Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases

Cancer Chemother Pharmacol. 2014 Nov;74(5):1023-8. doi: 10.1007/s00280-014-2578-6. Epub 2014 Sep 10.


Purpose: The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors.

Methods: We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell.

Results: Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration.

Conclusions: We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / secondary
  • Caco-2 Cells
  • Carbazoles / blood
  • Carbazoles / pharmacokinetics
  • Carbazoles / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Luminescent Measurements / methods
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Mice, Nude
  • Mice, SCID
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / metabolism
  • Piperidines / blood
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Tissue Distribution
  • Xenograft Model Antitumor Assays


  • Carbazoles
  • EML4-ALK fusion protein, human
  • Oncogene Proteins, Fusion
  • Piperidines
  • Protein Kinase Inhibitors
  • Luciferases
  • ALK protein, human
  • Alk protein, mouse
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • alectinib