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Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 5, pp 1023–1028 | Cite as

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

  • Tatsushi Kodama
  • Masami Hasegawa
  • Kenji Takanashi
  • Yuji Sakurai
  • Osamu Kondoh
  • Hiroshi Sakamoto
Original Article

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.

Keywords

NSCLC ALK ALK inhibitor Brain metastases Alectinib 

Notes

Acknowledgments

We thank T. Mizuno for the establishment of luciferase-expressing cells; A. Nakagawa and F. Sawamura for the in vivo experiments; and T. Shiga and K. Honda for the tissue-staining experiments.

Conflict of interest

All of the authors are employees of Chugai Pharmaceutical Co., Ltd.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Tatsushi Kodama
    • 1
  • Masami Hasegawa
    • 1
  • Kenji Takanashi
    • 1
  • Yuji Sakurai
    • 1
  • Osamu Kondoh
    • 1
  • Hiroshi Sakamoto
    • 1
  1. 1.Research DivisionChugai Pharmaceutical Co., Ltd.KamakuraJapan

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