Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study

Author(s): Meletios A. Dimopoulos, MD1; Stephen Opat, MBBS2; Shirley D’Sa, MD3; Wojciech Jurczak, MD4; Hui-Peng Lee, MBChB5; Gavin Cull, MBBS6; Roger G. Owen, MD7; Paula Marlton, MBBS8; Björn E. Wahlin, MD, PhD9; Ramon Garcia-Sanz, MD, PhD10; Helen McCarthy, MD11; Stephen Mulligan, PhD, MBBS12; Alessandra Tedeschi, MD13; Jorge J. Castillo, MD14; Jaroslaw Czyz, MD, PhD15; Carlos Fernández de Larrea, MD, PhD16; David Belada, PhD17; Edward Libby, MD18; Jeffrey Matous, MD19; Marina Motta, MD20; Tanya Siddiqi, MD21; Monica Tani, MD22; Marek Trněný, MD23; Monique C. Minnema, MD, PhD24; Christian Buske, MD25; Veronique Leblond, MD, PhD26; Steven P. Treon, MD, PhD14; Judith Trotman, MBChB27; Wai Y. Chan, PhD28; Jingjing Schneider, PhD28; Heather Allewelt, MD28; Sheel Patel, PharmD28; Aileen Cohen, MD28; and Constantine S. Tam, MD2,29
Source: DOI: 10.1200/JCO.22.02830 Journal of Clinical Oncology 41, no. 33 (November 20, 2023) 5099-5106.
Original Article
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Final results from the ASPEN study confirm the strong long-term superiority of zanubrutinib over ibrutinib in symptomatic WM. While overall survival (OS) and progression-free survival (PFS) end-points are still to be reached, demonstrating the good prognosis of this disease, toxicities and response rates are much better with zanubrutinib.  This is a cat-1 indication oof NCCN and a compelling option for use in this population.
The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88–mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.

Author Affiliations

1National and Kapodistrian University of Athens, Athens, Greece; 2Monash Health & Monash University, Clayton, VIC, Australia; 3Centre for Waldenström’s Macroglobulinemia & Associated Disorders, University College London Hospital Foundation Trust, London, United Kingdom; 4Maria Sklodowska-Curie National Institute of Oncology, Krakow, Poland; 5Flinders Medical Centre, Adelaide, SA, Australia; 6Sir Charles Gairdner Hospital, University of Western Australia, Perth, WA, Australia; 7St James University Hospital, Leeds, United Kingdom; 8Princess Alexandra Hospital and University of Queensland, Brisbane, QLD, Australia; 9Karolinska Universitetssjukhuset & Karolinska Institutet, Stockholm, Sweden; 10Hospital Universitario de Salamanca, Salamanca, Spain; 11Royal Bournemouth & Christchurch Hospital, Bournemouth, United Kingdom; 12Royal North Shore Hospital, Sydney, NSW, Australia; 13ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 14Dana-Farber Cancer Institute, Boston, MA; 15Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland; 16Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain; 17FN Hradec Králové, Hradec Králové, Czechia; 18Fred Hutchinson Cancer Center, Seattle, WA; 19Colorado Blood Cancer Institute, Denver, CO; 20AO Spedali Civili di Brescia, Lombardia, Italy; 21City of Hope National Medical Center, Duarte, CA; 22Ospedale Civile Santa Maria delle Croci, AUSL Ravenna, Ravenna, Italy; 23Všeobecná fakultní nemocnice v Praze, Prague, Czechia; 24University Medical Center Utrecht, Utrecht, the Netherlands; 25Institute of Experimental Cancer Research —CCC Ulm—Universitätsklinikum Ulm, Ulm, Baden-Württemberg, Germany; 26Sorbonne University, Pitié Salpêtrière Hospital, Paris, France; 27Concord Repatriation General Hospital, Sydney, NSW, Australia; 28BeiGene USA, Inc, San Mateo, CA; 29The Alfred Hospital, Melbourne, VIC, Australia

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