title: Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer.
abstract: OBJECTIVE
  c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor.
  
  
  METHODS
  Previously treated patients with EGFR TKI-naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required.
  
  
  RESULTS
  One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms.
  
  
  CONCLUSIONS
  The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA. lvsequist@partners.org
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.forename: Edward G
authors.initials: EG
authors.lastname: Garmey
authors.forename: Wallace L
authors.initials: WL
authors.lastname: Akerley
authors.forename: Wolfram
authors.initials: W
authors.lastname: Brugger
authors.forename: Dora
authors.initials: D
authors.lastname: Ferrari
authors.forename: Yinpu
authors.initials: Y
authors.lastname: Chen
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: David E
authors.initials: DE
authors.lastname: Gerber
authors.forename: Sergey
authors.initials: S
authors.lastname: Orlov
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.forename: Susan
authors.initials: S
authors.lastname: Arthur
authors.forename: Igor
authors.initials: I
authors.lastname: Gorbachevsky
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Joan H
authors.initials: JH
authors.lastname: Schiller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010919:Placebos / Q000008:administration & dosage; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D011804:Quinolines / Q000008:administration & dosage*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors; D016019:Survival Analysis
chemical_list: C551661:ARQ 197; D010919:Placebos; D011760:Pyrrolidinones; D011799:Quinazolines; D011804:Quinolines; D017978:Receptors, Growth Factor; D000069347:Erlotinib Hydrochloride; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met