title: Modeling and simulations relating overall survival to tumor growth inhibition in renal cell carcinoma patients.
abstract: OBJECTIVE
  To assess the link between tumor growth inhibition (TGI) and overall survival (OS) based on historical renal cell carcinoma (RCC) data. To illustrate how simulations can help to identify TGI thresholds based on target OS benefit [i.e., hazard ratio (HR) compared with standard of care] to support new drug development in RCC.
  
  
  METHODS
  Tumor size (TS) data were modeled from 2552 patients with first-line or refractory RCC who received temsirolimus, interferon, sunitinib, sorafenib or axitinib in 10 Phase II or Phase III studies. Three model-based TGI metrics estimates [early tumor shrinkage (ETS) at week 8, 10 or 12, time to tumor growth (TTG) and growth rate] as well as baseline prognostic factors were tested in multivariate lognormal models of OS. Model performance was evaluated by posterior predictive check of the OS distributions and hazard ratio across treatments.
  
  
  RESULTS
  TTG was the best TGI metric to predict OS. However, week 8 ETS had a satisfactory performance and was employed in order to maximize clinical utilization. The week 8 ETS to OS model was then used to simulate clinically relevant ETS thresholds for future Phase II studies with investigational treatments.
  
  
  CONCLUSIONS
  The published OS model and resultant simulations can be leveraged to support Phase II design and predict expected OS and HR (based on early observed TGI data obtained in Phase II or Phase III studies), thereby informing important mRCC development decisions, e.g., Go/No Go and dose regimen selection.
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara™ Company, 84 Chemin des Grives, 13013, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Claret
authors.forename: Francois
authors.initials: F
authors.lastname: Mercier
authors.forename: Brett E
authors.initials: BE
authors.lastname: Houk
authors.forename: Peter A
authors.initials: PA
authors.lastname: Milligan
authors.forename: Rene
authors.initials: R
authors.lastname: Bruno
mesh_terms: D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D016019:Survival Analysis