**6.3 ALK tyrosine kinase inhibitors**

ALK rearrangements are found in about 4–8% of NSCLCs, representing a distinct subgroup [110]. ALK-TKIs are active against CNS metastases and novel drugs are effective in treating brain metastases, even in patients with multiple intracranial tumors [123]. Crizotinib (Xalkoric) was the first ALK-TKI for metastatic ALKpositive NSCLCs. In phase 3, randomized clinical trial with a single-arm of crizotinib for patients with NSCLC with cerebral metastases, better intracranial response was obtained for patients who were also treated with RT [124] and median survivals of almost 50 months were recorded for patients with ALK-positive tumors [58]. Second-generation ALK-TKIs including brigatinib, ceritinib (Zykadia), and alectinib (Alecensa) have shown a better BBB penetration and activity against BM in crizotinib-resistant tumors [125]. Ceritinib appeared to be a powerful drug for patients with metastatic ALK-positive NSCLCs in whom treatment with crizotinib was not effective anymore. Ceritinib also showed activity against crizotinib-resistant tumors in the mouse models [126]. Patients with ALK-positive tumors with CNS lesions were treated with alectinib against crizotinib in the ALEX trial. The results showed that patients treated with alectinib had a longer progression-free survival (PFS) rate than patients treated with crizotinib [123]. In addition, nearly half of patients with ALK-positive NSCLCs with cerebral metastasis improved significantly upon treatment with alectinib. Taken together, these results indicate that Alectinib can be used as an effective treatment option for patients with NSCLC-positive ALK with cerebral metastasis [123].
