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

作者：Kodama Tatsushi; Hasegawa Masami; Takanashi Kenji; Sakurai Yuji; Kondoh Osamu; Sakamoto Hiroshi^*

来源：Cancer Chemotherapy and Pharmacology, 2014, 74(5): 1023-1028.

DOI：10.1007/s00280-014-2578-6

• NSCLC
• ALK
• ALK inhibitor
• Brain metastases
• Alectinib

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.
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 C-14-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell.
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.
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.

• 出版日期2014-11