title: Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial.
abstract: OBJECTIVE
  Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC.
  
  
  OBJECTIVE
  To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC.
  
  
  METHODS
  Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry.
  
  
  METHODS
  Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg).
  
  
  METHODS
  Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety.
  
  
  RESULTS
  Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab.
  
  
  CONCLUSIONS
  Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01662869.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Center for Advanced Digestive Care, New York-Presbyterian Hospital, New York.
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: University Cancer Center Leipzig, Leipzig, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lordick
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain5Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Alsina
authors.affiliation: Biostatistics Department, Roche (China) Holdings Ltd, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Genentech Inc, South San Francisco, California.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hack
authors.affiliation: Genentech Inc, South San Francisco, California.
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Bruey
authors.affiliation: Genentech Inc, South San Francisco, California.
authors.forename: Dustin
authors.initials: D
authors.lastname: Smith
authors.affiliation: Genentech Inc, South San Francisco, California.
authors.forename: Ian
authors.initials: I
authors.lastname: McCaffery
authors.affiliation: Genentech Inc, South San Francisco, California.
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.affiliation: Genentech Inc, South San Francisco, California.
authors.forename: See
authors.initials: S
authors.lastname: Phan
authors.affiliation: Royal Marsden Hospital, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D004311:Double-Blind Method; D058750:Epithelial-Mesenchymal Transition; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D057194:Intention to Treat Analysis / Q000379:methods; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D005472:Fluorouracil; D002955:Leucovorin; D009944:Organoplatinum Compounds; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C491743:MET protein, human; C584058:onartuzumab