The ALPINE trial established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma; here, we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n = 327) or ibrutinib (n = 325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.84), including in patients with del(17p)/TP53 mutation (HR, 0.51; 95% CI, 0.33-0.78) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). Although median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR, 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common nonhematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs 6 cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.

4th Department of Internal Medicine Haematology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

4th Department of Internal Medicine Haematology University Hospital Hradec Kralove Hradec Kralove Czech Republic

Cancer Immunotherapy Programme Malaghan Institute of Medical Research Wellington New Zealand

Clinical Development BeiGene Co Ltd Beijing China

Clinical Development BeiGene International GmbH Basel Switzerland

Clinical Development BeiGene USA Inc San Mateo CA

Clinical Research Division Fred Hutchinson Cancer Center Seattle WA

Department of Clinical Oncology Maria Sklodowska Curie National Research Institute of Oncology Krakow Poland

Department of Haematology Christchurch Hospital Christchurch New Zealand

Department of Haematology Monash University Melbourne VIC Australia

Department of Haematology The Alfred Hospital Melbourne VIC Australia

Department of Hematology Affiliated Cancer Hospital of Zhengzhou University Henan Cancer Hospital Zhengzhou China

Department of Hematology and Cancer Prevention Health Sciences Faculty Medical University of Silesia Katowice Poland

Department of Hematology and Medical Oncology Texas Oncology Tyler US Oncology Research Tyler TX

Department of Hematology and Transplantology Medical University of Gdańsk Gdańsk Poland

Department of Hematology Karolinska University Hospital Stockholm Sweden

Department of Hematology Medical University of Lodz Lodz Poland

Department of Internal Medicine Hematology and Oncology Masaryk University and University Hospital Brno Czech Republic

Department of Internal Medicine University of Cologne Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Cologne Germany

Department of Leukemia The University of Texas MD Anderson Cancer Center Houston TX

Department of Lymphoma and Myeloma State 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

Department of Medical Oncology Dana Farber Cancer Institute Boston MA

Department of Medicine University of Washington Seattle WA

Department of Oncology Pathology Karolinska Institutet Stockholm Sweden

Division of Hematology Oncology Department of Medicine Chao Family Comprehensive Cancer Center University of California Irvine CA

Hematologic Malignancies Section Department of Medicine Herbert Irving Comprehensive Cancer Center Columbia University New York NY

Medical Oncology and Hematology Blue Ridge Cancer Care Roanoke VA

Te Rerenga Ora Blood and Cancer Centre Te Whatu Ora Health New Zealand Capital Coast and Hutt Valley Wellington New Zealand

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ClinicalTrials.gov
NCT03734016