INTRODUCTION
CLL/SLL is usually characterized by consecutive relapses and response to therapy ultimately dictates survival. While ibrutinib, a first-generation Bruton tyrosine kinase inhibitor (BTKi), has become standard therapy, it has well-described off-target effects that can limit use. Compared with ibrutinib, zanubrutinib, a next-generation BTKi, provides improved BTK occupancy across disease-relevant tissues with greater kinase selectivity. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head-to-head with ibrutinib as treatment for R/R CLL/SLL. At predefined response analyses, zanubrutinib demonstrated superior overall response rate (ORR); data from the predefined final PFS analysis are reported here.
METHODS
Patients (pts) with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Stratification was based on age, refractory status, geographical region, and del(17p)/TP53 mutation status. As the primary endpoint of ORR was superior with zanubrutinib, the key secondary efficacy endpoint of PFS was tested for noninferiority under hierarchical testing when 205 PFS events were observed. If PFS noninferiority between zanubrutinib and ibrutinib was demonstrated, superiority of zanubrutinib vs ibrutinib could be tested and claimed if the 2-sided P-value was <.04996. Other endpoints included overall survival (OS), ORR including PR with lymphocytosis (PR-L) or better, and safety parameters including atrial fibrillation/flutter.
RESULTS
Pts (N=652) from 15 countries were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). Demographic and disease characteristics were balanced between zanubrutinib and ibrutinib arms (age ≥65 yrs [61.5 vs 61.5%]; male [65.1 vs 71.4%]; unmutated IGHV [73.1 vs 73.5%]; del(17p) [13.8 vs 15.4%]; TP53 mutated without del(17p) [9.2 vs 7.7%]). Across the study population, median age was 67 and 68 yrs, respectively; in both arms, median prior lines of therapy was 1.
CONCLUSIONS
As ALPINE is the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors, zanubrutinib has now proven superiority to ibrutinib in both ORR and PFS in pts with R/R CLL/SLL. Efficacy benefits with zanubrutinib were observed across all major subgroups, including high-risk pts. Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death. These data suggest zanubrutinib is more efficacious and better tolerated than ibrutinib as treatment for R/R CLL/SLL.
Author Affiliations
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Department of Internal Medicine, University of Cologne, Center for Integrated Oncology Aachen, Bonn, Cologne, Duesseldorf, Cologne, Germany
3St. James’s University Hospital, Leeds, United Kingdom
4Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
5Chao Family Comprehensive Cancer Center, University of California, Irvine, CA
6Monash University, Melbourne, Australia
7The Alfred Hospital, Melbourne, Australia
8State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
9Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland
10Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland
11Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
124th Department of Internal Medicine – Hematology, University Hospital, Kralove, Czech Republic
13Faculty of Medicine, Charles University, Prague, Czech Republic
14Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic
15Blue Ridge Cancer Care, Roanoke, VA
16Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
17Department of Haematology, Christchurch Hospital, Christchurch, New Zealand
18Te Rerenga Ora Blood and Cancer Centre, Te Whatu Ora Health New Zealand Capital Coast & Hutt Valley, Wellington, New Zealand
19Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand
20Department of Hematology and Cancer Prevention, Health Sciences Faculty, Medical University of Silesia, Katowice, Poland
21Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland
22Medical University of Lodz, Lodz, Poland
23Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
24Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
25Texas Oncology-Tyler/US Oncology Research, Tyler, TX
26BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc., San Mateo, CA
27Fred Hutchinson Cancer Center, Seattle, WA
28Department of Medicine, University of Washington, Seattle, WA
