ASPEN: RESULTS OF A PHASE 3 RANDOMIZED TRIAL OF ZANUBRUTINIB VERSUS IBRUTINIB FOR PATIENTS WITH WALDENSTRÖM MACROGLOBULINEMIA (WM)
Author(s): ,
Meletios Dimopoulos
Affiliations:
National and Kapodistrian University of Athens,Athens,Greece
,
Stephen Opat
Affiliations:
Monash Health,Clayton, Victoria,Australia;Monash University,Clayton, Victoria,Australia
,
Shirley D'Sa
Affiliations:
University College London Hospital Foundation Trust,London,United Kingdom
,
Wojciech Jurczak
Affiliations:
Maria Sklodowska-Curie National Institute of Oncology,Krakow,Poland
,
Hui-Peng Lee
Affiliations:
Flinders Medical Centre,Adelaide, South Australia,Australia
,
Gavin Cull
Affiliations:
Sir Charles Gairdner Hospital, Perth,Perth, Western Australia,Australia;University of Western Australia,Perth, Western Australia,Australia
,
Roger G. Owen
Affiliations:
St. James University Hospital,Leeds,United Kingdom
,
Paula Marlton
Affiliations:
Princess Alexandra Hospital and University of Queensland,Brisbane, Queensland,Australia
,
Bjorn E. Wahlin
Affiliations:
Karolinska Universitetssjukhuset and Karolinska Institutet,Stockholm,Sweden
,
Ramon Garcia Sanz
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Spain
,
Helen McCarthy
Affiliations:
Royal Bournemouth and Christchurch Hospital,Bournemouth,United Kingdom
,
Stephen Mulligan
Affiliations:
Royal North Shore Hospital,Sydney, New South Wales,Australia
,
Alessandra Tedeschi
Affiliations:
ASST Grande Ospedale Metropolitano Niguarda,Milan,Italy
,
Jorge Castillo
Affiliations:
Dana-Farber Cancer Institute,Boston, MA,United States;Harvard Medical School,Boston, MA,United States
,
Jaroslaw Czyz
Affiliations:
Szpital Uniwersytecki nr 2 im dr. Jana Biziela,Bydgoszcz,Poland;Department of Hematology,Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń,Bydgoszcz,Poland
,
Carlos Fernandez De Larrea Rodriguez
Affiliations:
Hospital Clinic de Barcelona,Barcelona,Spain
,
David Belada
Affiliations:
FN Hradec Kralove,Hradec Králové,Czech Republic
,
Edward Libby
Affiliations:
University of Washington/Seattle Cancer Care Alliance - Clinical Research,Seattle, WA,United States
,
Jeffrey Matous
Affiliations:
Colorado Blood Cancer Institute,Denver, CO,United States
,
Marina Motta
Affiliations:
AO Spedali Civili di Brescia,Lombardia,Italy
,
Tanya Siddiqi
Affiliations:
City Of Hope National Medical Center,Duarte,CA,United States
,
Monica Tani
Affiliations:
Ospedale Civile S.Maria delle Croc,AUSL Ravenna,Italy
,
Marek Trneny
Affiliations:
Vseobecna fakultni nemocnice v Praze,Prague,Czech Republic
,
Monique Minnema
Affiliations:
University Medical Center Utrecht,Utrecht,Netherlands
,
Christian Buske
Affiliations:
CCC Ulm - Universitätsklinikum Ulm,Ulm, Baden-Württemberg,Germany
,
Veronique Leblond
Affiliations:
Sorbonne University, Pitié Salpêtrière Hospital,Paris,France
,
Wai Y. Chan
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Jingjing Schneider
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Sunhee Ro
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Aileen Cohen
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Jane Huang
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
Constantine S. Tam
Affiliations:
Peter MacCallum Cancer Centre,Melbourne, Victoria,Australia;St Vincent's Hospital,Fitzroy, Victoria,Australia;University of Melbourne,Parkville, Victoria,Australia;Royal Melbourne Hospital,Parkville, Victoria,Australia
EHA Library. Dimopoulos M. 06/12/20; 295045; S225
Prof. Dr. Meletios Dimopoulos
Prof. Dr. Meletios Dimopoulos
Contributions
Abstract

Abstract: S225

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background
Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for Waldenström macroglobulinemia (WM). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. ASPEN is a randomized phase 3 study comparing ZANU, a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in patients with WM. 

Aims
To compare the efficacy and safety of ZANU versus IBR in patients with WM and MYD88 mutation.

Methods
Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutation were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary endpoint was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% versus 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at approximately 12 months after the last patient enrolled.

Results
In total, 201 patients were randomized from January 2017 to July 2018. While the treatment groups were well balanced for important baseline factors, in the ZANU arm, there were more elderly patients (aged >75 years, 33.3% vs 22.2%) and more patients with anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P=0.09). Landmark analysis at 12 months showed a trend toward longer progression-free survival and overall survival, particularly in the R/R population. Rates of adverse events leading to dose holds, dose reductions, drug discontinuation, and death were higher in the IBR arm than the ZANU arm (Table). Rates of atrial fibrillation, contusion, diarrhoea, haemorrhage, hypertension, muscle spasms, oedema peripheral, and pneumonia were lower with ZANU. The rate of neutropenia was higher with ZANU; however, grade ≥3 infection rates were similar (17.8% vs 19.4%).

Conclusion
ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, ZANU was associated with a higher CR+VGPR response rate, and demonstrated clinically meaningful advantages in safety and tolerability compared with IBR. ClinicalTrials.gov: NCT03053440.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Keyword(s): Kinase inhibitor, Waldenstrom's macroglobulinemia

Abstract: S225

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background
Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for Waldenström macroglobulinemia (WM). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. ASPEN is a randomized phase 3 study comparing ZANU, a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in patients with WM. 

Aims
To compare the efficacy and safety of ZANU versus IBR in patients with WM and MYD88 mutation.

Methods
Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutation were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary endpoint was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% versus 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at approximately 12 months after the last patient enrolled.

Results
In total, 201 patients were randomized from January 2017 to July 2018. While the treatment groups were well balanced for important baseline factors, in the ZANU arm, there were more elderly patients (aged >75 years, 33.3% vs 22.2%) and more patients with anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P=0.09). Landmark analysis at 12 months showed a trend toward longer progression-free survival and overall survival, particularly in the R/R population. Rates of adverse events leading to dose holds, dose reductions, drug discontinuation, and death were higher in the IBR arm than the ZANU arm (Table). Rates of atrial fibrillation, contusion, diarrhoea, haemorrhage, hypertension, muscle spasms, oedema peripheral, and pneumonia were lower with ZANU. The rate of neutropenia was higher with ZANU; however, grade ≥3 infection rates were similar (17.8% vs 19.4%).

Conclusion
ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, ZANU was associated with a higher CR+VGPR response rate, and demonstrated clinically meaningful advantages in safety and tolerability compared with IBR. ClinicalTrials.gov: NCT03053440.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Keyword(s): Kinase inhibitor, Waldenstrom's macroglobulinemia

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