title: Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease.
abstract: BACKGROUND
  Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program.
  
  
  METHODS
  Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented.
  
  
  RESULTS
  From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21-395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol.
  
  
  CONCLUSIONS
  Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC and CNS metastasis.
authors.affiliation: *Department of Pneumology, Thoracic Oncology and Respiratory Care Medicine, Mathias Spital Rheine, Rheine, Germany; †Department of Internal Medicine V, Division of Respiratory Medicine and Thoracic Oncology, University of Munich, Thoracic Oncology Centre Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, München, Germany; ‡III. Medical Department, University Hospital Mainz, Mainz, Germany; §Department of Medicine 1, University of Wuerzburg, Wuerzburg, Germany; ‖Department of Medicine A, University Hospital, Westfaelische Wilhelms-University, Muenster, Germany; ¶Department of Pneumology and Pulmonary Oncology, Klinikum München, München, Germany; #Department of Pneumologie III, Lungenklinik Hemer, Hemer, Germany; **Privat Clinic, Bonn, Germany; ††Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; and ‡‡Members of the Afatinib Compassionate Use Consortium (ACUC) are listed in Appendix.
authors.forename: Petra
authors.initials: P
authors.lastname: Hoffknecht
authors.forename: Amanda
authors.initials: A
authors.lastname: Tufman
authors.forename: Thomas
authors.initials: T
authors.lastname: Wehler
authors.forename: Theo
authors.initials: T
authors.lastname: Pelzer
authors.forename: Rainer
authors.initials: R
authors.lastname: Wiewrodt
authors.forename: Martin
authors.initials: M
authors.lastname: Schütz
authors.forename: Monika
authors.initials: M
authors.lastname: Serke
authors.forename: Jan
authors.initials: J
authors.lastname: Stöhlmacher-Williams
authors.forename: Angela
authors.initials: A
authors.lastname: Märten
authors.forename: Rudolf
authors.initials: R
authors.lastname: Maria Huber
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Dickgreber
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors