse events and exposure-adjusted incidence rates of adverse events of special interest. (A) Treatment-emergent adverse events (TEAE) reported in ≥10% or grade ≥3 TEAE in ≥5% of patients treated with zanubrutinib (N=1,550) are shown. TEAE were defined as adverse event (AE) preferred terms with an onset date or worsening in severity from baseline (prior to treatment) at or after the first dose of zanubrutinib and up to the last zanubrutinib dose date + 30 days or initiation of new anticancer therapy, whichever occurred first. Worsening of an event to grade 5 beyond the last zanubrutinib dose date + 30 days and prior to initiation of new anticancer therapy was also considered treatment emergent. (B, C) The AE of special interest (AESI) shown are grouped terms. The preferred terms for the TEAE included in each AESI category are as previously published,¹ except for “opportunistic infections,” which included preferred terms under the narrow standardized MedDRA query “opportunistic infections.” Exposure-adjusted incidence rates (EAIR) were calculated as the number of patients who experienced a specific AESI divided by the total exposure time (i.e., the first dose date to the first event date or to the treatment-emergent period end date if there was no event) in years for all patients and then multiplied by 100 to express as persons per 100 person-years. Of note, EAIR assumes that the risk of an event occurring is constant over time and serves as an additional means for evaluating safety events. In (B), data are shown for the total pooled zanubrutinib population (N=1,550). In (C), data are shown for the comparative analysis of patients treated with zanubrutinib (N=425) or ibrutinib (N=422) as part of the randomized studies ASPEN (cohort 1) or ALPINE. The Poisson regression model was used to compare EAIR between treatment groups, with the number of patients who experienced events as the dependent variable and log(exposure time) as the offset. The P value based on χ² test was reported. All statistical tests were two-sided, with P<0.05 considered significant; no adjustments for multiple comparisons were made. COVID-19: coronavirus disease 2019.

Importantly, across all ten trials, no zanubrutinib-treated patients discontinued due to hypertension.

In the comparative analysis, all EAIR of AESI, except for neutropenia, were numerically lower in patients treated with zanubrutinib versus ibrutinib (Figure 1C). Although the neutropenia EAIR was slightly higher with zanubrutinib, the infection EAIR was significantly lower (64.81 vs. 79.63 persons per 100 PY; P=0.0098) with zanubrutinib, even after excluding COVID-19-related infection terms (54.48 vs. 69.96 persons per 100 PY; P=0.0029). The EAIR for afib/flutter was also significantly lower with zanubrutinib versus ibrutinib (P<0.0001). The hypertension EAIR was also reduced in patients receiving zanubrutinib versus ibrutinib (P=0.0610). AESI EAIR analyzed over time were relatively constant or decreased with zanubrutinib (Figure 2; time to first event data, Online Supplementary Figure S1). In the comparative analysis, AESI EAIR over time were numerically lower with zanubrutinib versus ibrutinib, except for neutropenia, which was higher in the first 12 months of treatment and is considered an on-target effect of BTK inhibition.⁶ However, this was not accompanied by an elevated infection EAIR nor was neutropenia a substantial cause of discontinuation (7.1% [3/42]). Increases of >10 persons per 100 PY in the EAIR for anemia and hemorrhage were observed with ibrutinib between the >24-month exposure intervals. In contrast, the greatest increase between consecutive intervals with zanubrutinib was 4.1 persons per 100 PY (hemorrhage).

At all treatment intervals evaluated, the EAIR for afib/ flutter was 6.7 to 13.6 persons per 100 PY higher with ibrutinib than with zanubrutinib. In the present analysis, the afib/flutter EAIR was relatively constant in the first 2 years of ibrutinib exposure but steadily increased with each subsequent year of treatment. In contrast, the EAIR in patients who received zanubrutinib was much lower at all intervals, with only slight increases observed after 2 to 3 years of exposure. This relatively stable incidence of afib/flutter with zanubrutinib, despite extended exposure, is important for long-term treatment. Additionally, a lower incidence of afib may minimize the need for supportive care (e.g., anticoagulants, antiplatelet agents) that can further increase the bleeding risk associated with BTKi. Finally, although hypertension in patients receiving ibrutinib has been associated with increased incidence of major cardiovascular AE,⁷ the incidence of cardiac disorder TEAE was comparable for zanubrutinib across ALPINE, ASPEN, and SEQUOIA despite the higher hypertension EAIR observed in ALPINE.

Figure 2.Exposure-adjusted incidence rates of select adverse events of special interest over time. Adverse events of special interest (AESI) are grouped terms as defined in the legend for Figure 1. Exposure-adjusted incidence rates (EAIR) at each time interval were calculated as the number of patients who experienced a specific AESI during that time interval divided by the total exposure time in years at the corresponding time interval. This value was then multiplied by 100 to express as persons per 100 person-years (PY). Data are shown for the total pooled zanubrutinib population (N=1,550) and the comparative analysis patient populations (patients treated with zanubrutinib [N=425] or ibrutinib [N=422] as part of the randomized studies ASPEN cohort 1 or ALPINE; each treatment group is labeled as ASPEN/ALPINE).

