FIRST INTERIM ANALYSIS OF ALPINE STUDY: RESULTS OF A PHASE 3 RANDOMIZED STUDY OF ZANUBRUTINIB VS IBRUTINIB IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA
Author(s): ,
Peter Hillmen
Affiliations:
St James's University Hospital,Leeds,United Kingdom
,
Barbara Eichhorst
Affiliations:
Department of Internal Medicine,University of Cologne,Cologne,Germany
,
Jennifer R. Brown
Affiliations:
Department of Medical Oncology,Dana-Farber Cancer Institute,Boston, MA,United States
,
Nicole Lamanna
Affiliations:
Herbert Irving Comprehensive Cancer Center, Columbia University,New York, NY,United States
,
Susan O'Brien
Affiliations:
Chao Family Comprehensive Cancer Center, University of California,Irvine, CA,United States
,
Constantine S. Tam
Affiliations:
Peter MacCallum Cancer Centre,Melbourne, Victoria,Australia;University of Melbourne,Parkville, Victoria,Australia;St Vincent’s Hospital,Fitzroy, Victoria,Australia;Royal Melbourne Hospital,Parkville, Victoria,Australia
,
Lugui Qiu
Affiliations:
Chinese Academy of Medical Sciences, Peking Union Medical College,Tianjin,China
,
Maciej Kazmierczak
Affiliations:
Department of Hematology and Bone Marrow Transplantation,Poznan University of Medical Sciences,Poznan,Poland
,
Keshu Zhou
Affiliations:
Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital,Zhengzhou,China
,
Martin Šimkovič
Affiliations:
4th Department of Internal Medicine - Hematology,University Hospital,Hradec Kralove,Czech Republic;Faculty of Medicine, Charles University,Prague,Czech Republic
,
Jiri Mayer
Affiliations:
Department of Internal Medicine-Hematology and Oncology,Masaryk University and University Hospital,Brno,Czech Republic
,
Amanda Gillespie-Twardy
Affiliations:
Blue Ridge Cancer Care,Roanoke, VA,United States
,
Mazyar Shadman
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle, WA,United States;Department of Medicine,University of Washington,Seattle, WA,United States
,
Alessandra Ferrajoli
Affiliations:
Department of Leukemia,The University of Texas MD Anderson Cancer Center,Houston, TX,United States
,
Peter S. Ganly
Affiliations:
Department of Haematology,Christchurch Hospital,Christchurch,New Zealand;Department of Pathology and Biomedical Science,University of Otago,Christchurch,New Zealand
,
Robert Weinkove
Affiliations:
Wellington Blood and Cancer Centre, Capital and Coast District Health Board,Wellington,New Zealand;Malaghan Institute of Medical Research,Malaghan Institute of Medical Research, Wellington,New Zealand
,
Tommi Salmi
Affiliations:
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc.,San Mateo, CA,United States
,
Meng Ji
Affiliations:
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc.,San Mateo, CA,United States
,
Jessica Yecies
Affiliations:
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc.,San Mateo, CA,United States
,
Kenneth Wu
Affiliations:
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc.,San Mateo, CA,United States
,
William Novotny
Affiliations:
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc.,San Mateo, CA,United States
,
Jane Huang
Affiliations:
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc.,San Mateo, CA,United States
Wojciech Jurczak
Affiliations:
Maria Sklodowska-Curie National Institute of Oncology,Krakow,Poland
EHA Library. Hillmen P. 06/11/21; 330170; LB1900
Peter Hillmen
Peter Hillmen
Contributions
Abstract
This abstract is embargoed until Friday, June 11, 09:00 CEST

Presentation during EHA2021: The Presidential Symposium will be held on Friday, June 11, 2021 (16:00 - 17:30 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: LB1900

Type: Presidential Symposium

Session title: Presidential Symposium

Background
Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has been transformed with the advent of effective inhibitors of B-cell receptor signaling, such as Bruton tyrosine kinase (BTK) inhibitors. First-generation BTK inhibitor ibrutinib is a standard of care in CLL/SLL. Zanubrutinib is an irreversible, potent, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It was hypothesized that the increased specificity of zanubrutinib may minimize toxicities related to ibrutinib off-target inhibition (Coutre Blood Adv. 2019;3:1799-807) and more complete and sustained BTK occupancy may improve efficacy outcomes. Activity and tolerability of zanubrutinib in patients with CLL/SLL has been demonstrated in early phase trials (Tam Blood 2019;134:851-9; Tam Haematologica 2020;epub).

Aims
ALPINE (BGB-3111-305) is a global, randomized, phase 3 study comparing zanubrutinib vs ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL. Here we present the results of a pre-planned interim analysis scheduled approximately 12 mo after the first 415 out of 652 patients were enrolled.

Methods
Patients with R/R CLL/SLL were randomly assigned 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression. Randomization was stratified by age (<65 years vs ≥65 years), geographic region, refractory status, and del17p/TP53 mutation status. The primary end point was overall response rate (ORR) as determined by investigators using the 2008 iwCLL guidelines for CLL and the Lugano criteria for SLL. Sample size was calculated to provide 90% power to demonstrate non-inferiority of zanubrutinib to ibrutinib response ratio at the non-inferiority margin of 0.8558. A hierarchical testing approach was implemented to test the superiority of zanubrutinib over ibrutinib in ORR if non-inferiority was demonstrated.

