Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD-positive AML

Abstract

Mutations in FMS-related receptor tyrosine kinase 3 (FLT3) are among the most common alterations in acute myeloid leukemia (AML), present in ≈30% of newly diagnosed AML cases. Internal tandem duplications (ITD) in FLT3 (FLT3-ITD) occur in ≈25% of newly diagnosed AML cases and are associated with unfavorable outcomes. Quizartinib (formerly AC220) is a novel, second-generation, highly potent, and selective type II FLT3 inhibitor. Quizartinib is approved in Japan as monotherapy for the treatment of adult patients with FLT3-ITD-positive relapsed/refractory (R/R) AML. Quizartinib is also approved in the United States, Japan, Europe, and United Kingdom in combination with chemotherapy during induction and consolidation, and as maintenance monotherapy (but, in the United States, not after allogeneic hematopoietic cell transplantation [allo-HCT]), for the treatment of adult patients with newly diagnosed FLT3-ITD-positive AML. In this review, we summarize preclinical studies that established quizartinib as a potent and selective type II FLT3 inhibitor as well as early and pivotal phase 3 clinical studies (QuANTUM-R and QuANTUM-First) that led to the approvals of quizartinib. We also summarize mechanisms of resistance to quizartinib along with its safety profile. Furthermore, we review the ongoing post hoc analyses of the QuANTUM-First data elucidating the impact of allo-HCT, the presence of measurable residual disease, and number and length of ITD on the clinical outcomes of quizartinib. We also describe the impact of quizartinib on patient-reported outcomes. Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD-positive AML, patients with FLT3-ITD-negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD-negative AML.

Keywords: FLT3-ITD; AML; QuANTUM-First; QuANTUM-R; Quizartinib.