Aspen: Results of a phase 3 randomized trial of zanubrutinib versus ibrutinib for patients with waldenstrom macroglobulinemia (WM).

Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for Waldenstrom macroglobulinemia (WM). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. ASPEN is a randomized phase 3 study comparing ZANU, a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in patients with WM. Aim(s): To compare the efficacy and safety of ZANU versus IBR in patients with WM and MYD88 mutation. Method(s): Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutation were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary endpoint 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% versus 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at approximately 12 months after the last patient enrolled. Result(s): In total, 201 patients were randomized from January 2017 to July 2018. While the treatment groups were well balanced for important baseline factors, in the ZANU arm, there were 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%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P = 0.09). Landmark analysis at 12 months showed a trend toward longer progression-free survival and overall survival, particularly in the R/R population. Rates of adverse events leading to dose holds, dose reductions, drug discontinu