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67 Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Early Results from Arm D of the SEQUOIA (BGB-3111-304) Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Combination Small Molecules
Hematology Disease Topics & Pathways:
Fundamental Science, Clinical Trials, Lymphoid Leukemias, CLL, Lymphomas, Clinical Research, B Cell Lymphoma, Diseases, Lymphoid Malignancies
Saturday, December 11, 2021: 9:30 AM

Alessandra Tedeschi, MD1*, Emmanuelle Ferrant, MD2*, Ian W. Flinn, MD, PhD3, Constantine S. Tam, MBBS, MD4,5,6,7*, Paolo Ghia, MD, PhD8, Tadeusz Robak, MD, PhD9, Jennifer R. Brown, MD, PhD10*, Vanitha Ramakrishnan, PhD11*, Tian Tian, PhD11*, Sowmya B. Kuwahara, PharmD11*, Jason C. Paik, MD, PhD11*, Aileen Cohen, MD, PhD11*, Jane Huang, MD11* and Peter Hillmen, p.hillmen@leeds.ac.uk12

1ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
2Centre Hospitalier Lyon-Sud, University Claude Bernard Lyon 1, Pierre-Bénite, France
3Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN
4Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
5Royal Melbourne Hospital, Parkville, VIC, Australia
6University of Melbourne, Parkville, VIC, Australia
7St Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia
8Università Vita-Salute San Raffaele, Milan, Italy
9Medical University of Lodz, Lodz, Poland
10Dana-Farber Cancer Institute, Boston, MA
11BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc., San Mateo, CA
12St James's University Hospital, Leeds, United Kingdom

Background: Zanubrutinib is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (J Med Chem 2019;62:7923-40). Data from several phase 2 CLL trials assessing BCL-2 and BTK inhibitor combination treatment suggested that undetectable minimal residual disease (uMRD)-driven fixed-duration combination treatment was tolerable and enabled durable responses after treatment discontinuation (JAMA Oncol 2021;1649.; EHA 2021 S147). However, a limited number of patients with the high-risk feature, deletion of chromosome 17p13.1 [del(17p)], have been included in these studies. Preliminary data from Arm C of the SEQUOIA trial suggested that zanubrutinib monotherapy was active (18-mo progression-free survival: 90.6%) and well-tolerated in CLL/SLL patients with del(17p) (ASH 2020 1306). Here, we present early results for patients with TN del(17p) CLL/SLL receiving zanubrutinib + venetoclax in Arm D of the SEQUOIA trial (NCT03336333).

Methods: SEQUOIA is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm D) of patients with TN del(17p) CLL/SLL (Blood 2020;136 [supplement 1]:24-5). Patients in Arm D were treated with zanubrutinib (160 mg twice daily) for 3 mos followed by zanubrutinib (same dosing) + venetoclax (ramp-up cycle followed by 400 mg once daily) combination treatment for 12–24 cycles until progressive disease (PD), unacceptable toxicity, or achievement of uMRD at <10-4 sensitivity by flow cytometry (whichever occurred first). Adult patients with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446-56) were eligible if they had central verification of del(17p) by fluorescence in situ hybridization with >7% aberrant nuclei present. Initial safety and tolerability of zanubrutinib + venetoclax was assessed, including the risk of tumor lysis syndrome (TLS) both at baseline and prior to initiation of venetoclax. Responses for CLL and SLL were investigator-assessed per modified iwCLL criteria (Blood 2008;111:5446-56; J Clin Oncol 2012;30:2820-2) and Lugano criteria (J Clin Oncol 2014;32:3059-68), respectively. Bone marrow exams to confirm a suspected complete response (CR) or CR with incomplete hematological recovery were required starting at the end of Cycle 9.

Results: As of 1 JUN 2021 (data cutoff), 35 of approximately 80 planned patients with centrally confirmed del(17p) were enrolled. Median follow-up was 9.7 mos. In the safety analysis population (n=35), 94.3% had CLL and high-risk characteristics including Binet stage C (51.5%), bulky disease ≥5 cm (42.9%), unmutated immunoglobulin heavy chain variable locus (85.3%, n=34), median del(17p) frequency of 81.5%, and elevated β2-microglobulin (71.4%). At data cutoff, 29 patients had started combination therapy and 27 patients completed ramp-up venetoclax dosing. Thirty-two patients remained on study treatment and 3 patients ended treatment due to withdrawal of consent, PD, or adverse event (AE of lung cancer), all n=1. The patient with lung cancer had lung nodules present at screening and died due to lung adenocarcinoma. AEs and serious AEs were reported in 29 patients (82.9%) and 4 patients (11.4%), respectively. AEs reported in ≥10% of patients included diarrhea (n=5), neutropenia (n=5), fatigue (n=4), nausea (n=4), and petechiae (n=4). Thirteen patients (37.1%) had grade ≥3 AEs; most frequently neutropenia (n=4) and diarrhea (n=2). One patient with ongoing grade 2 atrial fibrillation at baseline reported grade 3 atrial fibrillation on study. To date, no AEs of TLS have been reported. At baseline, the TLS risk categories were high, medium, and low in 12 (34.3%), 22 (62.9%), and 1 (2.9%) patients, compared with 0 (0%), 21 (67.7%), and 10 (32.3%) patients, respectively, prior to initiation of venetoclax. For the 31 patients who reached the initial efficacy assessment at 3 mos after starting zanubrutinib, the overall response rate was 96.8% (30/31); one patient reported PD after having an initial partial response while on combination therapy.

Conclusion: Preliminary safety data with the 9.7-mo median follow-up suggest that zanubrutinib + venetoclax was generally well tolerated in this high-risk population, with no new safety signals identified and no TLS reported. Enrollment is ongoing; updated safety, efficacy, and biomarker data will be presented.

Disclosures: Tedeschi: AbbVie: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; BeiGene: Honoraria, Other: Advisory Board, Speakers Bureau; AstraZeneca: Honoraria, Other: Advisory Board, Speakers Bureau. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Flinn: Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding. Tam: Roche: Consultancy, Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Loxo: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria. Ghia: Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Brown: MEI Pharma: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Sun: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Beigene: Consultancy; Nextcea: Consultancy; Morphosys AG: Consultancy; TG Therapeutics: Research Funding; Acerta/Astra-Zeneca: Consultancy; Janssen: Consultancy; SecuraBio: Research Funding; Loxo/Lilly: Research Funding. Ramakrishnan: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses. Tian: AbbVie: Ended employment in the past 24 months; BeiGene: Current Employment. Kuwahara: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, 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; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen: BeiGene: Honoraria; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria.

OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN del(17p) CLL/SLL in the US

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