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202 Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Analysis and Treatment of High Risk and Treatment of Relapsed CLL or Richter Transformation
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, CLL, Diseases, Lymphoid Malignancies
Saturday, December 9, 2023: 2:45 PM

Jennifer R. Brown, MD, PhD1, Barbara F. Eichhorst, MD2, Nicole Lamanna, MD3, Susan M. O'Brien4, Constantine S. Tam, MD, MBBS5, Luqui Qiu6, Maciej Kaźmierczak, MD7*, Wojciech Jurczak, MD, PhD8, Keshu Zhou, MD9*, Martin Simkovic, MD10*, Jiri Mayer, MD11, Amanda L. Gillespie-Twardy, MD12, Alessandra Ferrajoli, MD13, Peter S. Ganly, PhD14, Robert Weinkove, MBBS, PhD, FRACP, FRCPA15*, Sebastian Grosicki, MD, PhD16*, Andrzej Mital17*, Tadeusz Robak18*, Anders Osterborg, MD, PhD19*, Habte A. Yimer, MD20, Megan (Der Yu) Wang21*, Tommi Salmi, MD22*, Liping Wang23*, Jessica Li, MSc21*, Kenneth Wu21*, Aileen Cleary Cohen, MD, PhD21 and Mazyar Shadman, MD, MPH24

1Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
2Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf German CLL Study Group University of Cologne, University Hospital Cologne, Cologne, Germany
3Herbert Irving Comprehensive Cancer Center, Columbia University, New York
4Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA
5Alfred Hospital and University of Melbourne, Melbourne, VIC, Australia
6State 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, CHN
7Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Krakow, Poland
8Dpt of Clinical Oncology, MSC National Research Institute of Oncology, Kraków, Poland
9Department of Hematology, Cancer Hospital Affiliated to Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
104th Department of Internal Medicine – Haematology, Faculty of Medicine in Hradec Králové, University Hospital and Charles University in Prague, Hradec Kralove, Czech Republic
11Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital, Brno, Czech Republic
12Blue Ridge Cancer Care, Roanoke, VA
13Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
14Department of Haematology, Christchurch Hospital, Christchurch, New Zealand
15Te Rerenga Ora Wellington Blood & Cancer Centre, Te Whatu Ora Health New Zealand Capital, Coast & Hutt Valley, Wellington, New Zealand
16Department of Hematology and Cancer Prevention, Faculty of Health Sciences, Medical University of Silesia, Katowice, Poland
17Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland
18Medical University of Lodz, Lodz, Poland
19Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
20Texas Oncology-Tyler/US Oncology Research, Tyler, TX
21BeiGene USA, Inc, San Mateo, CA
22BeiGene International GmbH, Basel, Switzerland
23BeiGene (Beijing) Co, Ltd, Beijing, China
24Fred Hutchinson Cancer Center, Seattle, WA

Introduction: ALPINE, a randomized, multinational phase 3 study (NCT03734016) in patients with R/R CLL/SLL, established the statistical and clinically meaningful superiority of zanubrutinib over ibrutinib on progression-free survival (PFS) and overall response rate (ORR) and confirmed the favorable safety/tolerability profile of zanubrutinib (Brown et al. NEJM; 2022). Now, with 3 years of overall study follow-up, we report the results of an extended follow-up analysis.

Methods: As previously published, patients with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib. Efficacy assessments, including PFS and ORR, were evaluated by the investigator based on 2008 iwCLL criteria; sensitivity analyses to confirm PFS results were also conducted. Updated safety analyses were performed. All reported P-values are descriptive.

Results: Overall, 652 patients were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). As of 15 May 2023, 63.3% (n=207/327) of patients remain on zanubrutinib and 52.3% (n=170/325) remain on ibrutinib. At a median study follow-up of 36.3 months, benefit of zanubrutinib over ibrutinib was sustained (HR: 0.67 [95% CI, 0.52-0.86]; 2-sided P=.002; Fig 1). At 36 months, the PFS rates were 65.8% with zanubrutinib and 54.3% with ibrutinib. Benefits in PFS with zanubrutinib were also observed across major subgroups, including in patients with del(17p)/TP53 mutations (HR: 0.52 [95% CI, 0.32-0.83] 2-sided P=.005) where 36-month PFS rates were 60.1% and 43.6%, respectively. Additionally, the zanubrutinib PFS benefit was confirmed in a sensitivity analysis that included only progression and death events that occurred on active treatment (HR: 0.69 [95% CI, 0.49-0.97]; 2-sided P=.031). ORR remained higher with zanubrutinib compared with ibrutinib (85.0% vs 74.8%; 2-sided P=.001). Responses deepened in both arms with CR/CRi rates of 10.1% (zanubrutinib) and 7.4% (ibrutinib); the rate of PR-L or better was 90.2% vs 82.8%, respectively. Fifty-nine (18.0%) patients treated with zanubrutinib and 71 (21.8%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.54-1.08]); 36-month OS rates were 82.6% (zanubrutinib) and 79.7% (ibrutinib).

