title: Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.
abstract: OBJECTIVE
  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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Kodama
authors.forename: Masami
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Takanashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Osamu
authors.initials: O
authors.lastname: Kondoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D018938:Caco-2 Cells; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000378:metabolism; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D002227:Carbazoles; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D008156:Luciferases; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib