Quizartinib has activity and is well tolerated in patients with relapsed or refractory AML.

  • Major finding: Quizartinib has activity and is well tolerated in patients with relapsed or refractory AML.

  • Clinical relevance: Quizartinib exhibits a long half-life and induces prolonged FLT3 suppression at low doses.

  • Impact: Quizartinib yields a high response rate, particularly in patients expressing FLT3-ITD mutations.

Acute myeloid leukemia (AML) is frequently characterized by activating mutations in fms-related tyrosine kinase 3 (FLT3), including point mutations and internal tandem duplications (ITD), that promote constitutive activity of the FLT3 receptor tyrosine kinase (RTK) and increased cell proliferation and survival. Quizartinib is a FLT3 inhibitor that targets both wild-type FLT3 and FLT3-ITD mutants with enhanced selectivity compared with other RTKs and has shown activity in preclinical models of AML. Cortes and colleagues performed an open-label, dose-escalation, first-in-human phase I trial to evaluate the safety and efficacy of quizartinib in 76 patients with relapsed or refractory AML, most of whom had received three or more prior chemotherapy treatments. Quizartinib was well tolerated, as most treatment-related toxicities were low grade and manageable with discontinuation or dose reduction; the most common grade 3 adverse events included anemia, fatigue, and prolonged electrocardiogram QT interval, and only two grade 4 events were reported. In addition, quizartinib and its active metabolite AC886 exhibited a favorable pharmacokinetic profile with a long plasma half-life, resulting in complete and prolonged inhibition of FLT3 phosphorylation ex vivo at doses below the maximum-tolerated dose. Furthermore, quizartinib treatment induced rapid clinical responses in 23 (30%) patients, including complete or partial remissions in 9 (53%) of 17 patients harboring FLT3-ITD mutations, 5 (14%) of 37 patients lacking FLT3-ITD, and 9 (41%) of 22 patients in whom FLT3-ITD status was indeterminate; the median overall survival was 14 weeks, and the median response duration was 13 weeks. These results suggest that single-agent quizartinib has potent activity in heavily pretreated patients with AML, particularly those expressing FLT3-ITD, and support additional clinical testing of this FLT3 inhibitor for the treatment of relapsed and refractory AML.

Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3–internal tandem duplication status. J Clin Oncol 2013 Sep 3 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013