In this extended follow-up, median treatment duration was 34.7 months (zanubrutinib) and 31.5 months (ibrutinib). Across both arms, the most common reasons for treatment discontinuation were AEs (20.2%, zanubrutinib; 24.9%, ibrutinib) and progressive disease (12.2%, zanubrutinib; 16.3%, ibrutinib). Dose interruption and dose reduction due to AEs were 59.6% vs 61.1% and 14.2% vs 17.6% with zanubrutinib vs ibrutinib, respectively.

The most common AEs of any grade with zanubrutinib and ibrutinib were COVID-19 (37.3% vs 25.6%), diarrhea (17.9% vs 25.6%), and upper respiratory tract infection (25.9% vs 17.3%). Rates of any grade ≥3 AEs and serious AEs were 72.2% vs 75.6% and 49.7% vs 57.4% with zanubrutinib vs ibrutinib, respectively. Most commonly reported grade ≥3 AEs were neutropenia (17.3% vs 16.4%) and hypertension (15.1% vs 12.0%). Rates of serious infections were 30.6% in each treatment arm. Discontinuation rates due to cardiac disorders were lower with zanubrutinib (0.6% [n=2]) vs ibrutinib (4.6% [n=15]). Overall cardiac events remain lower with zanubrutinib, including atrial fibrillation/flutter (6.2% vs 16.0%; 2-sided P<.0001). Across this study, no grade 5 AEs due to cardiac disorders were observed with zanubrutinib but were reported in 6 patients (1.9%) with ibrutinib (Table 1).

Conclusions: ALPINE was the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors. At a median follow-up of 3 years, the study showed sustained PFS benefits of zanubrutinib over ibrutinib. The durable PFS benefits with zanubrutinib were observed across major subgroups, including multiple sensitivity analyses. The overall safety/tolerability profiles were consistent with previous reports for both treatments. The cardiac safety profile remained favorable for zanubrutinib compared with ibrutinib, with no new safety signals emerging with longer follow-up. With over 3 years of treatment, zanubrutinib continues to be a more efficacious and better tolerated treatment than ibrutinib for patients with R/R CLL/SLL. At time of presentation, data with further follow-up will be presented.

Disclosures: Brown: Loxo/Lilly: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy; Numab Therapeutics: Consultancy; Merck: Consultancy; Gilead: Research Funding; Grifols Worldwide Operations: Consultancy; Kite: Consultancy; BeiGene: Consultancy, Research Funding; iOnctura: Consultancy, Research Funding; SecuraBio: Research Funding; Alloplex Biotherapeutics: Consultancy; Hutchmed: Consultancy; MEI Pharma: Research Funding; Pfizer: Consultancy; Genentech/Roche: Consultancy; Abbvie: Consultancy; Acerta/AstraZeneca: Consultancy. Eichhorst: Janssen: Consultancy, Research Funding, Speakers Bureau; Lilly: Consultancy, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lamanna: Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Octapharma: Research Funding; Eli Lilly/Loxo: Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; TG Therapeutics: Research Funding; Oncternal: Research Funding; MingSight: Research Funding; BeiGene: Consultancy, Research Funding. O'Brien: Johnson & Johnson: Consultancy; Janssen: Consultancy; Lilly: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Astrazeneca: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Regeneron: Research Funding; Pharmacyclics: Consultancy, Research Funding. Tam: AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; LOXO: Honoraria; Novartis: Honoraria; Roche: Honoraria. Qiu: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences: Current Employment; BeiGene, Janssen, Roche, AstraZeneca, Takeda: Speakers Bureau. Jurczak: AstraZeneca: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; Takeda: Research Funding. Simkovic: 4th Department of Internal Medicine-Haematology, Faculty of Medicine in Hradec Kralove, University Hospital and Charles University in Prague, Hradec Kralove, Czech Republic: Current Employment; AbbVie, AstraZeneca, Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie, AstraZeneca, J&J, Beigene, Gilead, Baxter, Novartis, Abbot, Sanofi, Merck, GSK, Sanofi, Vertex, Eli Lilly, Genmab: Current equity holder in publicly-traded company. Mayer: BeiGene: Research Funding. Ferrajoli: Genetech: Honoraria; GenMab: Research Funding; Beigene: Research Funding; Janssen: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Weinkove: Fisher & Paykel Healthcare: Current equity holder in publicly-traded company; BioOra: Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria. Robak: BeiGene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Regeneron: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; OctoPharma: Honoraria, Research Funding; Abbvie: Honoraria. Yimer: Abbvie, Amgen, AstraZeneca, BeiGene USA, Inc., GlaxoSmithKline, Janssen Biotech, Karyopharm Therapeutics, Takeda: Speakers Bureau. Wang: BeiGene: Current Employment, Current equity holder in publicly-traded company. Salmi: BeiGene: Current Employment, Current equity holder in publicly-traded company. Wang: BeiGene Inc.: Current Employment. Li: BeiGene: Current Employment, Current equity holder in publicly-traded company. Wu: BeiGene: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Shadman: BeiGene: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; ADC therapeutics: Consultancy; Vincerx: Research Funding; Eli Lilly: Consultancy; Genmab: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; MEI Pharma: Consultancy; Fate Therapeutics: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Regeneron: Consultancy; TG Therapeutics: Research Funding.

*signifies non-member of ASH