title: Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4).
abstract: OBJECTIVE
  This Phase I study determined the maximum-tolerated dose (MTD) of afatinib (Afatinib is an investigational compound and its safety and efficacy have not yet been established) (BIBW 2992; trade name not yet approved by FDA), an irreversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER)1 and 2, up to a dose of 50 mg/day in advanced non-small cell lung cancer (NSCLC), to establish the recommended dose for Phase II.
  
  
  METHODS
  Patients with advanced NSCLC who had received prior platinum-doublet chemotherapy and/or erlotinib/gefitinib therapy, or who were ineligible for, or not amenable to, treatment with established therapies, received oral afatinib once daily. The MTD was determined based on dose-limiting toxicities (DLTs); other assessments included safety, pharmacokinetic profile, antitumour activity according to response evaluation criteria in solid tumours and EGFR/HER1 mutation analysis where possible.
  
  
  RESULTS
  Twelve evaluable patients were treated at doses of 20-50 mg/day. One DLT was observed at 50 mg/day in Course 1 (Grade 3 mucositis). The most frequent drug-related adverse events were diarrhoea, dry skin, stomatitis, rash, paronychia and anorexia; most were Grade 1 or 2. Six out of 12 patients had tumour size reductions; durable stable disease was achieved in three patients including one with EGFR/HER1 exon 19 and T790 M mutations. Peak plasma concentrations of afatinib were reached 3-4 h after administration and declined with a half-life of 30-40 h. Afatinib 50 mg/day was well tolerated with an acceptable safety profile during Phase I.
  
  
  CONCLUSIONS
  Recommended dose for Phase II was defined as 50 mg/day for Japanese patients; the same as for non-Japanese patients.
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Murakami
authors.forename: T
authors.initials: T
authors.lastname: Tamura
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Nokihara
authors.forename: T
authors.initials: T
authors.lastname: Naito
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Nishio
authors.forename: Y
authors.initials: Y
authors.lastname: Seki
authors.forename: A
authors.initials: A
authors.lastname: Sarashina
authors.forename: M
authors.initials: M
authors.lastname: Shahidi
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib