Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study

Abstract

The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.

Trial registration: ClinicalTrials.gov NCT03053440.

FIG 1.

(A) Best overall response rates over time as assessed by investigator, (B) progression-free survival, and (C) overall survival in the intent-to-treat patients (99 receiving ibrutinib; 102 receiving zanubrutinib at each time point) and (D) prevalence analysis for adverse events of interest from 0 to >36 months (cohort 1). Data cutoff: October 31, 2021. ^aN is the number of patients who are on treatment in each time interval or who discontinued treatment. The time from first dose date to the earliest date (last dose date + 30 days, initiation of new anticancer therapy, end of study, death or cutoff date) is within the time interval. The prevalence of each interval is the No. of patients with a new or ongoing event during the interval, shown as % of N. HR, hazard ratio; MR, minor response; PR, partial response; SD, stable disease; VGPR, very good partial response.