Combination treatment with novel BCL-2 inhibitor sonrotoclax (BGB-11417) andzanubrutinib induces high rate of complete remission for patients withrelapsed/refractory (R/R) mantle cell lymphoma (MCL)
Authors: Constantine Tam,1,2 Stephen Opat,3 Marc Hoffmann,4 Jacob Soumerai,5 MasaLasica,6 Narendranath Epperla,7 Jing-Zhou Hou,8 Ramón García Sanz,9 Johannes
Schetelig,10 Robert Weinkove,11,12 Yiqian Fang,13 Sheel Patel,14 Wei Ding,14 Haiyi Guo,15Raul Cordoba16
Affiliations: 1Alfred Hospital, Melbourne, VIC, Australia; 2Monash University, Clayton, VIC,Australia; 3Lymphoma Research Group, School of Clinical Sciences at Monash Health,Monash University, Clayton, VIC, Australia; 4University of Kansas Medical Center, Fairway,KS, USA; 5Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston,MA, USA; 6St Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia; 7The James Cancer
Hospital And Solove Research Institute At Ohio State University, Columbus, OH, USA; 8
University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 9Hospital Universitario deSalamanca, Salamanca, Spain; 10Universitätsklinikum Carl Gustav Carus, TU Dresden,Dresden, Germany; 11Te Rerenga Ora Blood and Cancer Centre, Te Whatu Ora Health New
Zealand Capital Coast & Hutt Valley, Wellington, New Zealand; 12Cancer Immunotherapy
Programme, Malaghan Institute of Medical Research, Wellington, New Zealand; 13BeiGene(Beijing) Co, Ltd, Beijing, China; 14BeiGene USA, Inc, San Mateo, CA, USA; 15BeiGene(Shanghai) Co, Ltd, Shanghai, China; 16Hospital Universitario Fundación Jiménez Díaz,Madrid, Spain
Background: MCL is an aggressive and rare B-cell NHL subtype. Despite advanced
treatment, most patients experience R/R disease and require novel therapies to improve
clinical outcomes. The combination of BCL2 and Bruton tyrosine kinase (BTK) inhibition withvenetoclax + ibrutinib has shown efficacy in patients with R/R MCL. Sonrotoclax (BGB11417), a next-generation BCL2 inhibitor, is more selective and a more pharmacologicallypotent inhibitor of BCL2 than venetoclax. Zanubrutinib, a next-generation BTK inhibitor, has
shown improved PFS and OS and is approved for R/R MCL.
Aims: To report safety and efficacy data for patients with R/R MCL treated with sonrotoclax +zanubrutinib in the ongoing BGB-11417-101 (NCT04277637) study.
EHA 2024

Methods: Patients with R/R MCL (≥1 prior therapy) received zanubrutinib (standard dose:320 mg QD or 160 mg BID) 8-12 weeks before starting sonrotoclax in a dose escalation
cohort (target sonrotoclax doses: 80, 160, 320, or 640 mg QD) according to a ramp-up
schedule designed to mitigate potential risk of tumor lysis syndrome (TLS). This was followedby 2 sonrotoclax expansion cohorts at 160 mg and 320 mg. Patients were treated untilprogression or unacceptable toxicity. The primary endpoint was safety (treatment-emergent
adverse events [TEAEs] reported per CTCAEs v5.0), and a secondary endpoint was ORR(per Lugano 2014 criteria). TLS was assessed per Howard 2011 criteria.
Results: As of Oct 31, 2023, 35 patients with R/R MCL were enrolled across different cohorts(80 mg, n=6; 160 mg, n=12; 320 mg, n=14; 640 mg, n=3). The median age (range) was 68years (45-85 years), and 23 patients (66%) were men. The median number of priortreatments (range) was 1 (1-3), 11/35 (31%) patients had a prior autologous stem celltransplant, and 3 patients were previously treated with a BTK inhibitor. Dose escalation
occurred per protocol at all defined doses. The maximum tolerated dose was not reachedwith a maximum assessed dose of 640 mg. No DLTs occurred and the sonrotoclax 160 mg
and 320 mg dose levels were chosen for expansion cohorts. Three patients were still in thezanubrutinib lead-in phase and 29 had started sonrotoclax. Nine patients discontinued fromstudy treatment. Six patients discontinued both study drugs (progressive disease [PD], n=3;
AE, n=2 [MDS and diarrhea]; patient withdrawal, n=1). Three patients did not complete thezanubrutinib lead-in phase due to early progression (PD). Five patients died due to PD(including 3 during zanubrutinib lead-in). TEAEs occurring in ≥20% patients who received
sonrotoclax + zanubrutinib were neutropenia (31%), contusion (29%), thrombocytopenia(23%), and diarrhea (23%). Neutropenia was the most common grade ≥3 TEAE (20%). No
cases of laboratory or clinical TLS occurred and no cases of atrial or ventricular fibrillation
were reported. For 27 response-evaluable patients, the ORR was 85%, which included 18
complete responses (CRs; 67%). For response-evaluable patients in dose-expansion
cohorts, the CR rate and ORR, respectively, was 91% (10/11) and 91% (10/11) in the 320 mg
cohort, and 44% (4/9) and 88% (8/9) in 160 mg cohort (Figure). The median time to CR was6.4 months. Among 2 response-evaluable patients with previous progression on a BTK
inhibitor, 1 CR and 1 PD was observed.

EHA 2024

Summary/Conclusion: Sonrotoclax in combination with zanubrutinib is generally welltolerated and has demonstrated promising efficacy in R/R MCL, including deep and durable
responses. Further expansion of the 320 mg cohort is currently ongoing.
Figure. Best overall response by dose level

EHA 2024