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.

AO Spedali Civili di Brescia Lombardia Italy

ASST Grande Ospedale Metropolitano Niguarda Milan Italy

BeiGene USA Inc San Mateo CA

Centre for Waldenström's Macroglobulinemia and Associated Disorders University College London Hospital Foundation Trust London United Kingdom

City of Hope National Medical Center Duarte CA

Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Toruń Bydgoszcz Poland

Colorado Blood Cancer Institute Denver CO

Concord Repatriation General Hospital Sydney NSW Australia

Dana Farber Cancer Institute Boston MA

Flinders Medical Centre Adelaide SA Australia

FN Hradec Králové Hradec Králové Czechia

Fred Hutchinson Cancer Center Seattle WA

Hospital Clínic de Barcelona IDIBAPS Barcelona Spain

Hospital Universitario de Salamanca Salamanca Spain

Institute of Experimental Cancer Research CCC Ulm Universitätsklinikum Ulm Ulm Baden Württemberg Germany

Karolinska Universitetssjukhuset and Karolinska Institutet Stockholm Sweden

Maria Sklodowska Curie National Institute of Oncology Krakow Poland

Monash Health and Monash University Clayton VIC Australia

National and Kapodistrian University of Athens Athens Greece

Ospedale Civile Santa Maria delle Croci AUSL Ravenna Ravenna Italy

Princess Alexandra Hospital and University of Queensland Brisbane QLD Australia

Royal Bournemouth and Christchurch Hospital Bournemouth United Kingdom

Royal North Shore Hospital Sydney NSW Australia

Sir Charles Gairdner Hospital University of Western Australia Perth WA Australia

Sorbonne University Pitié Salpêtrière Hospital Paris France

St James University Hospital Leeds United Kingdom

The Alfred Hospital Melbourne VIC Australia

University Medical Center Utrecht Utrecht the Netherlands

Všeobecná fakultní nemocnice Praha Prague Czechia

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NCT03053440