Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Author(s): Jennifer R. Brown, M.D., Ph.D., Barbara Eichhorst, M.D., Peter Hillmen, M.B., Ch.B., Ph.D., Wojciech Jurczak, M.D., Ph.D., Maciej Kaźmierczak, M.D., Ph.D., Nicole Lamanna, M.D., Susan M. O’Brien, M.D., Constantine S. Tam, M.B., B.S., M.D., Lugui Qiu, M.D., Ph.D., Keshu Zhou, M.D., Ph.D., Martin Simkovic, M.D., Ph.D., Jiri Mayer, M.D., Amanda Gillespie-Twardy, M.D., Alessandra Ferrajoli, M.D., Peter S. Ganly, B.M., B.Ch., Ph.D., Robert Weinkove, M.B., B.S., Ph.D., Sebastian Grosicki, M.D., Ph.D., Andrzej Mital, M.D., Ph.D., Tadeusz Robak, M.D., Ph.D., Anders Osterborg, M.D., Ph.D., Habte A. Yimer, M.D., Tommi Salmi, M.D., Megan-Der-Yu Wang, Pharm.D., Lina Fu, M.S., Jessica Li, M.S., Kenneth Wu, Ph.D., Aileen Cohen, M.D., Ph.D., and Mazyar Shadman, M.D., M.P.H.
Source: N Engl J Med 2023; 388:319-332 DOI: 10.1056/NEJMoa2211582
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Final PFS results of the ALPINE study of Zanubrutinib vs. Ibrutinib in patients with >=2L CLL/SLL. Zanubritinib was superior in terms of PFS with an HR of 0.49; at two years PFs were 78% vs. 66% in favor of Zanubritinib; improvement was seen across all subgroups. OS data is not mature yet, and that data will be interesting. Of note, the SEQUOIA study showed this drug was superior compared to Bendamustine + rituximab in the 1L setting.


In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available.


We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05.


At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P=0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death.


In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE number, NCT03734016. opens in new tab.)

Author Affiliations

From the Department of Medical Oncology, Dana–Farber Cancer Institute, Boston (J.R.B.); the Department of Internal Medicine, University of Cologne, Center for Integrated Oncology Aachen Bonn Köln Düsseldorf, Cologne, Germany (B.E.); St. James’s University Hospital, Leeds, United Kingdom (P.H.); Maria Skłodowska–Curie National Research Institute of Oncology, Krakow (W.J.), the Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan (M.K.), the Department of Hematology and Cancer Prevention, Faculty of Health Sciences, Medical University of Silesia, Katowice (S.G.), the Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk (A.M.), and the Medical University of Lodz, Lodz (T.R.) — all in Poland; Herbert Irving Comprehensive Cancer Center, Columbia University, New York (N.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine (S.M.O.), and BeiGene USA, San Mateo (T.S., M.-D.-Y.W., L.F., J.L., K.W., A.C.) — both in California; the Alfred Hospital and Monash University — both in Melbourne, VIC, Australia (C.S.T.); the State Key Laboratory of Experimental Hematology, National Clinical Medical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin (L.Q.), the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou (K.Z.), and BeiGene (Beijing), Beijing (T.S., M.-D.-Y.W., L.F., J.L., K.W., A.C.) — all in China; the Fourth Department of Internal Medicine–Hematology, University Hospital, Hradec Kralove (M. Simkovic), the First Faculty of Medicine, Charles University, Prague (M. Simkovic), and the Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital, Brno (J.M.) — all in the Czech Republic; Blue Ridge Cancer Care, Roanoke, VA (A.G.-T.); the Leukemia Department , University of Texas M.D. Anderson Cancer Center, Houston (A.F.), and Texas Oncology–Tyler, US Oncology Network, Tyler (H.A.Y.) — both in Texas; the Department of Haematology, Christchurch Hospital, Christchurch (P.S.G.), and Te Rerenga Ora Blood and Cancer Centre, Te Whatu Ora Health New Zealand Capital Coast and Hutt Valley, and the Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington (R.W.) — all in New Zealand; the Department of Oncology–Pathology, Karolinska Institutet, and the Department of Hematology, Karolinska University Hospital — both in Stockholm (A.O.); and the Fred Hutchinson Cancer Center and the Department of Medicine, University of Washington — both in Seattle (M. Shadman).

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