Background: Bruton tyrosine kinase (BTK) is an important regulator of cell proliferation and cell survival in various B-cell malignancies. BTK inhibitors block BCR-induced BTK activation and its downstream signaling, leading to growth inhibition and cell death in malignant B-cells. First-generation BTK inhibitor, ibrutinib, revolutionized treatment; however, inhibition of off-target kinases such as EGFR, HER2, TEC, and CSK may be associated with toxicities, including gastrointestinal side effects, rash, bleeding, and atrial fibrillation, that limit its use. Zanubrutinib, a potent and selective next-generation Bruton tyrosine kinase (BTK) inhibitor, was designed to maximize BTK occupancy and minimize off-target effects.
Aims: To characterize the overall safety/tolerability profile of zanubrutinib monotherapy and compare the zanubrutinib profile with the profile of ibrutinib in patients (pts) with B-cell malignancies using the zanubrutinib clinical safety database.
Methods: In these post-hoc analyses, safety data were pooled from 10 clinical trials of zanubrutinib monotherapy; two of the included studies (ASPEN; ALPINE) compared zanubrutinib head-to-head with ibrutinib. Patients with CLL/SLL, MCL, MZL, WM, FL and other B-cell malignancies were included. Treatment-emergent adverse events (TEAEs) were summarized using MedDRA preferred terms (PT); adverse events of special interest (AESI) were defined using pooled terms. Rates of TEAEs, exposure-adjusted incidence rates (EAIR), and prevalence over time of AESIs were assessed.
Results: Pooled analyses included 1550 pts (median age, 67 yrs) treated with zanubrutinib monotherapy from multiple geographical regions and races. Median zanubrutinib exposure was 28.6 months with 31.2% of pts having treatment exposure of ≥36 mo. The most commonly reported non-hematologic AEs of any grade were upper respiratory tract infection (29.0%), diarrhea (19.9%), contusion (19.4%), cough (17.2%), and rash (16.2%); grade ≥3 non-hematologic AEs occurring in ≥5% of pts included pneumonia (7.9%) and hypertension (7.4%). The most common serious AE was pneumonia (7.5%). Zanubrutinib discontinuation due to any AE occurred in 12.3% of pts; AEs leading to dose reduction occurred in 9.6%. Disease progression was the most common cause of death (7.2%); deaths attributed to AEs occurred in 5.6% of pts, most (3.2%) were due to infections including COVID-19-related AEs.
The most commonly reported AESIs (any grade) in the pooled zanubrutinib population (N=1550) and in ibrutinib-treated pts from ASPEN and ALPINE (N=422) were infections and hemorrhage (Table). With the exception of neutropenia, EAIRs were numerically lower for zanubrutinib vs ibrutinib most notably hypertension (0.57 vs 1.15 person/100 person-months), anemia (0.54 vs 0.84 person/100 person-months), and atrial fibrillation or flutter (0.15 vs 0.70 person/100 person-months). Prevalence of zanubrutinib AESI tended to remain constant or decrease with longer follow-up.
Summary/Conclusion: As BTKi therapy requires continuous treatment, long-term tolerability and low treatment discontinuation rates are needed for successful outcomes. These pooled safety analyses demonstrate that zanubrutinib is well tolerated in pts with B-cell malignancies. Zanubrutinib AEs were generally mild-to-moderate in severity and tended not to lead to treatment discontinuation. Prevalence of AESI generally trended down over time without emergence of new safety signals, supporting zanubrutinib as a good option for long-term treatment.
Keywords: Marginal zone, Chronic lymphocytic leukemia, Mantle cell lymphoma, Waldenstrom’s macroglobulinemia