title: Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression.
abstract: BACKGROUND
  Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose-response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure-survival and exposure-safety and the impact of MET expression on these relationships.
  
  
  METHODS
  Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg(-1)), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan-Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure.
  
  
  RESULTS
  Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7-9.7) vs 4.4 (2.9-4.9) and 5.5 (4.2-6.8) months) and OS (13.4 (10.6-18.6) vs 5.7 (4.7-10.2) and 8.1 (6.9-11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients.
  
  
  CONCLUSIONS
  Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.
authors.affiliation: Translational Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Translational Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tang
authors.affiliation: Translational Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: S
authors.initials: S
authors.lastname: Doshi
authors.affiliation: Translational Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Oliner
authors.affiliation: Global Clinical Development, Amgen Inc., South San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dubey
authors.affiliation: Translational Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Oncology, Johns Hopkins Medical Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
authors.affiliation: Medical Oncology, University Hospital Southampton, Southampton, UK.
authors.forename: T
authors.initials: T
authors.lastname: Iveson
authors.affiliation: Global Clinical Development, Amgen Inc., South San Francisco, CA, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Loh
authors.affiliation: Translational Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C524459:rilotumumab; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met