Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial

Author(s): Peter Hillmen, MBChB, PhD1; Barbara Eichhorst, MD2; Jennifer R. Brown, MD, PhD3; Nicole Lamanna, MD4; Susan M. O’Brien, MD5; Constantine S. Tam, MBBS, MD6-9; Lugui Qiu, MD, PhD10; Maciej Kazmierczak, MD, PhD11; Keshu Zhou, MD, PhD12; Martin Šimkovič, MD, PhD13,14; Jiří Mayer, MD15; Amanda Gillespie-Twardy, MD16; Mazyar Shadman, MD, MPH17,18; Alessandra Ferrajoli, MD19; Peter S. Ganly, BMBCh, PhD20; Robert Weinkove, MBBS, PhD21,22; Sebastian Grosicki, MD, PhD23; Andrzej Mital, MD, PhD24; Tadeusz Robak, MD, PhD25; Anders Österborg, MD, PhD26,27; Habte A. Yimer, MD28; Tommi Salmi, MD29; Meng Ji, MD30; Jessica Yecies, PhD29; Adam Idoine, PhD29; Kenneth Wu, PhD29; Jane Huang, MD29; and Wojciech Jurczak, MD, PhD31
Source: DOI: 10.1200/JCO.22.00510 Journal of Clinical Oncology 41, no. 5 (February 10, 2023) 1035-1045.
Maem Hussein MD

Dr. Maen Hussein's Thoughts

Is ibrutininb’s days as a treatment for CLL over? Zanubrutinib is more effective and less toxic.


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.


ALPINE ( 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.


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.


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.

Author Affiliations

1St James’s University Hospital, Leeds, United Kingdom2Department I of Internal Medicine, Center for Integrated Oncology Aachen, University of Cologne, Bonn, Cologne, Düsseldorf, Germany3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA4Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY5Chao Family Comprehensive Cancer Center, University of California, Irvine, CA6Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia7University of Melbourne, Parkville, Victoria, Australia8St Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia9Royal Melbourne Hospital, Parkville, Victoria, Australia10State 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, China11Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland12Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China134th Department of Internal Medicine-Hematology, University Hospital, Hradec Kralove, Czech Republic14Faculty of Medicine, Charles University, Prague, Czech Republic15Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital, Brno, Czech Republic16Blue Ridge Cancer Care, Roanoke, VA17Fred Hutchinson Cancer Research Center, Seattle, WA18Department of Medicine, University of Washington, Seattle, WA19Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX20Department of Haematology, Christchurch Hospital, Christchurch, New Zealand21Wellington Blood and Cancer Centre, Capital and Coast District Health Board, Wellington, New Zealand22Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand23Department of Hematology and Cancer Prevention, Health Sciences Faculty, Medical University of Silesia, Katowice, Poland24Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland25Medical University of Lodz, Lodz, Poland26Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden27Department of Hematology, Karolinska University Hospital, Stockholm, Sweden28Texas Oncology-Tyler/US Oncology Research, Tyler, TX29BeiGene USA, Inc, San Mateo, CA30BeiGene (Beijing) Co, Ltd, Beijing, China31Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland

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