title: Rilotumumab exposure-response relationship in patients with advanced or metastatic gastric cancer.
abstract: OBJECTIVE
  Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab.
  
  
  METHODS
  Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between rilotumumab dose and OS.
  
  
  RESULTS
  Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18-0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W.
  
  
  CONCLUSIONS
  Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).
authors.affiliation: Amgen Inc., Thousand Oaks, California. sdoshi@amgen.com.
authors.forename: Sameer
authors.initials: S
authors.lastname: Doshi
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium.
authors.forename: Per Olsson
authors.initials: PO
authors.lastname: Gisleskog
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.affiliation: Amgen Inc., South San Francisco, California.
authors.forename: Elwyn
authors.initials: E
authors.lastname: Loh
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Perez Ruixo
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000069287:Capecitabine / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C066855:HGF protein, human; D015251:Epirubicin; C524459:rilotumumab; D017228:Hepatocyte Growth Factor; D000069287:Capecitabine; D002945:Cisplatin