Phase 3 Trial Comparing Zanubrutinib and Ibrutinib in Patients with WM ASPEN Study

Zanubrutinib (ZANU) is an orally bioavailable, next-generation Bruton tyrosine kinase inhibitor (BTKi) with improved potency and selectivity for BTK and reduced activity against tyrosine kinases in the TEC and EGFR families. The ASPEN study (NCT03053440) was an open-label, randomized phase 3 trial comparing ZANU to the first-generation BTKi Ibrutinib (IBR) in patients with WALDENSTRÖM MACROGLOBULINEMIA (WM). The median follow-up time in the data presented was 43 months. The study aimed to evaluate the effectiveness and safety of ZANU versus IBR in patients with MYD88 mutant (MYD88mut) WM and ZANU in patients with wild-type MYD88 (MYD88wt) WM. Patients with MYD88mut WM were randomly assigned to receive either ZANU 160 mg twice daily or IBR 420 mg once daily in cohort 1. Cohort 2 patients with MYD88wt were given 160 mg ZANU twice daily until disease progression. Sanger sequencing results for CXCR4 mutations and the number of prior lines of therapy (zero, one, three, or more) were used to stratify the randomization process—all pts provided written informed consent. Patients’ rates of very good partial response (VGPR) or better (VGPR + complete response [CR]) was the primary endpoint. The primary analysis was performed at a median follow-up of 19 months, and the final analysis is expected to be performed approximately 4 years after the first patient was enrolled.

Cohort 1 consisted of 102 patients (102 ZANU; 99 IBR), and cohort 2 consisted of 28. CXCR4 mutations by next-generation sequencing were different between patients treated with ZANU and IBR in cohort 1 (32% vs. 20%, or 33 of 98 vs. 20 of 92 available samples, respectively) and between patients aged >75 years (33% vs. 22%). Among those still receiving treatment, 67% did so after 42 months (ZANU), and 58% did so after 41 months (IBR). Cohort 1 had a 36% VGPR+CR rate with ZANU compared to 22% with IBR (descriptive p = 0.02), and cohort 2 had a 31% rate. In cohort 2, a single pt experienced a CR. Rates of VGPR+CR with ZANU versus IBR were 45% versus 28% (p = 0.04) and 21% versus 5% (p = 0.15), respectively, in patients with wild-type (65 ZANU; 72 IBR) or mutant CXCR4 (33 ZANU; 20 IBR) from cohort 1. Both the median of time without progression and the median of time alive were not achieved. Neutropenia (including grade 3) was the only AE of interest that was higher with ZANU (33.7%) vs. IBR (19.4%), which is consistent with less off-target inhibition. The rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, and AEs leading to discontinuation or death were all lower with ZANU vs. IBR. With ZANU, the rate of grade 3 infections was lower at 20.8% than with IBR’s 27.6%. Cohorts 1 and 2 experienced a similar rate of ZANU-related adverse events.

When comparing ZANU and IBR, the annual prevalence analysis for AEs in cohort 1 showed that the prevalence of hemorrhage decreased over time and was lower with ZANU. As treatment progressed, patients given ZANU saw a diminishing incidence of neutropenia and infections. At >24-36 months post-treatment, the neutropenia rate was similar between arms (8.8% vs. 9.7%, respectively), and the infection rate was lower in patients treated with ZANU than with IBR. When comparing ZANU and IBR, the lower prevalence at all intervals of atrial fibrillation and hypertension with ZANU is striking. When comparing ZANU and IBR, the incidence of atrial fibrillation/flutter and hypertension was consistently lower after adjusting for exposure (0.2 vs. 0.8 and 0.5 vs. 1.0 persons per 100 person-months, respectively; p 0.05).

Source:https://library.ehaweb.org/eha/2022/eha2022-congress/358020/meletios.dimopoulos.aspen.long-term.follow-up.results.of.a.phase.3.randomized.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26857%2Amarker%3D1769%2Afeatured%3D17676

Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT03053440

Dimopoulos M, Opat S, D’Sa S, Jurczak W, Lee H-P, Cull G, Owen R, Marlton P, Wahlin B, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo J, Czyz J, Rodriguez C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trneny M, Minnema M, Buske C, Leblond V, Treon S, Trotman J, Chan W, Schneider J, Allewelt H, Cohen A, Huang J & Tam C. ASPEN: LONG-TERM FOLLOW-UP RESULTS OF A PHASE 3 RANDOMIZED TRIAL OF ZANUBRUTINIB (ZANU) VS IBRUTINIB (IBR) IN PATIENTS (PTS) WITH WALDENSTRÖM MACROGLOBULINEMIA (WM). EHA Library. Dimopoulos M. 06/10/2022; 358020; P1161.