FLT3 Inhibitor Quizartinib Shows Activity in Relapsed/Refractory AML
Internal tandem duplications (ITDs) in the FMS-like tyrosine kinase 3 (FLT3) juxtamembrane region are observed in 20% to 30% of patients with acute myeloid leukemia (AML), and point mutations in the FLT3 activation loop are observed in 5% to 10%. FLT3-ITD mutations are associated with early relapse and poor survival. The investigational agent quizartinib is a potent and selective inhibitor of FLT3 kinase activity in preclinical AML models. In a phase I study reported in the Journal of Clinical Oncology, Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center, and colleagues found that quizartinib exhibited clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and was associated with an acceptable toxicity profile.
Study Details
In the study, 76 patients with relapsed/refractory AML were given oral quizartinib at escalating doses of 12 to 450 mg/d. Patients had a median age of 60 years (range, 23–86 years) and had received a median of 3 prior therapies (range, 0–12). FLT3-ITD was present in 17 patients and absent in 37 patients; 22 patients had indeterminate status or were not tested.
Response Rates by FLT3-ITD Status
Overall, responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions of any type. Response was observed in 9 (53%) of 17 FLT3-ITD–positive patients, including 1 complete remission, 1 complete remission with incomplete platelet recovery, 2 complete remissions with incomplete hematologic recovery, and 5 partial responses. Of 37 FLT3-ITD–negative patients, 5 (14%) had responses, including 2 with complete remission with incomplete platelet recovery and 3 with partial responses. Of 22 with FLT3-ITD-indeterminate/not tested status, 9 (41%) had responses, including 1 with complete remission, 3 with complete remissions with incomplete hematologic recovery, and 5 with partial responses. Median duration of response was 13.3 weeks, and median survival was 14.0 weeks. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay.
Safety Profile
The most common drug-related adverse events were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%), with most adverse events being ≤ grade 2. The maximum tolerated dose was 200 mg/d, and the dose-limiting toxicity was grade 3 QT prolongation.
The investigators concluded: “The encouraging efficacy results in both FLT3-ITD–positive and FLT3-ITD–negative patients and an acceptable safety profile in this high-risk population support continued clinical evaluation of quizartinib…. Additional phase II studies are being conducted in both FLT3-ITD–positive and FLT3-ITD–negative AML to confirm clinical efficacy and examine lower doses to reduce the incidence of QT prolongation and determine the optimal dose.”
The study was supported by Ambit Biosciences Corporation, the National Cancer Institute, and the American Society of Clinical Oncology.
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