Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation

Amir T. Fathi, Traci M. Blonquist, Daniela Hernandez, Philip C. Amrein, Karen K. Ballen, Malgorzata McMasters, David E. Avigan, Robin Joyce, Emma K. Logan, Gabriela Hobbs, Andrew M. Brunner, Christelle Joseph, Ashley M. Perry, Meghan Burke, Tanya Behnan, Julia Foster, Meghan K. Bergeron, Jenna A. Moran, Aura Y. Ramos, Tina T. SomJessica Rae, Kaitlyn M. Fishman, Kristin L. McGregor, Christine Connolly, Donna S. Neuberg, Mark J. Levis

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways. METHODS: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines. RESULTS: Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)–mutant cells. CONCLUSIONS: Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD–altered tyrosine kinases. Cancer 2018;124:306-14.

Original languageEnglish (US)
Pages (from-to)306-314
Number of pages9
JournalCancer
Volume124
Issue number2
DOIs
StatePublished - Jan 15 2018

Keywords

  • FMS-like tyrosine kinase 3 (FLT3)
  • acute myeloid leukemia
  • resistance mutations
  • targeted therapies
  • tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fathi, A. T., Blonquist, T. M., Hernandez, D., Amrein, P. C., Ballen, K. K., McMasters, M., Avigan, D. E., Joyce, R., Logan, E. K., Hobbs, G., Brunner, A. M., Joseph, C., Perry, A. M., Burke, M., Behnan, T., Foster, J., Bergeron, M. K., Moran, J. A., Ramos, A. Y., ... Levis, M. J. (2018). Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation. Cancer, 124(2), 306-314. https://doi.org/10.1002/cncr.31038