Preliminary pharmacokinetic and MRD results from AML patients treated with 7- and 14-day dosing schedule of emavusertib added to combination therapy with azacitidine and venetoclax

Abstract

Abstract Background Emavusertib, an oral IRAK4 and FLT3 inhibitor, is being tested in a Phase 1, single-arm, open-label, multi-center clinical study (EUCT No. 2023-505828-58) in combination with azacitidine and venetoclax for the treatment of acute myeloid leukemia (AML) patients who are in complete response (CR) but still measurable residual disease positive (MRD+) after no more than 6 courses of azacitidine and venetoclax. Optimizing dosing schedules in combination therapy to balance efficacy and tolerability is a critical objective. This study evaluates pharmacokinetic (PK) and MRD outcomes in AML CR MRD+ patients receiving emavusertib on 7-day versus 14-day dosing schedules in combination with azacitidine and venetoclax. Methods In this prospective cohort study, AML patients who were in CR MRD+ during azacitidine and venetoclax treatment were assigned to additionally receive emavusertib for either 7 or 14 consecutive days in a 28-day cycle. Patients remained on their current doses of azacitidine and venetoclax where they achieved a CR. Serial blood samples were collected for PK analysis (C1D4), and bone marrow aspirates were obtained at baseline and on-treatment for MRD assessment (C3D1) using multiparameter flow cytometry (central lab) and next-generation sequencing (central lab). Here we report preliminary data on emavusertib PK parameters and MRD analysis. Results As of 2 July 2025, 4 patients were enrolled in a 7 of 28-day dosing schedule, and 6 patients were enrolled in a 14 of 28-day dosing schedule. The median age was 71 (67, 81) with 40% being male. The European LeukemiaNet risk stratification was 2 adverse, 5 intermediate, and 3 favorable. The median baseline white blood cells (GI/L) was 4.0 (1.4, 10.3). Preliminary PK data indicate that the mean AUC0-8 was 32798 h*ng/mL, and the mean Cmax was 5087 ng/mL, which were both consistent with previously reported PK values across the emavusertib program. MRD conversion (positive to undetectable) was observed in 4 of 8 patients (50%). Of the 4 patients with undetectable MRD, 3 received the 14-day emavusertib dose. The MRD conversions occurred between 5 and 8 weeks post the addition of emavusertib. Of the 4 patients who remained MRD+, 1 patient achieved a 40% reduction from baseline in MRD. No patients who remained MRD+ by central lab testing progressed on study. Two dose-limiting toxicities (CPK increase and neutropenia) were observed in the 14-day dosing, and both resolved; additional dosing regimens will be explored. Conclusion The addition of emavusertib to azacitidine and venetoclax may induce/contribute to MRD clearance in AML patients. Optimization of dosing regimens in triplet combination continue to be investigated. These initial findings support further investigation of the addition of emavusertib to this regimen in order to improve patient outcomes in a hard-to-treat population.