ASPEN: Long-term follow-up results of a phase 3 randomized trial of zanubrutinib (ZANU) versus ibrutinib (IBR) in patients with Waldenström macroglobulinemia (WM).

Abstract

7521 Background: ASPEN is a randomized, open-label, phase 3 study comparing ZANU, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi IBR in patients with WM. We present data with a median follow-up of 43 months. Methods: Patients with MYD88 mutations were assigned to cohort 1 and randomized 1:1 to receive ZANU 160 mg twice daily or IBR 420 mg once daily. Randomization was stratified by CXCR4 mutational status and lines of prior therapy (0 vs 1-3 vs > 3). Patients without MYD88 mutations were assigned to cohort 2 and received ZANU 160 mg twice daily. The primary endpoint was proportion of patients achieving complete response or very good partial response (CR+VGPR). Results: A total of 201 patients (ZANU arm, n = 102; IBR arm, n = 99) were enrolled in cohort 1 and 28 patients were enrolled in cohort 2. A larger proportion of patients in the ZANU arm of cohort 1 vs IBR had CXCR4 mutations by next-generation sequencing (32% vs 20%, or 33 of 98 vs 20 of 92 with data available) and were aged > 75 years (33% vs 22%). Median duration of treatment was 42 months (ZANU) and 41 months (IBR), with 67% and 58% remaining on treatment, respectively. The CR+VGPR rate by investigator was 36% with ZANU vs 22% with IBR ( p= 0.02) in cohort 1, and 31% in cohort 2. One patient achieved CR (cohort 2). In patients with wild type or mutant CXCR4 from cohort 1, CR+VGPR rates with ZANU vs IBR were 45% vs 28% ( p= 0.04) and 21% vs 5% ( p= 0.15) , respectively. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, and adverse events leading to discontinuation or death were lower with ZANU vs IBR (Table). Exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension were lower with ZANU vs IBR (0.2 vs 0.8 and 0.5 vs 1.0 persons per 100 person-months, respectively; p< 0.05). Rate of neutropenia was higher and rate of grade ≥3 infection was lower with ZANU vs IBR. Safety outcomes of ZANU were similar between cohorts 1 and 2. Conclusions: ASPEN is the largest phase 3 trial with head-to-head BTKi comparison in WM. At a median follow-up of 43 months, ZANU was associated with higher CR+VGPR rate and demonstrated clinically meaningful advantages in long-term safety and tolerability vs IBR. Clinical trial information: NCT03053440. [Table: see text]

Coming of Age for BTK Inhibitor Therapy: A Review of Zanubrutinib in Waldenström Macroglobulinemia

“…In a long-term follow-up (median, 43 months) to the ASPEN study, the CR combined with VGPR rate in patients with the MYD88 mutation who received zanubrutinib ( n = 102) or ibrutinib ( n = 99) was 36% and 22%, respectively, and 31% in patients without the mutation who received zanubrutinib ( n = 28) [ 46 ]. Similar safety outcomes were observed between patients with and without the MYD88 mutation who received zanubrutinib.…”

A Canadian Perspective on the Treatment of Waldenström Macroglobulinemia

“…Approval of zanubrutinib is based on the phase 3 ASPEN trial, which randomized 201 patients with MYD88 mutated WM to treatment with twice-daily zanubrutinib or once-daily ibrutinib, until disease progression or unacceptable toxicity [ 66 ]. In an updated report of ASPEN, at a median follow-up of 43 months, zanubrutinib continued to demonstrate trends for more favourable very good partial response rates (36.3% vs. 25.0%) and PFS (42-month PFS rate: 78.3% vs. 69.7%); however, the results were not statistically significant [ 65 ]. Estimated 42-month OS rates were similar between arms.…”

“…BTK inhibitors are associated with less toxicity than BR and are thus more suitable for older patients with comorbidities. As zanubrutinib demonstrated similar efficacy but better tolerability than ibrutinib in the ASPEN trial [ 65 ], it is now generally preferred over ibrutinib, particularly for patients with cardiovascular comorbidities. Selection of either ibrutinib or zanubrutinib may also depend on ease of access to each agent.…”

“…Given the modest activity of ibrutinib in patients with MYD88 wild-type WM, a second, single-arm cohort of the ASPEN trial enrolled patients with MYD88 wild-type ( n = 26) or unknown ( n = 2) status to receive zanubrutinib monotherapy [ 83 , 84 ]. In this cohort, major response rates improved over time from 54% at a median follow-up of 17.9 months to 65% at a median follow-up of 42.9 months [ 65 ], suggesting some activity for zanubrutinib in patients with MYD88 wild-type, albeit at a slower rate. A larger study of zanubrutinib in patients with MYD88 wild-type is needed to confirm this signal.…”

“…A similar decrease in very good partial response for patients with CXCR4 mutations compared to those without mutations was observed for zanubrutinib and ibrutinib in the ASPEN trial [ 66 ]. An exploratory analysis of ASPEN observed deeper and faster responses with zanubrutinib versus ibrutinib in patients with CXCR4 mutations, although the study was not powered to examine a significant difference in response in this subgroup of patients [ 65 ]. In small phase 2 trials of carfilzomib- and ixazomib-based therapies, ORRs, major response rates, and PFS were similar between patients with and without CXCR4 mutations; however, responses were deeper and achieved faster in those patients without CXCR4 mutations [ 53 , 85 ].…”