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

Abstract

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.

Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases

“…Based on these data, Japan was the first country to approve the use of alectinib. This agent is also effective in cases resistant to crizotinib, which is a first-generation ALK-TKI, including cases with metastasis to the central nervous system (6)(7)(8)(9). Based on these positive results, alectinib received breakthrough therapy designation by the FDA.…”

Alectinib—a new chapter in the management of ALK-positive lung cancer

“…Preclinically, alectinib produces high CNS-to-plasma ratios and impressive intracranial disease activity in animal models (14). In the NP28761 and NP28673 studies, brain metastases were present at study entry in approximately 60% of crizotinib-resistant patients (8,9).…”

How might treatment of ALK-positive non-small cell lung cancer change in the near future?

“…Therefore, drugs with increased CNS activity are urgently needed. Alectinib is a very promising agent in this setting, since a preclinical study showed that it is not a substrate of P-glycoprotein (P-gp), a key efflux transporter that may impair drug penetration through the blood-brain barrier [18]. Consistently, a pooled analysis of crizotinib-pretreated patients with CNS metastases showed that alectinib provides a CNS-ORR of 64% in individuals with measurable CNS disease (n = 50) [19].…”