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LBA-6 Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, CLL, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies
Tuesday, December 13, 2022, 9:00 AM-10:30 AM

Jennifer R. Brown1, Barbara Eichhorst2, Peter Hillmen3, Nicole Lamanna, MD4, Susan M. O'Brien5, Constantine S. Tam6,7*, Lugui Qiu8, Maciej Kaźmierczak9*, Wojciech Jurczak10, Keshu Zhou11*, Martin Šimkovič12,13*, Jiri Mayer14, Amanda L. Gillespie-Twardy15*, Alessandra Ferrajoli16, Peter S. Ganly17, Robert Weinkove18,19, Sebastian Grosicki20, Andrzej Mital21*, Tadeusz Robak22, Anders Österborg23,24*, Habte A. Yimer25, Tommi Salmi26*, Megan (Der Yu) Wang26*, Lina Fu26*, Jessica Li26*, Kenneth Wu26*, Aileen Cohen26* and Mazyar Shadman27,28*

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Department of Internal Medicine, University of Cologne, Center for Integrated Oncology Aachen, Bonn, Cologne, Duesseldorf, Cologne, Germany
3St. James's University Hospital, Leeds, ENG, United Kingdom
4Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
5Chao Family Comprehensive Cancer Center, University of California, Irvine, CA
6Monash University, Melbourne, VIC, Australia
7The Alfred Hospital, Melbourne, VIC, Australia
8State 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
9Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland
10Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland
11Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
124th Department of Internal Medicine - Hematology, University Hospital, Kralove, Czech Republic
13Faculty of Medicine, Charles University, Prague, Czech Republic
14Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic
15Blue Ridge Cancer Care, Roanoke, VA
16Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
17Department of Haematology, Christchurch Hospital, Christchurch, New Zealand
18Te Rerenga Ora Blood and Cancer Centre, Te Whatu Ora Health New Zealand Capital Coast & Hutt Valley, Wellington, New Zealand
19Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand
20Department of Hematology and Cancer Prevention, Health Sciences Faculty, Medical University of Silesia, Katowice, Poland
21Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland
22Medical University of Lodz, Lodz, Poland
23Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
24Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
25Texas Oncology-Tyler/US Oncology Research, Tyler, TX
26BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc., San Mateo, CA
27Fred Hutchinson Cancer Center, Seattle, WA
28Department of Medicine, University of Washington, Seattle, WA

Introduction: CLL/SLL is usually characterized by consecutive relapses and response to therapy ultimately dictates survival. While ibrutinib, a first-generation Bruton tyrosine kinase inhibitor (BTKi), has become standard therapy, it has well-described off-target effects that can limit use. Compared with ibrutinib, zanubrutinib, a next-generation BTKi, provides improved BTK occupancy across disease-relevant tissues with greater kinase selectivity. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head-to-head with ibrutinib as treatment for R/R CLL/SLL. At predefined response analyses, zanubrutinib demonstrated superior overall response rate (ORR); data from the predefined final PFS analysis are reported here.

Methods: Patients (pts) with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Stratification was based on age, refractory status, geographical region, and del(17p)/TP53 mutation status. As the primary endpoint of ORR was superior with zanubrutinib, the key secondary efficacy endpoint of PFS was tested for noninferiority under hierarchical testing when 205 PFS events were observed. If PFS noninferiority between zanubrutinib and ibrutinib was demonstrated, superiority of zanubrutinib vs ibrutinib could be tested and claimed if the 2-sided P-value was <.04996. Other endpoints included overall survival (OS), ORR including PR with lymphocytosis (PR-L) or better, and safety parameters including atrial fibrillation/flutter.

Results: Pts (N=652) from 15 countries were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). Demographic and disease characteristics were balanced between zanubrutinib and ibrutinib arms (age ≥65 yrs [61.5 vs 61.5%]; male [65.1 vs 71.4%]; unmutated IGHV [73.1 vs 73.5%]; del(17p) [13.8 vs 15.4%]; TP53 mutated without del(17p) [9.2 vs 7.7%]). Across the study population, median age was 67 and 68 yrs, respectively; in both arms, median prior lines of therapy was 1.

With a median follow-up of 29.6 mo (data cutoff, 8 Aug 2022), zanubrutinib PFS, assessed by independent review committee (PFSIRC), was superior to ibrutinib in the ITT population (HR: 0.65 [95% CI, 0.49-0.86]; 2-sided P=.0024 [Fig 1]); identical statistical values were reported when assessed by investigator (INV). Median PFSIRC was 35.0 mo (95% CI, 33.2-44.3) for ibrutinib-treated pts but not reached for zanubrutinib-treated pts. In a predefined subgroup of pts with del(17p)/TP53 mutation, longer PFSIRC was demonstrated with zanubrutinib than ibrutinib (Fig 2). PFS, regardless of IRC or INV assessment, consistently favored zanubrutinib across other major predefined subgroups, including IGHV status. Compared with ibrutinib, zanubrutinib had a higher ORRIRC (86.2 vs 75.7%, nominal 2-sided P=.0007), with a rate of PR-L or better of 91.7% vs 83.1% (nominal 2-sided P=.001).