Results
Between 5 Nov 2018 and 20 Dec 2019, 415 patients were randomized. Treatment groups were well balanced for demographic and disease characteristics: age ≥65 years 62.3% vs 61.5%, male 68.6% vs 75%, >3 prior lines of therapy 7.2% vs 10.1%, del17p 11.6% vs 12.5%, TP53 mutated without del17p 8.2% vs 5.8%, in zanubrutinib and ibrutinib arms, respectively. At a median follow-up of 15 mo, ORR was significantly higher with zanubrutinib vs ibrutinib (78.3% vs 62.5%, 2-sided P=0.0006 compared with pre-specified alpha of 0.0099 for interim analysis). ORR was higher in patients with del11q (83.6% vs 69.1%) and del17p (83.3% vs 53.8%) with zanubrutinib, as were overall 12-mo PFS (94.9% vs 84.0%, Figure) and OS rates (97.0% vs 92.7%). The rate of atrial fibrillation/flutter, a pre-specified safety endpoint, was significantly lower with zanubrutinib vs ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014, compared with pre-specified alpha of 0.0099 for interim analysis). Rates of major bleeding (2.9% vs 3.9%), and adverse events leading to discontinuation (7.8% vs 13.0%) or death (3.9% vs 5.8%) were also lower with zanubrutinib. Rate of neutropenia was higher with zanubrutinib (28.4% vs 21.7%), while grade ≥3 infections were lower with zanubrutinib (12.7% vs 17.9%).

Conclusion
In this interim analysis of a randomized, phase 3 ALPINE study in patients with R/R CLL/SLL, zanubrutinib was shown to have a superior response rate, an improved PFS and a lower rate of atrial fibrillation/flutter as compared with ibrutinib. These data confirm that more selective BTK inhibition, with more complete and sustained BTK occupancy results in improved efficacy and safety outcomes. NCT03734016

Keyword(s): Chronic lymphocytic leukemia, Immunotherapy, Refractory, Relapse

This abstract is embargoed until Friday, June 11, 09:00 CEST

Presentation during EHA2021: The Presidential Symposium will be held on Friday, June 11, 2021 (16:00 - 17:30 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: LB1900

Type: Presidential Symposium

Session title: Presidential Symposium

Background
Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has been transformed with the advent of effective inhibitors of B-cell receptor signaling, such as Bruton tyrosine kinase (BTK) inhibitors. First-generation BTK inhibitor ibrutinib is a standard of care in CLL/SLL. Zanubrutinib is an irreversible, potent, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It was hypothesized that the increased specificity of zanubrutinib may minimize toxicities related to ibrutinib off-target inhibition (Coutre Blood Adv. 2019;3:1799-807) and more complete and sustained BTK occupancy may improve efficacy outcomes. Activity and tolerability of zanubrutinib in patients with CLL/SLL has been demonstrated in early phase trials (Tam Blood 2019;134:851-9; Tam Haematologica 2020;epub).

Aims
ALPINE (BGB-3111-305) is a global, randomized, phase 3 study comparing zanubrutinib vs ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL. Here we present the results of a pre-planned interim analysis scheduled approximately 12 mo after the first 415 out of 652 patients were enrolled.

Methods
Patients with R/R CLL/SLL were randomly assigned 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression. Randomization was stratified by age (<65 years vs ≥65 years), geographic region, refractory status, and del17p/TP53 mutation status. The primary end point was overall response rate (ORR) as determined by investigators using the 2008 iwCLL guidelines for CLL and the Lugano criteria for SLL. Sample size was calculated to provide 90% power to demonstrate non-inferiority of zanubrutinib to ibrutinib response ratio at the non-inferiority margin of 0.8558. A hierarchical testing approach was implemented to test the superiority of zanubrutinib over ibrutinib in ORR if non-inferiority was demonstrated.

Results
Between 5 Nov 2018 and 20 Dec 2019, 415 patients were randomized. Treatment groups were well balanced for demographic and disease characteristics: age ≥65 years 62.3% vs 61.5%, male 68.6% vs 75%, >3 prior lines of therapy 7.2% vs 10.1%, del17p 11.6% vs 12.5%, TP53 mutated without del17p 8.2% vs 5.8%, in zanubrutinib and ibrutinib arms, respectively. At a median follow-up of 15 mo, ORR was significantly higher with zanubrutinib vs ibrutinib (78.3% vs 62.5%, 2-sided P=0.0006 compared with pre-specified alpha of 0.0099 for interim analysis). ORR was higher in patients with del11q (83.6% vs 69.1%) and del17p (83.3% vs 53.8%) with zanubrutinib, as were overall 12-mo PFS (94.9% vs 84.0%, Figure) and OS rates (97.0% vs 92.7%). The rate of atrial fibrillation/flutter, a pre-specified safety endpoint, was significantly lower with zanubrutinib vs ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014, compared with pre-specified alpha of 0.0099 for interim analysis). Rates of major bleeding (2.9% vs 3.9%), and adverse events leading to discontinuation (7.8% vs 13.0%) or death (3.9% vs 5.8%) were also lower with zanubrutinib. Rate of neutropenia was higher with zanubrutinib (28.4% vs 21.7%), while grade ≥3 infections were lower with zanubrutinib (12.7% vs 17.9%).

Conclusion
In this interim analysis of a randomized, phase 3 ALPINE study in patients with R/R CLL/SLL, zanubrutinib was shown to have a superior response rate, an improved PFS and a lower rate of atrial fibrillation/flutter as compared with ibrutinib. These data confirm that more selective BTK inhibition, with more complete and sustained BTK occupancy results in improved efficacy and safety outcomes. NCT03734016

Keyword(s): Chronic lymphocytic leukemia, Immunotherapy, Refractory, Relapse

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