AUTHORS
Guru Subramanian Guru Murthy, MD, Jake Shortt, MBBS, FRACP, FRCPA, PhD2, Chun Fong I, MD, PhD3, Sophie Leitch4, Shuh Ying Tan, MBBS, FRACP, FRCPA5, Xiaojun Huang, MD,PhD6, Emma Searle, MD, PhD7, Pau Montesinos, MD8, Madlen Jentzsch, MD9, Uwe Platzbecker, MD10, Courtney DiNardo, MD, MSCE11, Thomas Cluzeau, MD, PhD12, Roberto Cairoli, MD13, Jun Ho Jang, MD, PhD14, Zaixing Shi15, Gabriel Man16, Rui Li17, Vaibhav Mundra18, Wai Chan19, Wei Ding20, Jun Wu, MSc, MB21, Andrew H. Wei, MBBS, PhD22
AFFILIATIONS
1 Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Monash Health, Melbourne, Victoria, Australia
3 Austin Health, Melbourne, Victoria, Australia
4 North Shore Hospital, Auckland, New Zealand
5 St. Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
6 Peking University People's Hospital, Beijing, China
7 The Christie NHS Foundation Trust & University of Manchester, Manchester, United Kingdom
8 Hospital Universitari i Politècnic La Fe, Valencia, Spain
9 Universitätsklinikum Leipzig AöR, Leipzig, Germany
10 University Hospital Carl Gustav Carus, Dresden, Germany
11 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
12 Hôpital l'Archet, Centre Hospitalier Universitaire de Nice, Nice, France
13 Niguarda Cancer Center, Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
14 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Rep. of South
15 Beone Medicines Co, Ltd, Shanghai, China
16 Beone Medicines Co, Ltd, Shanghai, China
17 Beone Medicines Co, Ltd, Shanghai, China
18 Beone Medicines Co, Ltd, Shanghai, China
19 Beone Medicines Co, Ltd, Shanghai, China
20 Beone Medicines Co, Ltd, Shanghai, China
21 Beone Medicines Co, Ltd, Shanghai, China
22 Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia
ABSTRACT
Introduction: The European LeukemiaNet (ELN) 2024 is a genomic risk stratification framework for treatment-naïve (TN) acute myeloid leukemia (AML) treated with lower-intensity hypomethylating agent (HMA)-based therapies. Sonrotoclax is a next-generation BCL2 inhibitor designed to have high target selectivity, enhanced pharmacologic potency, and an optimized pharmacokinetic profile characterized by a shorter half-life and minimal drug accumulation. These properties may enable deeper target inhibition while mitigating toxicity. In an ongoing phase 1b/2 trial (BGB-11417-103; NCT04771130), the safety and efficacy of sonrotoclax plus azacitidine were evaluated across ELN 2024 risk groups in TN AML unfit for intensive therapy.
Methods: Patients with TN AML were defined as unfit if aged ≥65 years or had ≥1 protocol-defined comorbidity. Sonrotoclax once daily was evaluated across target doses of 40-320 mg and durations of 10-28 days in combination with azacitidine 75 mg/m2 for 7 days in 28-day cycles. In cycle 1, a 4-day sonrotoclax ramp-up began at 1/8th the target dose. DLTs were assessed through day 28 for nonhematologic events and through day 42 or cycle 2 initiation for hematologic events. TEAEs were classified per MedDRA v29.0 and graded per CTCAE v5.0. Antileukemic activity was assessed per ELN 2017 criteria. MRD was assessed by flow cytometry, with MRD negativity defined as <10-3 leukemic cells. Post-hoc ELN 2024 risk stratification was performed based on centrally available mutation data.
Results: As of May 1, 2026, 95 patients with TN unfit AML (74% de novo; 26% secondary) were treated. Median age was 73 (range, 59-91) years; 98% were aged ≥65 years. Among patients with secondary AML (n=25), 6 had received prior HMA for MDS; 2 had prior SCT. At a median follow-up of 11.5 (range, 0.3-59.0) months, 88% of patients discontinued treatment, and 12% remained on therapy. The most common reasons for discontinuation were leukemia relapse (28%), followed by investigator decision (21%) and AEs (13%). Five (5%) patients proceeded to allogeneic SCT. Across cohorts, 6 DLTs occurred in 5 patients due to grade 4 neutropenia (n=2) and grade 4 thrombocytopenia (n=4). No cohort met the prespecified safety stopping criteria. Ninety-four (99%) patients experienced at least 1 grade ≥3 TEAE. The most common (≥20%) grade ≥3 TEAEs were neutropenia (46%), febrile neutropenia (43%), neutrophil count decreased (42%), anemia (39%), thrombocytopenia (38%), platelet count decreased (34%), and pneumonia (20%). Grade 5 TEAEs occurred in 12% of patients, most frequently due to infections and infestations (6%). Tumor lysis syndrome occurred in 4 patients (2 clinical); all resolved in ≤4 days without sequelae. Fifty-two (55%) patients achieved complete remission (CR), with 87% of these achieving CR by the end of cycle 4. The CR/CR with incomplete hematologic recovery (CRi) rate was 68%. Median times to CR and CR/CRi were 1.9 and 1.3 months. Among 63 patients with mutation data, 33 (52%), 20 (32%), and 10 (16%) had ELN 2024 favorable-, intermediate-, and adverse-risk disease, respectively. Mutations included IDH1/2 (n=15), NPM1 (n=12), FLT3-ITD (n=7), DDX41 (n=3), NRAS (n=13), KRAS (n=6), TP53 (n=10), and MDS-related gene mutations (n=42). CR and CR/CRi rates were 67% and 82% in the ELN 2024 favorable-risk group, 55% and 70% in the intermediate-risk group, and 40% and 60% in the adverse-risk group. Median follow-up for patients with mutation data was 12.6 (range, 0.3-56.7) months. Among patients achieving CR, median duration of response was 21.2 (95% CI, 7.5-NE), 6.9 (95% CI, 2.4-8.7), and 12.8 (95% CI, 6.3-NE) months in the favorable-, intermediate-, and adverse-risk groups, respectively. By the end of cycle 7, MRD negativity (<10-3) among CR patients was 46-50% across risk groups. Follow-up for survival is ongoing. Preliminary exposure-response analyses indicated higher response rates at sonrotoclax doses ≥160 mg. Among patients in the pooled sonrotoclax 160/320-mg, 14-day dosing cohorts, CR and CR/CRi rates were 57% and 93% (8/14; 13/14), 63% and 63% (5/8 for both), and 50% and 50% (2/4 for both) in the ELN 2024 favorable-, intermediate-, and adverse-risk groups, respectively.
Conclusion: Sonrotoclax plus azacitidine was tolerable and demonstrated promising efficacy in TN unfit AML, with favorable CR rates across all ELN 2024 risk groups. These findings further support the broad clinical activity of sonrotoclax across hematologic malignancies.
DISCLOSURES
Guru Subramanian Guru Murthy, MD: Amgen, Beone, Astra Zeneca, Daiichi Sankyo, Syndax, Geron, BMS, Caribou Biosciences - Honoraria; Amgen, Stemline - Honoraria; BeOne, Daiichi, Merck, Schrodinger, Oryzon, Astra Zeneca, Xencor, Kura - Research Funding; Amgen, Stemline - Consultancy (Includes expert testimony)