Safety and efficacy results of a phase 1 study of the novel BCL2 inhibitor sonrotoclax(BGB-11417) for relapsed/refractory Waldenström's macroglobulinemia
Authors: Chan Cheah,1-3 Constantine Tam,4,5 Ramón García Sanz,6 Mazyar Shadman,7Sophie Leitch,8 Christopher D'Angelo,9 Lydia Scarfo,10 Yiqian Fang,11 Sheel Patel,12 WeiDing,12 Haiyi Guo,13 Peter Browett,14Affiliations: 1Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine, Nedlands,WA, Australia; 2Medical School, University of Western Australia, Crawley, WA, Australia;
3Linear Clinical Research, Nedlands, WA, Australia; 4Alfred Hospital, Melbourne, VIC,Australia; 5Monash University, Clayton, VIC, Australia; 6Hospital Universitario de Salamanca,Salamanca, Spain; 7Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 8North
Shore Hospital, Auckland, New Zealand; 9University Of Nebraska Medical Center, Omaha,NE, USA; 10Università Vita Salute and IRCCS Ospedale San Raffaele, Milan, Italy; 11BeiGene(Beijing) Co, Ltd, Beijing, China; 12BeiGene USA, Inc, San Mateo, CA, USA; 13BeiGene(Shanghai) Co, Ltd, Shanghai, China; 14Department of Haematology, Auckland City Hospital,Grafton, Auckland, New Zealand
Background: BCL2, a key regulator of apoptosis, is overexpressed in many hematologic
malignancies, including Waldenström’s macroglobulinemia (WM), and plays a significant rolein cell survival. In previous studies, the BCL2 inhibitor venetoclax demonstrated antitumor
activity in patients with WM (Castillo 2022), but it is not approved for the treatment of thisdisease. Therefore, a need remains for development of BCL2 inhibitors for treatment ofpatients with WM whose disease progresses on standard treatments. Sonrotoclax (BGB11417), a novel BCL2 inhibitor, is more selective and a more pharmacologically potent
inhibitor of BCL2 than venetoclax. Sonrotoclax monotherapy is being studied in dose
escalation in the ongoing BGB-11417-101 (NCT04277637) study in B-cell malignancies.
Aims: To report updated safety and efficacy data for patients with relapsed/refractory (R/R)
WM treated with sonrotoclax in BGB-11417-101.
Methods: Patients with R/R WM (≥1 prior therapy) received sonrotoclax (planned dose
escalation: 80, 160, 320, or 640 mg QD) with a ramp-up schedule to the intended dose toEHA 2024

mitigate potential risk of tumor lysis syndrome (TLS). Patients were treated until progression
or unacceptable toxicity. The primary endpoint is safety reported per CTCAE v5.0 and thesecondary endpoint is ORR (minor response [MR] or better per Modified Owens 2013
criteria). TLS was assessed per Howard 2011 criteria.
Results: As of Oct 31, 2023, a total of 17 patients with R/R WM have been enrolled in 3
dose-escalation cohorts (80 mg, n=6; 160 mg, n=8; 320 mg, n=3); none were enrolled in the640–mg cohort as of the cutoff date). Overall, the median age (range) was 68 (48-87) years.
The median number of prior treatments (range) was 2 (1-9); 10 patients were previously
treated with a BTK inhibitor (1 noncovalent, 9 covalent) and 14 were previously treated with
anti-CD20. Median follow-up (range) was 10.6 (1-24) months. Six patients discontinued
treatment: 4 due to progressive disease (PD) and 2 due to adverse events (AEs; multifocal
neurological syndrome and COVID-19). Four patients died while on study: 2 due to PD, 1 due
to COVID-19 pneumonia, and 1 due to pneumonia. Treatment-emergent AEs (TEAEs) thatoccurred in ≥20% of patients who received sonrotoclax were anemia (n=6, 35%), COVID-19(n=6, 35%), pyrexia (n=5, 29%), neutropenia (n=4, 24%), and pruritus (n=4, 24%). Anemia
was the most common grade ≥3 TEAE (n=4; 24%). No DLTs or cases of TLS occurred up tothe highest dose tested (320 mg). No cases of atrial or ventricular fibrillation were reported.
No deaths or AEs leading to discontinuation of therapy were determined to be related to
study treatment by the investigator. All 17 patients were evaluable for response assessments.
The overall, major, and very good partial response (VGPR) rates were 76% (13/17), 41%(7/17), and 12% (2/17), respectively (Figure). Seven patients had a BTK inhibitor as their last
therapy and achieved an ORR of 70% (MR, n=2; PR, n=1; VGPR, n=2). For all patients in the320–mg cohort, the median follow-up (range) was 3.3 (1-5) months and the ORR was 100%(n=3), with 1 VGPR.
Summary/Conclusion: Sonrotoclax monotherapy was well tolerated in patients with R/RWM, and the preliminary antitumor activity is encouraging in this heavily pretreated R/R WM
population. Based on findings of this study, further evaluation of sonrotoclax monotherapy inpatients with R/R WM is ongoing in a potentially pivotal phase 2 study.
Figure. Treatment responses and duration
EHA 2024

EHA 2024