title: CYP2C19 genotype-based phase I studies of a c-Met inhibitor tivantinib in combination with erlotinib, in advanced/metastatic non-small cell lung cancer.
abstract: BACKGROUND
  A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population.
  
  
  METHODS
  Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs.
  
  
  RESULTS
  Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade ≥3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (≥24 weeks) were reported.
  
  
  CONCLUSIONS
  Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Murakami
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: T
authors.initials: T
authors.lastname: Hirashima
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: M
authors.initials: M
authors.lastname: Satouchi
authors.forename: K
authors.initials: K
authors.lastname: Miyoshi
authors.forename: S
authors.initials: S
authors.lastname: Akinaga
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D065731:Cytochrome P-450 CYP2C19; D018450:Disease Progression; D054796:Drug Dosage Calculations; D000069347:Erlotinib Hydrochloride; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: C551661:ARQ 197; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011799:Quinazolines; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019859:Proto-Oncogene Proteins c-met