PURPOSE: 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.
EXPERIMENTAL DESIGN: 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).