Molecular Characterization of Clinical Response in Relapsed/Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Patients Treated with Single Agent Emavusertib

Introduction Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are myeloid malignancies that exhibit a dynamic mutational landscape as the disease progresses. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of interleukin-1 receptor-associated kinase 4 (IRAK4), which is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Splicing factor mutations are frequently reported in AML and MDS and have been associated with disease progression and poor prognosis in relapsed/refractory (R/R) diseases. Emavusertib is a potent oral inhibitor of IRAK4 as well as Fms-like tyrosine kinase 3 (FLT3). The safety, clinical activity, and potential biomarkers of emavusertib in AML or high-risk MDS (HR-MDS) are investigated in the ongoing open-label, phase 1/2a TakeAim Leukemia trial (NCT04278768). Methods Eligible patients with R/R AML or HR-MDS were enrolled and treated with emavusertib. The exploratory objectives of the study are to assess the association between clinical activity and target-related biomarkers, gene expression signatures, and molecular subtypes. Bone marrow or peripheral blood were collected at the baseline and on treatment. To characterize the mutational profiles of enrolled patients and further define the targeted population, targeted next generation sequencing (NGS) of 68 genes was performed on genomic DNA from bone marrow or peripheral blood mononuclear cells. A minimum coverage of 100x, variant allele frequency (VAF) of >1%, and a VARSCAN-assigned variant p<0.001 were used as thresholds for single nucleotide variants (SNV) calling and presumed somatic driver mutations were identified as previously reported (Metzeler et al. Blood 2016). Mutations from patients’ molecular pathology reports were also documented. Results As of December 16, 2021, 49 patients have been treated with emavusertib monotherapy at one of dose levels of 200, 300, 400, or 500 mg BID, including 30 R/R AML and 19 R/R HR-MDS. The median number of prior anti-cancer therapies was 2 (range 1-5). This abstract is intended to add additional molecular findings to the patient subset presented in 2022 ASCO, of which 6 AML and 7 HR-MDS had splicing factor SF3B1 or U2AF1 mutations and 3 AML had FLT3 mutations, including 2 AML with both splicing factor and FLT3 mutations (hereafter referred to as "targeted mutations"). In the patients with targeted mutations, with available mutational profile data or molecular reports from sites, there were 6 responders: 1 CR, 1 CRh, and 4 mCR. In this responder population, the most common co-mutation was ASXL1. During emavusertib treatment, FLT3-mutated clones became undetectable in 2 of 3 (67%) FLT3-mutated AML patients. One of the 3 patients (33%) with a FLT3 mutation achieved CR and the remaining 2 patients achieved SD (1 with > 90% blast reduction). Additional gene mutations, such as ASXL1, RUNX1, CEBPA, ETNK1, ETV6, and SRSF2, became undetectable during emavusertib treatment. New mutations that emerged after ≥ 1 cycle of emavusertib treatment include NRAS, SETBP1, RUNX1, WT1, STAG2, KRAS, CCND2, DNMT3A, ASXL1, and NOTCH1. Analysis of genomic and transcriptomic profiles will be updated. Conclusion Emavusertib demonstrated anti-cancer activity in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1, SF3B1, or FLT3 mutations. Our preliminary NGS data is suggestive of molecular responses and disease-modifying activity of emavusertib. Patients with targeted mutations responded to emavusertib, even in the presence of co-mutations of ASXL1 that are typically associated with poor prognosis. We will continue to explore potential genomic biomarkers of emavusertib sensitivity and resistance