Preliminary safety and antileukemic activity of sonrotoclax (BGB-11417), a potent and selective BCL2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia.

Abstract

Introduction: Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, 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 pts with R/R AML from the ongoing phase 1b/2 BGB-11417-103 (NCT04771130; EudraCT: 2021-003285-12) study are presented. Method(s): Eligible pts had AML, myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm. Prior HMA, but not prior BCL2 inhibitor, were allowed. In cycle 1, a 4-day sonrotoclax ramp-up began at 1/8 of the target dose. DLTs were assessed up to day 28 for nonhematologic toxicities and day 42 or cycle 2 initiation for hematologic toxicities. The primary endpoint was safety per CTCAE v5.0. Response was assessed per European Leukemia Net (ELN) 2017 criteria. Result(s): As of 25Sep2023, 39 pts with R/R AML (HMA failure, 13%) were enrolled across 7 dose cohorts (Table). Pts had a median of 1 (range, 1-4) prior treatment and 59% had adverse-risk AML per ELN 2017 criteria. Ten remain on treatment. At a median follow-up of 6.3 months, 1 pt had a DLT (grade 4 thrombocytopenia; 320 mg x 14 days). All pts had >=1 TEAE. The most common grade >=3 nonhematologic TEAEs were vomiting, hypokalemia, and hypotension (all 8%); common grade >=3 hematologic TEAEs were neutropenia (49%), anemia (36%), febrile neutropenia (36%), and thrombocytopenia (33%). Grade >=3 infections occurred in 46% of pts. TEAEs led to sonrotoclax dose reduction in 6 pts (15%). The most common TEAE class leading to sonrotoclax discontinuation was infection (5%). No TLS occurred. In 36 efficacy-evaluable pts, CR and CR/CRh rates were 28% and 47%, respectively. Median time to CR and CR/CRh was 2.8 and 1.5 months, respectively. Median duration of CR and CR/CRh was 13.1 months. Eight pts (21%) proceeded to allogeneic stem cell transplant. Preliminary median OS was 11.8 (95% CI, 7.4-NE) months. Conclusion(s): In this dose-escalation trial, sonrotoclax + AZA was generally well tolerated and demonstrated promising antileukemic activity in pts with R/R AML, including in the lowest-dose cohort. Further evaluation in pts with R/R AML is ongoing.