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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 5/2014

01-11-2014 | Original Article

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

Authors: Tatsushi Kodama, Masami Hasegawa, Kenji Takanashi, Yuji Sakurai, Osamu Kondoh, Hiroshi Sakamoto

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2014

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Abstract

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 14C-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.
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Metadata
Title
Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases
Authors
Tatsushi Kodama
Masami Hasegawa
Kenji Takanashi
Yuji Sakurai
Osamu Kondoh
Hiroshi Sakamoto
Publication date
01-11-2014
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-014-2578-6

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