ALK on my mind: alectinib takes an early lead in managing intracranial disease in non-small cell lung cancer with ALK rearrangements
Non-small cell lung cancers (NSCLC) harboring oncogenic anaplastic lymphoma kinase fusions (ALK+) embody the paradigm and success of precision medicine. Despite high overall response rates (ORR) with the first ALK inhibitor crizotinib, a pattern of central nervous system (CNS) failure emerged, highlighting the need for CNS-specific study and assessment. In fact, the CNS is the first site of progressive disease (PD) in nearly 70% of ALK+ patients taking crizotinib (1). Unlike crizotinib and ceritinib, alectinib is not a substrate of P-glycoprotein, a key efflux transporter that hinders drug penetration through the blood-brain barrier (BBB) and may partly underlie observations of pharmacologic failure (2,3). The ratio of alectinib to plasma in cerebrospinal fluid (CSF) approaches 0.75 indicating a very high degree of CNS penetration (4). Early small data sets showed that the intracranial response rate of alectinib ranged from 40% to 57% (Table 1) (14). Additionally, alectinib was reported to have activity in ALK+ NSCLC patients with leptomeningeal disease (15,16).