Due to the continuous dosing of BTKi in most B-cell malignancies, low treatment discontinuation rates and long-term tolerability are key considerations, particularly in patients with B-cell malignancies such as chronic lymphocytic leukemia/small lymphocytic lymphoma who tend to be aged >65 years and have other (e.g., cardiovascular) comorbidities.^8,9 The first-in-class BTKi ibrutinib has drastically improved treatment of numerous B-cell malignancies, but cardiac arrhythmias and their associated outcomes are a frequently cited concern^10-12 and are possibly due to off-target inhibition of kinases such as TEC and CSK.^13,14 Such toxicities can limit the duration and, consequently, the benefit¹⁵ of treatment. Zanubrutinib was designed with greater selectivity to minimize off-target effects. In this analysis, zanubrutinib remained well tolerated, consistent with the previous analysis,¹ with no emergence of new safety signals, even at a median treatment duration of approximately 3 years. In the comparative analysis, zanubrutinib exhibited a more favorable safety profile than ibrutinib, as demonstrated by the longer median treatment duration and lower frequency of TEAE, including cardiac disorders, that led to treatment discontinuation or death. These analyses support zanubrutinib as an appropriate long-term treatment option for patients with B-cell malignancies.

Footnotes

• Received September 5, 2023
• Accepted February 14, 2024

Correspondence

°Current address: ProKidney Corp., Winston-Salem, NC, USA

J.R. BROWN - Jennifer_Brown@dfci.harvard.edu

Disclosures

JRB discloses consultancy for AbbVie, Acerta/AstraZeneca, Alloplex Biotherapeutics, BeiGene, Galapagos NV, Genentech/Roche, Grifols Worldwide Operations, InnoCare Pharma Inc, iOnctura, Kite, Loxo/ Lilly, Merck, Numab Therapeutics, Pfizer and Pharmacyclics; research funding from BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma and TG Therapeutics. PG discloses honoraria from AbbVie, ArQule/MSD, AstraZeneca, BeiGene, Celgene/Juno/Bristol Myers Squibb, Janssen, Lilly/Loxo, MEI Pharma, Roche and Sanofi; research funding from AbbVie, AstraZeneca, Janssen and Sunesis. WJ discloses consultancy for Janssen, AstraZeneca, MEI Pharma, Lilly, Takeda, Roche, AbbVie and BeiGene; research funding from AbbVie, Bayer, BeiGene, Celgene, Janssen, Roche, Takeda, TG Therapeutics, AstraZeneca, MEI Pharma and Lilly. BSK discloses research funding from BeiGene to Washington University School of Medicine (St Louis, MO, USA); consulting fees from AbbVie, AstraZeneca, BeiGene, Janssen and Pharmacyclics. NL discloses consultancy for AbbVie, AstraZeneca, BeiGene, Lilly/Loxo, Genentech, Janssen and Pharmacyclics; research funding from AbbVie, AstraZeneca, BeiGene, Lilly/Loxo, Genentech, Octapharma, Oncternal, MingSight and TG Therapeutics. TR discloses research funding from BeiGene, Octapharma, AstraZeneca, Janssen, Regeneron and GSK; honoraria from AstraZeneca, BeiGene, Janssen, AbbVie, Octapharma, Regeneron and GSK; travel, accommodations, expenses from AstraZeneca. MS discloses consultancy for AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, BeiGene, Bristol Myers Squibb, MorphoSys/Incyte, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Lilly, Adaptimmune, Mustang Bio, Regeneron, Merck, Fate Therapeutics, MEI Pharma and Atara Biotherapeutic; research funding from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Sunesis, Atara Biotherapeutics, Genmab, MorphoSys/Incyte and Vincerx. CST discloses research funding from Janssen, AbbVie and BeiGene; honoraria from Janssen, AbbVie, BeiGene, Loxo and AstraZeneca. LQ discloses consultancy for and speakers bureau of Janssen, AstraZeneca, Takeda, Roche, AbbVie and BeiGene. TS discloses employment at BeiGene Switzerland GmbH; is an equity holder of BeiGene Ltd. MZ, JP, LW, JZ and HM disclose employment at BeiGene. AC discloses employment at BeiGene; is an equity holder of BeiGene; discloses travel, accommodations, expenses from BeiGene. AT discloses consultancy for BeiGene, AstraZeneca, AbbVie and Janssen; honoraria from BeiGene, AstraZeneca, AbbVie and Janssen; speakers bureau of BeiGene, AstraZeneca, AbbVie and Janssen; travel, accommodations, expenses from BeiGene, AstraZeneca, AbbVie and Janssen.

Contributions

JRB, PG, WJ, BSK, NL, TR, MS, CST, LQ, and AT enrolled patients, performed research, and contributed to data collection, analysis, and interpretation. JP, TS, LW, MZ, AC, and HM contributed to this study’s conceptualization and design, data curation, formal analysis, data interpretation, methodology, and validation. All authors contributed to the writing, review, editing, and final approval of this manuscript.

Funding

Acknowledgments

The authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers for the clinical trials included in this analysis. This analysis was sponsored by BeiGene Co, Ltd. Medical writing and editorial assistance were provided by Jenna M. Gaska, PhD, of Nucleus Global, an Inizio Company, and supported by BeiGene.