Please use this identifier to cite or link to this item: https://repository.monashhealth.org/monashhealthjspui/handle/1/51202
Conference/Presentation Title: Combination Treatment with Sonrotoclax (BGB-11417), a Second-Generation BCL2 Inhibitor, and Zanubrutinib, a Bruton Tyrosine Kinase (BTK) Inhibitor, Is Well Tolerated and Achieves Deep Responses in Patients with Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (TN-CLL/SLL): Data from an Ongoing Phase 1/2 Study.
Authors: Tam C.S.;Anderson M.A.;Lasica M.;Verner E.;Opat S.S.;Ma S.;Weinkove R.;Cordoba R.;Soumerai J.;Ghia P.;Leitch S.;Hilger J.;Fang Y.;Simpson D.;Guo H.;Cheah C.Y.
Monash Health Department(s): Haematology
Institution: (Tam) Alfred Hospital, Melbourne, Australia
(Tam) Monash University, Clayton, Australia
(Anderson) Division of Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute, Parkville, Australia
(Anderson) Peter Mac Callum Cancer Centre, Melbourne, Australia
(Lasica) Department of Haematology, St Vincent's Hospital Melbourne, Victoria, Australia, Fitzroy, Australia
(Verner) Concord Repatriation General Hospital, Concord, Australia
(Verner) University of Sydney, Sydney, Australia
(Opat) School of Clinical Sciences, Monash University, Melbourne, Australia
(Opat) Monash Health, Clayton, Australia
(Ma) Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
(Weinkove) Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand, New Zealand
(Weinkove) Te Rerenga Ora Wellington Blood & Cancer Centre, Te Whatu Ora Health New Zealand Capital, Coast & Hutt Valley, Wellington, New Zealand, New Zealand
(Cordoba) Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
(Soumerai) Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, United States
(Ghia) Universita' Vita-Salute San Raffaele C.F. 97187560152, Milano, Italy
(Leitch) Waitemata District Health Board, Auckland, New Zealand, New Zealand
(Hilger) BeiGene USA, Inc., San Mateo, United States
(Fang) BeiGene (Shanghai) Co., Ltd., Shanghai, China
(Simpson) BeiGene USA, Inc., San Mateo, CA, United States
(Guo) BeiGene (Shanghai) Co., Ltd, Shanghai, China
(Cheah) Linear Clinical Research and Sir Charles Gairdner Hospital, Nedlands, Australia
(Cheah) Department of Haematology, Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine, Nedlands, Australia
(Cheah) Medical School, University of Western Australia, Crawley, Australia
Presentation/Conference Date: 22-Feb-2024
Copyright year: 2023
Publisher: Elsevier B.V.
Publication information: Blood. Conference: 65th ASH Annual Meeting. San Diego United States. 142(supplement 1) (pp 327), 2023. Date of Publication: 28 Nov 2023.
