FLX-925

Several FLT3 inhibitors(i) are available to treat relapsed/refractory (R/R) FLT3‐internal tandem duplicated acute myeloid leukemia (AML). This study analyzes the efficacies of various FLT3i (types 1 and 2) tested in clinical trials in treating R/R AML and high‐risk myelodysplastic syndromes (HR‐MDS). PubMed and EMBASE databases were searched for single/double‐arm phase I/II/III R/R AML or HR‐MDS clinical trials published between 1/1/2000 and 6/1/2021. The outcomes studied were composite response rate (CRc) and overall response rate (ORR). Toxicities were compared based on the organ system. The 28 studies analyzed had 1927 patients. The pooled ORR and (CRc) for all FLT3i were 53% (95% CI, 43%–63%) and 34% (95% CI, 26%–44%). Pooled ORR and CRc were 37% (95% CI, 25%–51%) and 35% (95% CI, 21%–52%) for type 1 and 58% (95% CI, 43%–71%) and 38% (95% CI, 27%–50%) for type 2, respectively. Gastrointestinal (GI) and hematological toxicity occurred in 22% (95% CI, 19%–25.4%) and 74.6% (95% CI, 70%–79%) with type 1 and 13.9% (95% CI, 12%–16%) and 57.7% (95% CI, 54.6%–60.8%) with type 2 FLT3i. QTc prolongation occurred in 2.06% (95% CI, 1.03%–3.65%) with type 1 and 7% (95% CI, 5.3%–9%) with type 2 FLT3i. Type 2 FLT3i had less GI toxicity but more QTc prolongation. Prospective studies are needed to compare the efficacy of type 1 and 2 FLT3i.

FLT3 mutations, which are found in a third of patients with acute myeloid leukemia (AML), are associated with poor prognosis. Responses to currently available FLT3 inhibitors in AML patients are typically transient and followed by disease recurrence. Thus, FLT3 inhibitors with new inhibitory mechanisms are needed to improve therapeutic outcomes. AMG925 is a novel, potent, small-molecule dual inhibitor of FLT3 and CDK4/6. In this study. we determined the antileukemic effects and mechanisms of action of AMG925 in AML cell lines and primary samples, in particular AML stem/progenitor cells. AMG925 inhibited cell growth and promoted apoptosis in AML cells with or without FLT3 mutations. Reverse-phase protein array profiling confirmed its on-target effects on FLT3-CDK4/6-regulated pathways and identified unrevealed signaling network alterations in AML blasts and stem/progenitor cells in response to AMG925. Mass cytometry identified pathways that may confer resistance to AMG925 in phenotypically defined AML stem/progenitor cells and demonstrated that combined blockade of FLT3-CDK4/6 and AKT/mTOR signaling facilitated stem cell death. Our findings provide a rationale for the mechanism-based inhibition of FLT3-CDK4/6 and for combinatorial approaches to improve the efficacy of FLT3 inhibition in both FLT3 wild-type and FLT3-mutated AML.