title: Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib.
abstract: BACKGROUND
  Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-positive patients remains poorly understood as these patients have been routinely excluded from clinical trials.
  
  
  METHODS
  We describe four ALK-positive patients with LM who were treated with the next-generation ALK inhibitor alectinib through single-patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors--crizotinib and ceritinib. Patients received alectinib at a starting dose of 600 mg twice daily.
  
  
  RESULTS
  Four ALK-positive NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clinical and radiographic improvements in LM upon treatment with alectinib. A fourth patient had stable intracranial disease for 4 months before eventual systemic disease progression. Overall, alectinib was well tolerated. One patient required dose reduction due to grade 2 hyperbilirubinemia.
  
  
  CONCLUSIONS
  Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Additional prospective studies of alectinib in ALK-positive patients with LM are warranted.
authors.affiliation: *Department of Medicine, Massachusetts General Hospital, Boston, MA; †Department of Medicine, Medical University of South Carolina, Charleston, SC; and ‡Department of Neurology, Massachusetts General Hospital, Boston, MA.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sherman
authors.forename: Kathryn
authors.initials: K
authors.lastname: Willoughby
authors.forename: Jennifer
authors.initials: J
authors.lastname: Logan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kennedy
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Brastianos
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010880:Piperidines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib