The FLT3 Inhibitor Gilteritinib Has Activity in Patients with AML

Internal tandem duplications in FLT3 occur frequently in patients with acute myeloid leukemia (AML) and are associated with aggressive disease, rapid relapse, and poor overall survival. FLT3 inhibitors have had limited success, but rapid resistance generally develops, often due to FLT3^D835 mutations. Gilteritinib is an oral FLT3 inhibitor that has demonstrated activity against FLT3 internal tandem duplications and D835 point mutations in vitro, suggesting that it might overcome resistance to other FLT3 inhibitors. Perl, Altman, and colleagues performed an open-label, first-in-human, phase I/II, dose-escalation and dose-expansion study to assess the safety, tolerability, and activity of gilteritinib in 252 patients with relapsed or refractory AML. The primary endpoints were the safety, tolerability, and pharmacokinetic profile of gilteritinib. Secondary endpoints included overall response, duration of response, and overall survival. Gilteritinib treatment inhibited FLT3 phosphorylation at all dose levels. Gilteritinib was well tolerated, and the maximum tolerated dose was determined to be 300 mg/day. The most common grade 3–4 adverse events were febrile neutropenia (39%), anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%). Of 249 evaluable patients, 100 (40%) achieved responses, including 19 complete remissions, 10 complete remissions with incomplete platelet recovery, 46 complete remissions with incomplete hematologic recovery, and 25 partial remissions. The median duration of response was 17 weeks, and median overall survival was 25 weeks. In the 191 patients with FLT3 mutations, 93 (49%) achieved an overall response, whereas only 7 of 58 (12%) FLT3 wild-type patients achieved responses. Collectively, the results of this trial suggest that gilteritinib monotherapy is well tolerated and has antileukemia activity in patients with relapsed or refractory FLT3-mutant AML, supporting further clinical investigation, and trials of gilteritinib in combination with other therapies are ongoing.

Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol 2017 Jun 20 [Epub ahead of print].

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