title: Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma.
abstract: OBJECTIVE
  Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.
  
  
  METHODS
  Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).
  
  
  RESULTS
  Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.
  
  
  CONCLUSIONS
  Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.forename: Ulka
authors.initials: U
authors.lastname: Vaishampayan
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Logan
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Harzstark
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.forename: Laurel M
authors.initials: LM
authors.lastname: Adams
authors.forename: Lone H
authors.initials: LH
authors.lastname: Ottesen
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Laubscher
authors.forename: Laurie
authors.initials: L
authors.lastname: Sherman
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Haas
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Robert
authors.initials: R
authors.lastname: Ross
authors.forename: Peter
authors.initials: P
authors.lastname: Eisenberg
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Ramaprasad
authors.initials: R
authors.lastname: Srinivasan
mesh_terms: D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D012189:Retrospective Studies; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000813:Anilides; D014408:Biomarkers, Tumor; C544831:GSK 1363089; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2