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3255 Deep and Sustained Responses in Patients with CLL Treated with Zanubrutinib or Zanubrutinib + Obinutuzumab in Phase 1/2 AU-003 and Phase 1b GA-101 Studies: A Report from the Zanubrutinib Extension Study

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Lymphomas, Diseases, Lymphoid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Constantine S. Tam, MD, MBBS1, Stephen S. Opat, MBBS, FRACP, FRCPA2, Eileen Grace Merriman, MD, FRACP, FRCPA3*, Jan A. Burger, MD, PhD 4, Emma Verner, MBBS5*, Paula Marlton6*, David Gottlieb, MD, MBBS, FRACP, FRCPA7*, Ian W. Flinn, MD, PhD8, Sumit Madan, MD9, Matthew Ku, MBBS, PhD10*, Radha Prathikanti, MPH, MBA11*, Heather Allewelt, MD11*, Tian Tian, PhD11*, Remus Vezan, MD, PhD11* and Gavin Cull, MBBS, DM, FRACP, FRCPA12

1Alfred Hospital and Monash University, Melbourne, VIC, Australia
2Lymphoma Research Group, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
3NorthShore Hospital, Auckland, New Zealand
4The University of Texas MD Anderson Cancer Center, Houston, TX
5Concord Repatriation General Hospital, University of Sydney, Concord, NSW, Australia
6Princess Alexandra Hospital and University of Queensland, Brisbane, QLD, Australia
7Westmead Institute for Medical Research, Sydney, NSW, Australia
8Tennessee Oncology/OneOncology, Nashville, TN
9Banner MD Anderson Cancer Center at Banner Gateway Medical Center, Gilbert, AZ
10St Vincent’s Hospital, Melbourne, VIC, Australia
11BeiGene USA, Inc, San Mateo, CA
12Sir Charles Gairdner Hospital, Perth, Australia

Introduction: The phase 1/2 AU-003 study (BGB-3111-AU-003; NCT02343120) evaluated zanubrutinib monotherapy in patients with various B-cell malignancies, including chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL). The phase 1b GA-101 study (NCT02569476) evaluated zanubrutinib in combination with obinutuzumab (ZO) for 6 cycles followed by continuous zanubrutinib monotherapy in patients with CLL/SLL and follicular lymphoma. At the end of each study, eligible patients could enroll in a long-term extension study, BGB-3111-LTE1 (LTE1, NCT04170283), for continued treatment with zanubrutinib or survival follow-up. Here, we report outcomes in patients with CLL/SLL from AU-003 and GA-101, with extended follow-up from LTE1.

Methods: This ad hoc analysis included all patients with CLL/SLL from AU-003 and GA-101 and incorporated long-term follow-up data for patients who enrolled in LTE1 upon completion of these studies. In LTE1, safety outcomes, including the occurrence of treatment-emergent adverse events (TEAEs), were evaluated at least every 3 months. Investigators assessed disease response at least every 6 months, using modified iWCLL guidelines [CLL: Hallek et al. 2008; SLL: Cheson et al. 2014]; a response category of “no evidence of progressive disease” was also available.

Results: In total, 170 patients with CLL/SLL were treated in AU-003 (n=125) and GA-101 (n=45), of whom 117 (AU-003, 84; GA-101, 33) enrolled in LTE1 (108 continued zanubrutinib). At parent study enrollment, median age was 68 years (range, 24-87), and 75.3% had relapsed/refractory (R/R) CLL/SLL, with 1 median prior therapy line (mean, 2; range, 1-10). Del(17p) was present in 17.1% (TN, 19.0%; R/R, 16.4%) and TP53 mutation in 18.2% of patients (TN, 21.4%; R/R, 17.2%). At LTE1 enrollment, median age was 71 years (range, 40-91) and the median time since zanubrutinib treatment initiation in the parent studies was 44.1 months (range, 20.0-71.6) (TN, 47.9 months; R/R, 40.5 months). As of April 15, 2024, the median follow-up time (parent study + LTE1) was 78.1 months (range, 5.3-106.9) and the median treatment duration was 67.9 months (range, 0.8-106.9). Grade ≥3 and serious TEAEs occurred in 84.1% and 69.4% of patients, respectively. TEAEs led to zanubrutinib and/or obinutuzumab treatment discontinuation in 13.5%, dose reduction in 12.9%, and death in 7.1% (COVID-19, n=2). The prevalence of atrial fibrillation/flutter at >0-3 years, >3-5 years and >5-6 years was 2.9%, 4.0% and 5.4%, and of hypertension was 14.7%, 19.0% and 20.4%, respectively.

