BTK Inhibitor Zanubrutinib vs Ibrutinib Among Patients With Waldenström Macroglobulinemia

Results from a Final Analysis of the Phase 3 ASPEN Trial

Findings from a final analysis of the open-label, phase 3 ASPEN trial published in the Journal of Clinical Oncology indicated that Bruton’s kinase tyrosine (BTK) inhibitor zanubrutinib exhibited similar efficacy and improved safety and tolerability compared to ibrutinib among patients with Waldenström macroglobulinemia (WM). 

“Zanubrutinib is a potent, selective next-generation covalent Bruton tyrosine kinase inhibitor approved in several countries for Waldenström macroglobulinemia (WM) in adults,” stated Meletios A. Dimopoulos, MD, National and Kapodistrian University of Athens, Athens, Greece, and coauthors. 

With 2 years of follow-up to the phase 3 ASPEN trial, the study authors present analyses on the long-term efficacy and safety of zanubrutinib compared to ibrutinib among patients with Waldenström macroglobulinemia. The primary end point was the sum of very good partial response (VGPR) and complete response (CR) rates. 

A total of 201 patients with myeloid differentiation primary response 88-mutant WM were enrolled into cohort 1, with 102 patients receiving zanubrutinib and 99 receiving ibrutinib. Cohort 2 consisted of 28 patients with myeloid differentiation primary response 88 wild-type WM who received zanubrutinib, 26 of whom were evaluable for efficacy. 

At a median follow-up of 44.4 months, the VGPR and CR rates were 36.3% for zanubrutinib and 25.3% for ibrutinib in cohort 1, and 30.8% with 1 patient reaching CR in cohort 2. Among patients with CXC motif chemokine receptor 4 mutation within cohort 1, the VGPR and CR rates were 21.2% for zanubrutinib and 10.0% for ibrutinib. The median progression-free survival and overall survival were not reached. 

Regarding safety, adverse events of any grade were more prevalent among patients treated with ibrutinib compared to zanubrutinib. These adverse events included diarrhea (34.7% versus 22.8%), muscle spasms (28.6% versus 11.9%), hypertension (25.5% versus 14.9%), atrial fibrillation/flutter (23.5% versus 7.9%), and pneumonia (18.4% versus 5.0%). In contrast, neutropenia was less prevalent among patients receiving ibrutinib (20.4%) versus zanubrutinib (34.7%) in cohort 1. Zanubrutinib was also associated with a lower risk of patients discontinuing treatment due to adverse events. 

“Extended follow-up results confirm improved long-term safety and tolerability of zanubrutinib compared with ibrutinib and support deeper, earlier, and more durable responses in patients with WM regardless of previous treatment or CXCR4 and MYD88 mutational statuses,” the study authors concluded. 

Source: 

Dimopoulos MΑ, Opat S, D’Sa S, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: final analysis from the randomized phase III ASPEN study. J Clin Oncol. Published online July 21, 2023. doi:10.1200/jco.22.02830