Taking aim at ALK across the blood-brain barrier.

Journal of Thoracic Oncology • Volume 8, Number 4, April 2013 The remarkable clinical efficacy of crizotinib has quickly established anaplastic lymphoma kinase (ALK) positivity as a key molecular feature in non–small-cell lung cancer (NSCLC). Together with the efficacy of epidermal growth factor receptor (EGFR) inhibitors in EGFR mutant disease, thoracic oncologists have become hungry for new molecular subtypes of NSCLC to identify and control with novel targeted therapies. Yet, a series of recent case reports in this journal remind us that significant health gains could be achieved in advanced NSCLC without the need for new targets. Specifically, tremendous progress could be made if we could just inhibit the molecular targets that we already know are important when those targets are located within the central nervous system (CNS). Both Gandhi et al. and Maillet et al. report cases of ALK+ NSCLC responding to crizotinib outside the CNS, but progressing within the CNS. In a recent retrospective analysis, the lifetime incidence of brain metastases in ALK+ lung cancer appeared similar in patients that either received or never received crizotinib, suggesting that crizotinib was not altering the natural history of the disease in the CNS. Consistent with this, and with these case reports, 13 of 28 ALK+ patients (46%) first progressed on crizotinib within the CNS, with 85% having ongoing extra-CNS disease control at the time. One potential explanation comes from the pharmacokinetic analyses of a single ALK+ patient progressing within the CNS. Five hours after taking 250 mg, the cerebrospinal fluid (CSF) crizotinib concentration was 0.0014 μmol/L with the CSF to plasma ratio only 0.0026. Put another way, the CSF levels in this patient were more than 170-fold lower than the concentration required for 50% growth inhibition in an ALK+ cell line in vitro. If the CNS really is crizotinib’s Achilles’ heel, then routine surveillance of the CNS should probably be considered for all crizotinib patients, although, in the absence of detailed data, the optimal frequency of this surveillance remains uncertain. When CNS disease is detected, it may be treatable with radiotherapy. Radiotherapy to sites of progression, in conjunction with continuing the crizotinib was permitted in the early crizotinib trials. Although no randomized study has yet addressed the benefit of ongoing crizotinib post-CNS progression, in the face of extra-CNS disease control retrospective data suggest the inhibitor should not be stopped. When patients with either EGFR mutant or ALK+ disease and isolated CNS progression on erlotinib or crizotinib, respectively, received brain radiotherapy and the relevant inhibitor was kept going, further progression took more than 7 months to occur. As radiotherapy may increase the local permeability of the blood–brain barrier, there is also the possibility that the same inhibitor may be more beneficial in the CNS postradiation than it was preirradiation. Consistent with this, Kaneda et al. describe the seemingly exceptional case of an ALK+ patient with progression in a previously irradiated CNS lesion which then responded to crizotinib. Similarly, standard doses of crizotinib produced a response in a mesenchymal epithelial transition factor (MET)-amplified glioblastoma, approximately 5 months after prior radiotherapy. If CNS progression on crizotinib primarily reflects inadequate drug exposures, then another way of getting ALK+ CNS disease back under control would be to get drugs active against crizotinib-naive cancer into the CNS. An intrathecal formulation of crizotinib has been discussed with Pfizer, but has not yet been prioritized for clinical development. In