Please use this identifier to cite or link to this item: https://repository.monashhealth.org/monashhealthjspui/handle/1/50589
Conference/Presentation Title: A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 As Monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with CLL/SLL: Preliminary Data.
Authors: Cheah C.Y.;Tam C.S.;Lasica M.;Verner E.;Browett P.J.;Anderson M.A.;Hilger J.;Fang Y.;Simpson D.;Opat S. 
Monash Health Department(s): Haematology
Monash University - School of Clinical Sciences at Monash Health
Institution: (Cheah) Medical School, University of Western Australia, Crawley, Australia, Australia
(Cheah) Department of Haematology, Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine, Nedlands, Australia, Australia
(Cheah) Linear Clinical Research, Nedlands, Australia, Australia
(Tam, Opat) Monash University, Clayton, Australia, Australia
(Tam) Alfred Hospital, Melbourne, Australia, Australia
(Lasica) St Vincent's Hospital Melbourne, Fitzroy, Australia, Australia
(Verner) Concord Repatriation General Hospital, Concord, Australia, Australia
(Verner) University of Sydney, Sydney, Australia, Australia
(Browett) Department of Haematology, Auckland City Hospital, Auckland, New Zealand, New Zealand
(Anderson) Division of Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute, Parkville, Australia, Australia
(Anderson) Peter MacCallum Cancer Centre, Melbourne, Australia, Australia
(Hilger, Fang, Simpson) BeiGene (Shanghai) Co., Ltd., Shanghai, China and BeiGene USA, Inc., San Mateo, CA
(Opat) Monash Health, Clayton, Australia, Australia
Presentation/Conference Date: 22-Nov-2023
Copyright year: 2022
Publisher: Elsevier B.V.
Publication information: Blood. Conference: 64th ASH Annual Meeting. New Orleans United States. 140(Supplement 1) (pp 2321-2323), 2022. Date of Publication: 15 Nov 2022.
Journal: Blood
Abstract: Abstract: Background/introduction: The effectiveness of Bcl-2 inhibitors as a treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was established by the approval of venetoclax in pts with CLL/SLL across all lines of therapy. However, the related adverse events (AEs) and emergence of BCL2 mutations, resulting in resistance, can limit the utility of venetoclax. BGB-11417 is a highly selective Bcl-2 inhibitor with potency >10 times that of venetoclax in biochemical assays. BGB-11417 monotherapy is tolerable, with no maximum tolerated dose (MTD) reached after dose escalation through all planned doses to 640 mg once daily (QD) in pts with non-Hodgkin lymphoma (EHA 2022. Abstract P687). The combination of Bcl-2 and Bruton tyrosine kinase (BTK) inhibitors is tolerable with synergistic activity in CLL and mantle cell lymphoma (MCL) (J Clin Oncol 2019;37:2722-9; N Engl J Med 2019;380:2095-103; EHA 2020. Abstract S158; N Engl J Med 2018;378:1211-23). ZANU, a next-generation BTK inhibitor, has shown favorable activity and safety in pts with CLL/SLL (EHA 2021. Abstract LB1900) and Waldenstrom macroglobulinemia (Blood. 2020;136(18):2038-2050). BGB-11417-101 is an ongoing first-in-human phase 1/1b dose-escalation/expansion study (NCT04277637). Pts with various B-cell malignancies were enrolled; data from CLL/SLL cohorts are presented here. Method(s): In separate monotherapy and combination therapy cohorts, pts received escalating doses of BGB-11417 (40, 80, 160, 320, or 640 mg QD) with a ramp-up to the intended target dose to minimize risk of tumor lysis syndrome (TLS). In combination therapy cohorts, pts received ZANU (320 mg QD or 160 mg twice daily) beginning 8-12 weeks before BGB-11417. Dose-limiting toxicity for each cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at the intended dose. AEs were reported per Common Terminology Criteria for AEs v5.0. Minimal residual disease (MRD) was assessed by a European Research Initiative on CLL flow cytometry assay. Result(s): As of May 15 2022, 50 pts with CLL received treatment: 6 monotherapy (all relapsed/refractory [R/R]) and 44 