Outcomes after transition from ibrutinib to zanubrutinib in patients with Waldenström macroglobulinemia from the ASPEN study

Zanubrutinib is a next-generation covalent Bruton tyrosine kinase (BTK) inhibitor designed to provide complete and sustained BTK occupancy for efficacy across disease-relevant tissues, with fewer off-target effects than other covalent BTK inhibitors. In the phase 3 ASPEN study (BGB-3111-302), comparable efficacy and a favorable safety profile vs ibrutinib were demonstrated in patients with MYD88 (myeloid differentiation primary response 88)-mutated Waldenström macroglobulinemia (WM), leading to approval of zanubrutinib for patients with WM. BGB-3111-LTE1 (LTE1) is a long-term extension study to which eligible patients, including patients from comparator treatment arms, could enroll after participation in various parent studies of zanubrutinib to treat B-cell malignancies. Here, safety and efficacy are reported in the 47 patients who transitioned from ibrutinib treatment in ASPEN to zanubrutinib in LTE1. The median time from ibrutinib treatment initiation to LTE1 enrollment was 50.4 months (range, 26-59.3). At median LTE1 study follow-up of 15.3 months (range, 6.0-35.1), 85% of patients in this subgroup remained on zanubrutinib treatment. The median zanubrutinib treatment duration was 15.3 months. Despite advanced and increasing patient age, most ibrutinib treatment-emergent adverse events of interest for BTK inhibitors did not recur or worsen with zanubrutinib. WM disease response was maintained or improved in 44 of 46 efficacy-evaluable patients (96%; n = 2 converted to negative immunofixation). Although limited by sample size and nonrandomized/ad hoc analyses, data suggest that patients who tolerate ibrutinib may switch to zanubrutinib without compromising safety or efficacy. Long-term follow-up is ongoing. These trials were registered at www.ClinicalTrials.gov as #NCT03053440 and #NCT04170283.