ASPEN: results of a phase 3 randomized trial of zanubrutinib versus ibrutinib for patients with waldenstrom macroglobulinemia (WM). [Haematologica]

Abstract

Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. Aim/Objective: ASPEN (NCT03053440) is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in patients with WM. Method(s): Patients with MYD88 mutation-positive (MYD88mut+) WM were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort to receive ZANU; these results are reported separately. Randomization was stratified by CXCR4 mutational status and lines of prior therapy (0 vs 1-3 vs >3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory WM. Primary analysis was planned to occur at ~12 months after the last patient enrolled Results: In total, 201 patients were randomized to receive ZANU (n=102) or IBR (n=99) between Jan 2017 and Jul 2018. While the treatment groups were well balanced for most of the important baseline factors, more elderly patients (aged >75 years, 33.3% vs 22.2%) and more patients with anemia (hemoglobin <=110 g/L, 65.7% vs 53.5%) were randomized to receive ZANU. At a median follow-up of 19.4 months, the rate of VGPR was 28.4% with ZANU and 19.2% with IBR (2-sided P=.09; Table). No CRs were observed. Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events leading to discontinuation or death were lower with ZANU compared with IBR. Although the rate of neutropenia was higher with ZANU (Table 1), grade >=3 infection rates were similar between treatment arms (17.8% vs 19.4%). Conclusion(s): ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, compared with IBR, ZANU was associated with a higher VGPR response rate and demonstrated clinically meaningful advantages in safety and tolerability. (Table Presented).