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Category: Encore

2010 - Zanubrutinib vs bendamustine + rituximab (BR) in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: extended follow-up of the SEQUOIA study

Introduction: Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor designed to minimize off-target binding and limit associated side effects that is approved in the US and EU for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from the SEQUOIA study (NCT03336333), at a median follow-up of 26.2 months, demonstrated superior progression-free survival (PFS) by independent review for zanubrutinib vs BR in patients with treatment-naive CLL/SLL without del(17p); patients with del(17p) treated with zanubrutinib in a separate cohort had similar outcomes to patients without del(17p). We report updated efficacy and safety results from the SEQUOIA study after approximately 18 months of additional follow-up.

Methods: Patients without del(17p) were randomized to receive zanubrutinib or BR. Patients with del(17p) were assigned to zanubrutinib monotherapy. Investigator-assessed (INV) PFS, overall survival (OS), overall response rate (ORR), and safety/tolerability were evaluated. Adverse events (AEs) were recorded until disease progression or start of next-line therapy.

Results: As of 31 October 2022, a total of 479 patients without del(17p) were randomized to receive zanubrutinib (n=241) or BR (n=238). At a median follow-up of 43.7 months (range, 0-60 months), median PFS was not reached with zanubrutinib; however, median PFS with BR was 42.2 months (HR, 0.30; 95% CI, 0.21-0.43; Figure). At 42 months, the estimated PFS rate was 82.4% with zanubrutinib. With additional follow-up, PFS with zanubrutinib vs BR was improved for patients with mutated IGHV
(HR, 0.35; 95% CI, 0.19-0.64) and was sustained in patients with unmutated IGHV (HR, 0.23; 95%
CI, 0.14-0.37) or del(11q) (HR, 0.26; 95% CI, 0.13-0.51). Complete response/complete response with incomplete hematologic recovery (CR/CRi) rates in patients without del(17p) were 17.4% and 21.8% with zanubrutinib and BR, respectively. While median OS was not reached in either arm, the HR for OS was 0.87 (95% CI, 0.50-1.48) with zanubrutinib vs BR and the estimated 42-month OS rates were 89.4% and 88.3%, respectively. For 110 patients with del(17p) assigned to zanubrutinib monotherapy, after a median follow-up of 47.9 months, the estimated 42-month PFS and OS rates were 79.4% and 89.5%, respectively. In this population, the CR/CRi rate was 14.5%. As of 31 Oct 2022, zanubrutinib treatment was ongoing in 74.7% patients without del(17p) and 70.3% patients with del(17p). The most common causes for treatment discontinuation were AEs and progressive disease for both patients without del(17p) (14.9%, 5.8%, respectively) and with del(17p) (13.5%, 13.5%). AEs of interest (AEI), using pooled terms, were as expected for the class in patients without del(17p) (zanubrutinib vs BR). AEI included any-grade atrial fibrillation/flutter (5.0% vs 2.6%), hypertension (17.5% vs 13.7%), bleeding
(48.8% vs 12.3%), infection (72.9% vs 62.6%), anemia (7.1% vs 20.7%), thrombocytopenia (6.3% vs 18.1%), and neutropenia (16.7% vs 56.8%). Additionally, grade ≥3 AEI included bleeding (5.8% vs 1.8%), infection (23.8% vs 22.0%), anemia (0.4% vs 2.2%), thrombocytopenia (2.1% vs 7.9%), and neutropenia (12.5% vs 51.1%).

Conclusions: Extended follow-up SEQUOIA data demonstrated that the efficacy of zanubrutinib was maintained in patients without del(17p) with a safety profile aligned with long-term follow-up for the BTK inhibitor class. Longer follow-up showed benefit in patients with mutated IGHV. Patients with del(17p) continue to demonstrate PFS benefits consistent with the randomized cohort. Zanubrutinib continues to be well tolerated with low rates of treatment discontinuation and remains a valuable frontline treatment option for CLL/SLL.

    Primary Author; Presenting Author(s)

  • Jennifer R. Brown, MD, PhD

    Director, CLL Center & Institute Physician, DFCI; Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology, HMS
    Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI); Department of Medicine, Harvard Medical School (HMS)
    Boston, MA, United States

    • Co-Author(s)

  • Talha Munir, MBBS, PhD

    Consultant Haematologist
    Clinical Haematology, Leeds Teaching Hospitals NHS Trust
    Leeds, England, United Kingdom

  • Mazyar Shadman, MD, MPH

    Associate Professor of Medicine
    Fred Hutchinson Cancer Center / University of Washington School of Medicine
    Seattle, WA, United States