Journal: Blood
Abstract: Background: The combination of BCL2 and BTK inhibitors has shown synergistic activity. The combination of venetoclax, a BCL2 inhibitor, and ibrutinib, a BTK inhibitor, is an effective treatment for CLL/SLL. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency >10x that of venetoclax in biochemical assays. Zanubrutinib, a next-generation BTK inhibitor, has shown improved PFS with fewer cardiac adverse events (AEs) vs ibrutinib in a randomized study of patients with CLL/SLL (Brown et al. N Engl J Med. 2023). BGB-11417-101 (NCT04277637) is an ongoing, first-in-human, phase 1/1b dose-escalation/expansion study of patients with various B-cell malignancies. In a preliminary report, sonrotoclax, alone or in combination with zanubrutinib, was well tolerated at all doses tested up to 640 mg. This abstract describes the safety and efficacy data from patients with treatment-naive (TN) CLL/SLL who received the combination of sonrotoclax and zanubrutinib. Method(s):Patients received zanubrutinib (320 mg QD or 160 mg BID) 8-12 weeks before starting sonrotoclax using a ramp-up schedule starting from 1 mg to the intended target dosage of 160 mg or 320 mg QD (doubling weekly [W] or 30% increase every day 5 d/week [D]) to mitigate risk of tumor lysis syndrome (TLS). Patients were treated until progression, unacceptable toxicity, or could elect to stop. TLS was assessed per Howard (2011) criteria; mitigation included mandatory oral hydration and antihyperuricemics. Primary endpoint was safety (reported per CTCAEs v5.0); a secondary endpoint was ORR (per iwCLL 2008 criteria) and minimal residual disease assessed in blood by ERIC flow every 24 weeks (uMRD4; <1 CLL cell per 10,000 leukocytes, or <0.01%) was an exploratory endpoint. Result(s): As of May 21, 2023, 94 patients with TN-CLL/SLL were enrolled (sonrotoclax 160 mg QD, n=41 [26 W, 15 D] and 320 mg QD, n=53 [25 W, 28 D]); 15 patients were still receiving zanubrutinib monotherapy and 79 started sonrotoclax (160 mg, n=32 [25 W, 7 D] and 320 mg, n=47 [24 W, 23 D]). Median follow-up was 8.5 mo (range: 0.6-18.2) for all patients; 160 mg, 12.1 mo (range: 0.6-18.2); 320 mg, 7.0 mo (range: 1.1-14.6). No deaths have occurred, and all patients remain on study. Treatment-emergent AEs (TEAEs) occurring in >=20% patients who received sonrotoclax plus zanubrutinib (n=79) are listed in theTable; TEAE frequencies were similar between the two sonrotoclax cohorts. Contusion, neutropenia, and low-grade gastrointestinal toxicity were the most common TEAEs; neutropenia was the most common grade >=3 TEAE (n=13 [17%]). No cases of clinical or laboratory TLS occurred in either ramp-up schedule; no patient experienced atrial fibrillation. One TEAE (cryptococcal meningitis at 11 weeks treated with azoles) led to treatment discontinuation. Sonrotoclax dose holds occurred in 17 patients (22%) for a median duration of 11 days (range: 3-37) and three patients (4%) had dose reduction. The most common TEAEs resulting in dose holds were COVID-19 (n=9 [11%]) and diarrhea (n=3 [4%]). A total of 56 patients had a response assessment. The ORR was 100% (CR: 160 mg, n=9 [36%]; 320 mg, n=6 [19%]). Across all doses, rate of CR increased with time; overall median time to CR was 10.1 mo (range: 5.4, 17.1). No progression was reported in either cohort (Figure). Week 24 blood uMRD4 rates were 50% (n=12/24) in 160 mg and 65% (n=13/20) in 320 mg patients. Week 48 blood uMRD4 rates were 73% in 160 mg (n=11/15) and 100% (n=1/1) in 320 mg; no patient has lost uMRD4. Conclusion(s): Sonrotoclax (160 mg and 320 mg) in combination with zanubrutinib was well tolerated in patients with TN CLL/SLL. Only one patient discontinued treatment and three patients had dosage reductions. No TLS was seen with either ramp-up schedule. Acknowledging the short follow up, efficacy is encouraging with 100% ORR in assessed patients and no PFS events. High rates of blood uMRD4 occurred early. Based on these data, a phase 3 study assessing this combination is planned.Copyright © 2023 The American Society of Hematology
Conference Name: 65th ASH Annual Meeting
Conference Start Date: 2023-12-09
Conference End Date: 2023-12-12
Conference Location: San Diego, United States
DOI: http://monash.idm.oclc.org/login?url=https://dx.doi.org/10.1182/blood-2023-179541
URI: https://repository.monashhealth.org/monashhealthjspui/handle/1/51202
Type: Conference Abstract
Subjects: atrial fibrillation
chronic lymphatic leukemia
contusion
coronavirus disease 2019
cryptococcal meningitis
diarrhea
gastrointestinal toxicity
neutropenia
small lymphocytic lymphoma
tumor lysis syndrome
Type of Clinical Study or Trial: Clinical trial
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