PURPOSE: Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS: ALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS: Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION: Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.

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

Affiliated Cancer Hospital of Zhengzhou University Henan Cancer Hospital Zhengzhou China

BeiGene Co Ltd Beijing China

BeiGene USA Inc San Mateo CA

Blue Ridge Cancer Care Roanoke VA

Cancer Immunotherapy Programme Malaghan Institute of Medical Research Wellington New Zealand

Chao Family Comprehensive Cancer Center University of California Irvine CA

Department 1 of Internal Medicine Center for Integrated Oncology Aachen University of Cologne Bonn Cologne Düsseldorf Germany

Department of Haematology Christchurch Hospital Christchurch New Zealand

Department of Hematology and Bone Marrow Transplantation Poznan University of Medical Sciences Poznan Poland

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

Department of Hematology and Transplantology Medical University of Gdańsk Gdańsk Poland

Department of Hematology Karolinska University Hospital Stockholm Sweden

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

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

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

Faculty of Medicine Charles University Prague Czech Republic

Fred Hutchinson Cancer Research Center Seattle WA

Herbert Irving Comprehensive Cancer Center Columbia University New York NY

Maria Sklodowska Curie National Research Institute of Oncology Krakow Poland

Medical University of Lodz Lodz Poland

Peter MacCallum Cancer Centre Melbourne Victoria Australia

Royal Melbourne Hospital Parkville Victoria Australia

St James's University Hospital Leeds United Kingdom

St Vincent's Hospital Melbourne Fitzroy Victoria Australia

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

Texas Oncology Tyler US Oncology Research Tyler TX

University of Melbourne Parkville Victoria Australia

Wellington Blood and Cancer Centre Capital and Coast District Health Board Wellington New Zealand

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$a PURPOSE: Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS: ALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS: Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION: Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.

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