title: Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial.
abstract: BACKGROUND
  Microphthalmia transcription factor (MITF)-associated (MiT) tumors are a family of rare malignancies, including alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), and translocation-associated renal cell carcinoma (tRCC) that have dysregulated expression of oncogenic MITF family proteins. The MET receptor tyrosine kinase gene is transcriptionally activated by MITF family proteins, making MET a potential therapeutic target for MiT tumors. This study assessed the activity of tivantinib (ARQ 197), a selective MET inhibitor, in patients with MiT-associated tumors.
  
  
  METHODS
  This multicenter, single-arm, phase 2 trial enrolled patients with advanced MiT tumors. Patients initially received tivantinib 120 mg orally twice daily, then 360 mg twice daily per protocol amendment. The primary endpoint was overall response rate. Secondary endpoints included safety, progression-free survival, pharmacokinetics, and correlative studies.
  
  
  RESULTS
  A total of 47 patients (median age, 25 years; range, 11-73 years) with ASPS (n = 27), CCS (n = 11), tRCC (n = 6), or other tumor types (n = 3) were enrolled. Common grade 3/4 drug-related adverse events included anemia (4%) and neutropenia (4%). Three patients (6.4%) experienced 4 treatment-related serious adverse events (grade 3 febrile neutropenia, thrombocytopenia, and deep vein thrombosis, and grade 4 thrombocytopenia). Best response was partial response in 1 CCS patient (2%) and stable disease in 28 patients (60%). Median progression-free survival was 3.6 months (overall), 5.5 months (ASPS), and 1.9 months (CCS and tRCC). Baseline MET expression was strongly or focally positive in tumor samples from 14 of 19 patients (74%).
  
  
  CONCLUSIONS
  Tivantinib was safe and tolerable in patients with MiT tumors, but antitumor activity was modest.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA. awagner@partners.org
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: John M
authors.initials: JM
authors.lastname: Goldberg
authors.forename: Steven G
authors.initials: SG
authors.lastname: Dubois
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.forename: Lee
authors.initials: L
authors.lastname: Rosen
authors.forename: Alberto
authors.initials: A
authors.lastname: Pappo
authors.forename: James
authors.initials: J
authors.lastname: Geller
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: David
authors.initials: D
authors.lastname: Hogg
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
authors.forename: Feng
authors.initials: F
authors.lastname: Chai
authors.forename: Carol
authors.initials: C
authors.lastname: Waghorne
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D002648:Child; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018234:Sarcoma, Alveolar Soft Part / Q000188:drug therapy; D018227:Sarcoma, Clear Cell / Q000188:drug therapy
chemical_list: C551661:ARQ 197; D051739:Microphthalmia-Associated Transcription Factor; D011760:Pyrrolidinones; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met