  • Tadeusz Robak, MD, PhD

    Professor of Hematology
    Medical University of Lodz
    Lodz, Lodzkie, Poland

  • BK

    Brad S. Kahl, MD

    Washington University School of Medicine
    St. Lois, MO, United States

  • Paolo Ghia, MD, PhD

    Professor of Medical Oncology
    Strategic Research Program on Chronic Lymphocytic Leukemia, Division of Experimental Oncology, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy
    Milan, Lombardia, Italy

  • Krzysztof Giannopoulos, MD

    Experimental Hematooncology Department, Medical University of Lublin, Lublin, Poland; Hematology Department, St John's Cancer Centre, Lublin, Poland

  • M

    Martin Šimkovič, MD, PhD

    Consultant
    4th Department of Internal Medicine – Hematology, University Hospital Hradec Králové
    Hradec Králové, Kralovehradecky kraj, Czech Republic

  • A

    Anders Österborg, Professor, MD, PhD

    Department of oncology-pathology, Karolinska Institutet, Stockholm, Sweden; Lymphoma Unit, Karolinska University Hospital
    Stockholm, Sweden

  • LL

    Luca Laurenti, MD

    Section of Hematology, Department of Radiological and Hematological Sciences, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
    Rome, Italy

  • PW

    Patricia Walker, MD

    Peninsula Health and Peninsula Private Hospital
    Frankston, Australia

  • SO

    Stephen Opat, MD

    Monash Health and Clinical Haematology Unit, Monash University, Clayton
    Clayton, Australia

  • HC

    Hanna Ciepluch, MD

    Department of Hematology, Copernicus Regional Oncology Centre
    Gdansk, Poland

  • RG

    Richard Greil, MD

    Professor
    Third Medical Department with Hematology, Medical Oncology, Rheumatology and Infectiology, Paracelsus Medical University, Salzburg, Austria; Salzburg Cancer Research Institute Center for Clinical Cancer and Immunology Trials, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria
    Salzburg, Salzburg, Austria

  • MH

    Merit Hanna, MD

    Department of Haematology, Waitemata District Health Board
    Takapuna, New Zealand

  • MT

    Monica Tani, MD

    Santa Maria delle Croci Hospital
    Ravenna, Italy

  • Marek Trněný, MD

    Dept. chair
    First Department of Medicine, First Faculty of Medicine, Charles University, General Hospital, Prague, Czech Republic
    Prague, Czech Republic

  • Danielle M. Brander, MD

    Assistant Professor of Medicine, Division of Hematologic Malignancies & Cellular Therapy
    Duke University Medical Center
    Durham, NC, United States

  • IF

    Ian W. Flinn, MD, PhD

    Sarah Cannon Research Institute/Tennessee Oncology
    Nashville, TN, United States

  • SG

    Sebastian Grosicki, MD

    Department of Hematology and Cancer Prevention, School of Public Health, Silesian Medical University
    Katowice, Poland

  • EV

    Emma Verner, MD

    Concord Repatriation General Hospital, Concord, NSW, Australia; University of Sydney
    Sydney, Australia

  • AT

    Alessandra Tedeschi, MD

    Department of Hematology, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
    Milan, Italy

  • SD

    Sophie De Guibert, MD

    Hôpital de Pontchaillou, Rennes, France
    Rennes, France

  • GT

    Gayane Tumyan, MD

    Department of Chemotherapy of Hemoblastosis, Blokhin Russian Cancer Research Center
    Moscow, Russia

  • KL

    Kamel Laribi, MD

    MD
    Hematology Department, Centre Hospitalier du Mans, Le Mans, France

  • JG

    José A. A. García-Marco, MD

    Unidad de Citogenetica Molecular, Servicio de Hematología, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
    Majadahonda, Madrid, Spain

  • JL

    Jianyong Li, MD, PhD

    Chief of Hematology department
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital
    Nanjing, China (People's Republic)

  • TT

    Tian Tian, N/A

    BeiGene USA, Inc.
    San Mateo, CA, United States

  • VR

    Vanitha Ramakrishnan, PhD

    BeiGene USA, Inc.
    San Mateo, CA, United States

  • YL

    Yu Liu, PhD

    BeiGene USA, Inc.
    San Mateo, CA, United States

  • AS

    Andy Szeto, PharmD

    BeiGene USA, Inc.
    San Mateo, CA, United States

  • JP

    Jason Paik, MD, PhD

    BeiGene USA, Inc.
    San Mateo, CA, United States

  • AC

    Aileen C. Cohen, MD, PhD

    Vice President Clinical Development
    BeiGene USA, Inc.
    San Mateo, CA, United States

  • CT

    Constantine S. Tam, MD, MBBS

    Consultant Haematologist
    Alfred Hospital and Monash University
    Melbourne, Victoria, Australia

  • Wojciech Jurczak, MD, PhD

    Consultant, Head of Dpt of Lymphoid Malignancies
    Maria Skłodowska-Curie National Research Institute of Oncology
    Kraków, Malopolskie, Poland