combination (22 R/R; 22 treatment naive [TN]). The monotherapy CLL cohort received BGB-11417 doses up to 160 mg. Based on emerging safety data from other cohorts, pts in combination cohorts with R/R CLL received BGB-11417 up to 640 mg and pts with TN CLL received up to 320 mg (data include 8 pts in ZANU pretreatment not yet dosed with BGB-11417). MTD has not yet been reached for any CLL cohort, with dose escalation ongoing. Median follow-up was 11.5 mo (range 8.5-18.3) for monotherapy and 5.8 mo (range 0.2-10.5) for combination. Treatment-emergent AEs (TEAEs) across all doses are listed in the Table. With monotherapy, cytopenias were the most common TEAEs (>=50%), with 33% grade >=3. With combination, contusion, neutropenia, and low-grade gastrointestinal toxicity were the most common TEAEs (>=22.7%); neutropenia was the most common grade >=3 TEAE (11.4%) with 5 pts. No pts discontinued monotherapy treatment, and 1 pt discontinued combination treatment (disease progression; Richter transformation). Only 1 high-risk pt with CLL on monotherapy had laboratory TLS that resolved with no intervention (overall laboratory TLS <=2%). No clinical TLS was reported. Diarrhea was mostly grade 1 and grade >=3 was not seen. Although efficacy data are early, most pts with CLL/SLL had notable reductions in absolute lymphocyte count (ALC) with responses seen at doses as low as 1 mg (Figure), consistent with improved potency of BGB-11417 vs venetoclax. Four responses (66%, partial response [PR] or better) and 32 responses (72.7%, PR with lymphocytosis or better) were observed with mono- and combination therapy, respectively. MRD data are early: among 4 MRD evaluable pts at 160 mg, 3 pts (2 monotherapy; 1 combination) had a peripheral blood CLL count <10-4 at 24 weeks after BGB-11417 initiation. Conclusion(s): These preliminary data show BGB-11417, alone or in combination with ZANU, was well-tolerated in most patients. Grade >=3 neutropenia was uncommon and manageable. Efficacy is supported by the rapid reduction in ALC during ramp-up, and early response data are promising. TLS rates are low; the prophylactic measures and ramp-up schedule seem to adequately mitigate TLS across all dose levels tested. Mature MRD data are forthcoming, and venetoclax-treated CLL/SLL cohorts will soon be open for enrollment. [Formula presented] Disclosures: Cheah: AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: 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; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam: LOXO: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria; Beigene: Honoraria, Research Funding. Lasica: Janssen: Other: Education. Verner: Janssen Cilag Pty Ltd: Research Funding. Browett: Arrowhead: Honoraria; BeiGene: Research Funding; MSD: Honoraria; Roche: Research Funding; Abbvie: Honoraria; Eysa Pharma: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Anderson: Gilead: Honoraria; CSL: Honoraria; The Walter and Eliza Hall Institute: Current Employment; Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; AstraZeneca: Honoraria. Hilger: BeiGene: Current Employment, Current equity holder in private 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. Simpson: BeiGene: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Other: Travel, Accommodations, Expenses. Opat: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding.Copyright © 2022 The American Society of Hematology
Conference Name: 64th ASH Annual Meeting
Conference Start Date: 2022-12-10
Conference End Date: 2022-12-13
Conference Location: New Orleans, United States
DOI: http://monash.idm.oclc.org/login?url=https://dx.doi.org/10.1182/blood-2022-169662
URI: https://repository.monashhealth.org/monashhealthjspui/handle/1/50589
Type: Conference Abstract
Subjects: B cell lymphoma
chronic lymphatic leukemia
lymphocytosis
neutropenia
non-Hodgkin lymphoma
Type of Clinical Study or Trial: Clinical trial
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