Treatment discontinuation rate was lower with zanubrutinib (26.3%) vs ibrutinib (41.2%) with most due to AEs (16.2 vs 22.8%) or progressive disease (7.3 vs 12.9%); discontinuation rates due to cardiac disorders were 0.3% vs 4.3%. Rates of grade ≥3 AEs (67.3 vs 70.4%), serious AEs (42.0% vs 50.0%), dose interruption (50.0% vs 56.8%), and dose reduction (12.3 vs 17.0%) were also lower with zanubrutinib vs ibrutinib. Rate of atrial fibrillation/flutter was lower with zanubrutinib compared with ibrutinib (5.2% vs 13.3%); rates of other AEs of special interest were similar between treatments. There were no grade 5 AEs due to cardiac disorders with zanubrutinib vs 6 (1.9%) with ibrutinib. Overall, 48 (14.7%) pts treated with zanubrutinib and 60 (18.5%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.51-1.11]).

Conclusions: As ALPINE is the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors, zanubrutinib has now proven superiority to ibrutinib in both ORR and PFS in pts with R/R CLL/SLL. Efficacy benefits with zanubrutinib were observed across all major subgroups, including high-risk pts. Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death. These data suggest zanubrutinib is more efficacious and better tolerated than ibrutinib as treatment for R/R CLL/SLL.

Disclosures: Brown: Abbvie: Consultancy; Acerta/Astra-Zeneca: Consultancy; Beigene: Consultancy, Research Funding; Bristol-Myers Squibb/Juno/Celgene: Consultancy; Catapult: Consultancy; Genentech/Roche: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy, Research Funding; Morphosys AG: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Rigel: Consultancy; Gilead: Research Funding; Loxo/Lilly: Research Funding; Verastem/SecuraBio: Research Funding; Sun: Research Funding; TG Therapeutics: Research Funding; Invectys: Other: served on the data safety monitoring committee; Grifols Worldwide Operations: Consultancy; Hutchmed: Consultancy; iOnctura: Consultancy, Research Funding; Pharmacyclics: Consultancy; SecuraBio: Research Funding. Eichhorst: University Hospital of Cologne, Internal Medicine, Oncology: Current Employment; Janssen: Honoraria, Research Funding; Gilead: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; Celgene: Honoraria; MSD: Speakers Bureau. Hillmen: AstraZeneca: Consultancy, Speakers Bureau; Apellis: Consultancy, Current Employment, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; BeiGene: Other: Financial or material support, Speakers Bureau; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau. Lamanna: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenenca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo Oncology/Eli Lilly and Company: Consultancy, Research Funding; Mingsight: Research Funding; Octapharma: Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding. O'Brien: Nova Research Company, Pfizer, Pharmacyclics, TG Therapeutics, Vaniam Group LLC, Verastem, Vida Ventures: Consultancy; AbbVie, Alexion, Amgen, Aptose Biosciences, Astellas, AstraZeneca, Autolus, Bristol Myers Squibb, Celgene, DynaMed, Eli Lilly and Company, Gilead, GlaxoSmithKline, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, MEI Pharma Inc, Merck: Consultancy; Acerta, Alliance, Beigene Ltd, Caribou Biosciences Inc, Gilead, Kite, Loxo Oncology, Mustang, Nurix Therapeutics Inc, Pfizer, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics.: Research Funding. Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Research Funding; LOXO: Honoraria; AstraZeneca: Honoraria. Qiu: Janssen: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Jurczak: Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Mei Pharma: Research Funding; Lilly: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Bayer: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Loxo Oncology: Consultancy, Research Funding; Sandoz: Consultancy, Research Funding; Merck: Research Funding; Morphosys: Research Funding; Novo Nordisk: Research Funding. Šimkovič: Baxter: Current holder of stock options in a privately-held company; Novartis: Current holder of stock options in a privately-held company; Abbot: Current holder of stock options in a privately-held company; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; J&J: Current holder of stock options in a privately-held company; Sanofi: Current holder of stock options in a privately-held company; AbbVie: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead: Current holder of stock options in a privately-held company; BeiGene: Current holder of stock options in a privately-held company; AstraZeneca: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Mayer: Novartis: Other: Travel support, Research Funding; BeiGene: Research Funding. Ferrajoli: Beigene: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weinkove: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Robak: Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; OctaPharma: Honoraria, Research Funding; Regeneron: Honoraria, Research Funding; GSK: Honoraria, Research Funding. Yimer: Texas Oncology: Current Employment; AstraZeneca: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Karyopharm: Consultancy, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Divested equity in a private or publicly-traded company in the past 24 months; Beigene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Pharmacyclics: Speakers Bureau; Sanofi: Speakers Bureau. Salmi: BeiGene Switzerland GmbH: Current Employment; BeiGene Ltd: Current equity holder in publicly-traded company. Wang: BeiGene, Ltd: Current Employment, Current equity holder in publicly-traded company. Fu: BeiGene: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb: Ended employment in the past 24 months. Li: BeiGene: Current Employment, Current equity holder in publicly-traded company. Wu: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Shadman: AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Kite Pharma: Consultancy; Adaptive Biotechnologie: Consultancy; Epizyme: Consultancy; Eli Lilly: Consultancy; Adaptimmune: Consultancy; Mustang Bio: Consultancy, Research Funding; Regeneron: Consultancy; Merck: Consultancy; Fate Therapeutics: Consultancy; MEI Pharma: Consultancy; Atara Biotherapeutic: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding; Sunesis: Research Funding; Genmab: Research Funding.

OffLabel Disclosure: Zanubrutinib is not yet approved for CLL/SLL treatment

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