Preliminary safety and antileukemic activity of sonrotoclax (BGB-11417), a potent and selective BLCl2 inhibitor, in treatment-naive patients with acute myeloid leukemia.

Abstract

Introduction: Sonrotoclax (BGB-11417) is a more selective and pharmacologically potent inhibitor of BCL2 vs venetoclax in biochemical assays. Preliminary safety and antileukemic activity of sonrotoclax + azacitidine (AZA) in patients (pts) with newly diagnosed AML in the ongoing phase 1b/2 BGB-11417-103 (NCT04771130; EudraCT: 2021-003285- 12) study are presented. Method(s): Eligible pts had TN AML and were unfit for intensive chemotherapy (aged >=65 years or with comorbidities). In cycle 1, a 4-day sonrotoclax ramp-up began at one-eighth of the target dose. DLTs were assessed up to day 28 for nonhematologic toxicities and day 42 or cycle 2 initiation for hematologic toxicities. TEAEs were graded per CTCAE v5.0. Response was assessed per European Leukemia Net 2017 criteria. Result(s): As of 25Sept2023, 42 pts were treated across dose escalation and expansion cohorts (Table) and were included in efficacy analyses; 16 (38%) remain on treatment. Median age was 75 years, and median follow-up was 9.6 mo. All pts had >=1 TEAE. The most common grade >=3 nonhematologic TEAEs were pneumonia (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 (sonrotoclax, n=4; AZA, n=9). The most common TEAE class leading to sonrotoclax discontinuation was infection (n=5). No deaths due to treatment-related TEAEs or clinical TLS occurred; 1 pt had laboratory TLS (160 mg x 10 days, cycle 2; resolved in 4 days). The mortality rate within 30 days was 2% (1 pt). CR and CR/CRh rates were 50% and 62%, respectively; median time to response was 1.7 and 1.3 mo, respectively, and median duration of response was 18.8 mo for both. Preliminary median OS was 20.6 mo (95% CI, 9.5-NE), with 64% OS at 12 mo. Conclusion(s): In this dose escalation and expansion study, sonrotoclax + AZA was generally well tolerated, with promising antileukemic activity in TN unfit AML pts, including in the lowest-dose cohort. Dose escalation is ongoing, and the recommended phase 2 dose is being determined.