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

Cancer. 2018 Jan 15;124(2):306-314. doi: 10.1002/cncr.31038. Epub 2017 Sep 28.

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. © 2017 American Cancer Society.

Keywords: FMS-like tyrosine kinase 3 (FLT3); acute myeloid leukemia; resistance mutations; targeted therapies; tyrosine kinase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anilides / adverse effects
  • Anilides / therapeutic use*
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mutation*
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / chemistry
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • Anilides
  • Protein Kinase Inhibitors
  • Pyridines
  • cabozantinib
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3