In patients receiving zanubrutinib monotherapy (AU-003), with median follow-up of 76 months (range, 5.3-106.9), the overall response rate (ORR; ≥ partial response with lymphocytosis; 95% CI) was 100% (84.6, 100) for TN patients, and 94.2% (87.8, 97.8) for patients with R/R CLL/SLL. The complete response (CR)/CR with incomplete bone marrow recovery (CRi) rate (95% CI) was 36.4% (17.2, 59.3) for TN patients, and 25.2% (17.2, 34.8) for patients with R/R CLL/SLL. COVID-adjusted 72-month event-free rates for progression-free survival (PFS; 95% CI) were 76.2% (51.9, 89.3) for TN patients, and 61.1% (49.8, 70.5) for patients with R/R CLL/SLL. COVID-adjusted 72-month event-free rates for overall survival (OS; 95% CI) were 90.5% (67.0, 97.5) and 81.5% (71.8, 88.1) for patients with TN and R/R CLL, respectively.

In patients receiving ZO (GA-101), with median follow-up of 88.1 months (range, 7.9-98.5), the ORR (95% CI) was 95.6% (84.9, 99.5); the ORR was 100% (83.2, 100) for TN patients and 92.0% (74.0, 99.0) for patients with R/R CLL/SLL. The CR/CRi rate (95% CI) was 60% (36.1, 80.9) for TN patients and 36.0% (18, 57.5) for patients with R/R CLL/SLL. COVID-adjusted 72-month event-free rates for PFS were 78.5% (52.3, 91.4) for TN patients and 44.6% (24.3, 63.2) for patients with R/R CLL/SLL. COVID-adjusted 72-month OS rates were 84.2% (58.7, 94.6) and 63.0% (40.8, 78.8) for patients with TN and R/R CLL, respectively.

Conclusions: Patients with CLL/SLL treated with zanubrutinib monotherapy or ZO for 6 cycles followed by continuous zanubrutinib monotherapy had high rates of overall and complete response, with particularly high CR rates in patients with TN CLL/SLL. With a median follow-up of 6.5 years, the durability of these responses was demonstrated. The tolerability/safety profile of zanubrutinib, alone and in combination with obinutuzumab, remained favorable.

Disclosures: Tam: BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Lilly: Honoraria. Opat: Pharmacyclics: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Burger: BeiGene: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy; AstraZeneca: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Novartis: Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau. Verner: Janssen Cilag Pty Ltd: Research Funding. Marlton: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, BeiGene: Speakers Bureau; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas; Janssen; BeiGene; AstraZeneca; Otsuka; AbbVie; Menarini; Pfizer; MSD; Jazz; Novartis: Membership on an entity's Board of Directors or advisory committees. Gottlieb: Haemalogix: Consultancy; Takeda: Consultancy. Flinn: Vincerx Pharma, 2seventybio: Research Funding; TG Therapeutics: Research Funding; Tessa Therapeutics: Research Funding; Step Pharma: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Rhizen Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Pfizer: Research Funding; Nurix: Research Funding; Novartis: Research Funding; Myeloid Therapeutics: Research Funding; MorphoSys: Research Funding; Millennium Pharmaceuticals: Research Funding; Merck: Research Funding; Marker Therapeutics: Research Funding; Loxo: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Infinity Pharmaceuticals: Research Funding; IGM Biosciences: Research Funding; InnoCare Pharma: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Epizyme: Research Funding; Fate Therapeutics: Research Funding; Biopharma: Research Funding; CTI: Research Funding; Curis: Research Funding; Constellation Pharmaceuticals: Research Funding; City of Hope Medical Center: Research Funding; Celgene: Research Funding; CALGB: Research Funding; BMS: Research Funding; CALIBR: Research Funding; BioPath: Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; Agios: Research Funding; Vincerx: Consultancy; Acerta: Research Funding; Roche: Consultancy; Kite, a Gilead Company: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Vincerx Advisory Committee: Membership on an entity's Board of Directors or advisory committees; Tennessee Oncology & OneOncology: Current Employment; Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding. Madan: Harpoon, Karyopharm: Other: Travel, accommodations, expenses; Karyopharm, Sanofi, Pfizer, Janssen: Consultancy; Karyopharm, Harpoon, Pfizer, Iteos: Research Funding. Ku: F. Hoffmann-La Roche Ltd, AbbVie: Consultancy; Roche, Abbvie: Consultancy; Beigene: Research Funding; St Vincent's Hospital, Melbourne: Current Employment. Prathikanti: BeiGene: Current Employment. Allewelt: St. Jude Children’s Research Hospital: Patents & Royalties; Nkarta: Current Employment, Current equity holder in publicly-traded company, Other: Travel support; BeiGene: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Tian: BeiGene: Current Employment. Vezan: BeiGene: Current Employment. Cull: Glycomimetics: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding.

*signifies non-member of ASH