title: Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline.
abstract: OBJECTIVE
  To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data.
  
  
  METHODS
  Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated.
  
  
  RESULTS
  A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79].
  
  
  CONCLUSIONS
  A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara™ Company, Marseille, France.|Genentech/Roche, Clinical Pharmacology, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Claret
authors.affiliation: Global Clinical Pharmacology, Pfizer Pharmacometrics, La Jolla, CA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara™ Company, Wintzenheim, France.|Roche, pRED, Basel, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Mercier
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara™ Company, Lyon, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chanu
authors.affiliation: Pfizer Global Clinical Pharmacology, La Jolla, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Pfizer Global Clinical Statistics, La Jolla, CA, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Rosbrook
authors.affiliation: Pfizer Global Clinical Pharmacology, La Jolla, CA, USA.
authors.forename: Pithavala
authors.initials: P
authors.lastname: Yazdi
authors.affiliation: Global Clinical Pharmacology, Pfizer Pharmacometrics, Sandwich, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Milligan
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara™ Company, Marseille, France. rbruno100@gmail.com.|, 84 Chemin des Grives, 13013, Marseille, France. rbruno100@gmail.com.|Genentech/Roche, Clinical Pharmacology, Marseille, France. rbruno100@gmail.com.
authors.forename: Rene
authors.initials: R
authors.lastname: Bruno
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007191:Indazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D016898:Interferon-alpha / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016015:Logistic Models; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D000077157:Sorafenib; D000077210:Sunitinib; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077784:Axitinib; D000077210:Sunitinib
keywords: Early tumor shrinkage; Predictive model; Progression-free survival; Renal cell carcinoma; Tumor growth inhibition