Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia

Abstract

SummaryAdvances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML. Initial kinase studies showed that gilteritinib, a type I tyrosine kinase inhibitor, was highly selective for both FLT3 and AXL while having weak activity against c-KIT. Gilteritinib demonstrated potent inhibitory activity against the internal tandem duplication (FLT3-ITD) and FLT3-D835Y point mutations in cellular assays using MV4–11 and MOLM-13 cells as well as Ba/F3 cells expressing mutated FLT3. Gilteritinib also inhibited FLT3-F691 mutations, although to a lesser degree, in these assays. Furthermore, gilteritinib decreased the phosphorylation levels of FLT3 and its downstream targets in both cellular and animal models. In vivo, gilteritinib was distributed at high levels in xenografted tumors after oral administration. The decreased FLT3 activity and high intratumor distribution of gilteritinib translated to tumor regression and improved survival in xenograft and intra-bone marrow transplantation models of FLT3-driven AML. No overt toxicity was seen in mouse models treated with gilteritinib. These results indicate that gilteritinib may be an important next-generation FLT3 inhibitor for use in the treatment of FLT3 mutation-positive AML.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-017-0470-z) contains supplementary material, which is available to authorized users.

Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open‐label phase 1 study

“…Despite these limitations, no significant differences in response rate, safety or PK profiles of gilteritinib were observed between our study and the phase 1/2 study . Furthermore, the demonstrated activity of gilteritinib against FLT3‐TKD mutations suggest a potential benefit in treatment‐resistant FLT3 mutation‐positive AML …”

“…Gilteritinib is a highly specific, potent FLT3/AXL inhibitor with demonstrated activity against FLT3 receptors containing FLT3‐ITD and FLT3‐TKD D835 mutations . Preclinical studies have demonstrated that gilteritinib is a robust inhibitor of FLT3 and AXL, as well as anaplastic lymphoma kinase and leukocyte receptor tyrosine kinase .…”

“…Because gilteritinib also blocks AXL, which has been shown to suppress the growth of FLT3‐ITD AML and decrease tumor size, this dual inhibition mechanism may enhance the benefit of gilteritinib in AML . Furthermore, gilteritinib has a minimal inhibitory effect on c‐Kit, suggesting a lower risk of myelosuppression compared with other tyrosine kinase inhibitors . In a recently published phase 1/2 dose‐escalation/expansion study of once‐daily oral gilteritinib in patients with relapsed/refractory (R/R) AML from the USA, Germany and Italy, gilteritinib was well tolerated with a maximum tolerated dose (MTD) of 300 mg/d .…”

“…4,[7][8][9] Gilteritinib is a highly specific, potent FLT3/AXL inhibitor with demonstrated activity against FLT3 receptors containing FLT3-ITD and FLT3-TKD D835 mutations. 10,11 Preclinical studies have demonstrated that gilteritinib is a robust inhibitor of FLT3 and AXL, as well as anaplastic lymphoma kinase and leukocyte receptor tyrosine kinase. 11 In leukemic cells, gilteritinib strongly inhibited FLT3 receptors expressing FLT3-ITD and FLT3-TKD D835 mutations, and was a weak inhibitor of FLT3 receptors expressing F691 gatekeeper mutations.…”

“…10,11 Preclinical studies have demonstrated that gilteritinib is a robust inhibitor of FLT3 and AXL, as well as anaplastic lymphoma kinase and leukocyte receptor tyrosine kinase. 11 In leukemic cells, gilteritinib strongly inhibited FLT3 receptors expressing FLT3-ITD and FLT3-TKD D835 mutations, and was a weak inhibitor of FLT3 receptors expressing F691 gatekeeper mutations. 10 AXL, an oncogenic tyrosine kinase that promotes FLT3 activation and may be involved in FLT3 inhibitor resistance, is often overexpressed in patients with AML.…”