title: Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer.
abstract: OBJECTIVE
  The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma.
  
  
  METHODS
  Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥ 25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity.
  
  
  RESULTS
  From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25-88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9-7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment.
  
  
  CONCLUSIONS
  These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer.
authors.affiliation: The Weill Cornell Medical College/New York-Presbyterian Hospital, New York, New York, USA. mas9313@med.cornell.edu
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.forename: Daniel V T
authors.initials: DV
authors.lastname: Catenacci
authors.forename: Howard S
authors.initials: HS
authors.lastname: Hochster
authors.forename: James
authors.initials: J
authors.lastname: Ford
authors.forename: Pamela
authors.initials: P
authors.lastname: Kunz
authors.forename: Fa-Chyi
authors.initials: FC
authors.lastname: Lee
authors.forename: Howard
authors.initials: H
authors.lastname: Kallender
authors.forename: Fabiola
authors.initials: F
authors.lastname: Cecchi
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Rabe
authors.forename: Harold
authors.initials: H
authors.lastname: Keer
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Martin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Gagnon
authors.forename: Peter
authors.initials: P
authors.lastname: Bonate
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Tona
authors.initials: T
authors.lastname: Gilmer
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C544831:GSK 1363089; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2