Preliminary Safety and Antileukemic Activity of Sonrotoclax (BGB-11417), a Potent andSelective BCL2 Inhibitor, in Treatment-Naive Patients with Acute Myeloid LeukemiaAuthors: Jake Shortt,1 Shuh Ying Tan,2 Sophie Leitch,3 James Mao-Chun Liang,4 Chun Yew
Fong,5 Sundra Ramanathan,6 Qiubai Li,7 Pau Montesinos,8 Courtney DiNardo,9 Jinhua Zhong,10Wai Y. Chan,11 Rui Li,10 Oleg Zernovak,11 Amit Agarwal,11 Andrew H. Wei12Affiliations: 1Monash Health and Monash University, Clayton, VIC, Australia; 2St Vincent's
Hospital, Melbourne, VIC, Australia; 3North Shore Hospital, Auckland, New Zealand;
Middlemore Hospital, Auckland, New Zealand; 5Austin Health, Melbourne, Australia; 6St George

4Hospital, Kogarah, NSW, Australia; 7Union Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, China; 8Hospital Universitari I Politecnic La Fe,Valencia, Spain; 9MD Anderson Cancer Center, Houston, TX, USA; 10BeiGene (Shanghai) Co.,
Ltd., Shanghai, China; 11BeiGene USA, Inc, San Mateo, CA, USA; 12Peter MacCallum Cancer
Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia
Background: B-cell lymphoma 2 (BCL2), a key regulator of apoptosis, is overexpressed inmany hematologic malignancies. The BCL2 inhibitor venetoclax + azacitidine (AZA) has
improved outcomes for treatment-naive (TN) patients (pts) with newly diagnosed acute myeloid
leukemia (AML) unfit for intensive chemotherapy (TN unfit AML), with median overall survival(OS) of 14.7 months and complete remission in 36.7%. However, primary or secondary
resistance is common, and long-term survival is suboptimal. Sonrotoclax (BGB-11417), a nextgeneration BCL2 inhibitor, is a selective and pharmacologically potent inhibitor of BCL2. Inongoing phase 1 studies, sonrotoclax has been well tolerated with preliminary antitumor activity
in B-cell malignancies, AML/myelodysplastic syndrome (MDS), and multiple myeloma.
Aims: To present preliminary safety and antileukemic activity of sonrotoclax + AZA in TN unfit
AML pts in BGB-11417-103 (NCT04771130; EudraCT: 2021-003285-12).
Methods: BGB-11417-103 is an ongoing, phase 1b/2, global, multicenter, dose finding andexpansion study evaluating sonrotoclax + AZA in pts with AML (TN unfit [≥65 years old or withcomorbidities] or relapsed/refractory [R/R]), MDS, or MDS/myeloproliferative neoplasm. AmongTN unfit AML pts, dose cohorts were evaluated to explore sonrotoclax 40 mg x 10 days, 80 mgx 10 days, 160 mg x 10 days, 160 mg x 28 days, 320 mg x 21 days, or 320 mg x 14 days + AZA

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(75 mg/m2 x 7 days). For cycle 1, a 4-day sonrotoclax ramp-up was incorporated starting at oneeighth the target dose. Dose-limiting toxicities (DLTs) were assessed up to day 28 for
nonhematologic toxicities and day 42 for hematologic toxicities (unless cycle 2 was initiated).
Treatment-emergent adverse events (TEAEs) were graded per CTCAE v5.0. Response
assessment was conducted per European Leukemia Net 2017 criteria.

Results: As of September 25, 2023, 42 enrolled TN pts with AML received study drug acrossdose escalation and expansion cohorts and were included in efficacy analyses; 16 (38%)
remain on treatment. Median age was 75 years and median follow-up was 9.6 months (Table bycohort). All pts had ≥1 TEAE. The most common grade ≥3 nonhematologic TEAEs werepneumonia (17%) and hypokalemia (14%); common grade ≥3 hematologic TEAEs were
neutropenia (64%), thrombocytopenia (48%), febrile neutropenia (48%), and anemia (43%).
Grade ≥3 infections occurred in 52% of pts. The most common TEAE leading to dose reduction
was neutropenia (n=4, sonrotoclax reduction; n=9, AZA reduction). The most common TEAE
class leading to sonrotoclax discontinuation was infection (n=5). No deaths due to treatmentrelated TEAEs or clinical tumor lysis syndrome (TLS) occurred; 1 pt had laboratory TLS (160 mgx 10 days, cycle 2, hyperuricemia and hyperphosphatemia, resolved in 4 days). Mortality rate
within 30 days was 2% (1 pt). CR and CR/CRh rates were 50% and 62%, with median time toresponse of 1.7 and 1.3 months, respectively; median duration of response for both was 18.8months. Preliminary median OS was 20.6 (95% CI, 9.5-NE) months, with 64% OS at 12 months.

Summary/Conclusion: In this phase 1b/2 dose escalation and expansion study, sonrotoclax +AZA was generally well tolerated with promising antileukemic activity in TN unfit AML pts.
Efficacy was seen starting at the lowest dose cohort. The study is ongoing in escalation, and therecommended phase 2 dose is still being determined.

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