476P - A Model Relating Overall Survival to Tumor Growth Inhibition in Renal Cell Carcinoma

Abstract

ABSTRACT Aim: Tumor growth inhibition (TGI) metrics estimated with longitudinal tumor size (TS) models have been shown to be predictive of overall survival (OS) in a variety of tumor types. Methods: TS data from 2490 patients with 1st line or refractory RCC who received temsirolimus, interferon, sunitinib, sorafenib or axitinib in 10 Phase 2 or Phase 3 studies were used. TGI metrics (Early tumor shrinkage (ETS) at week 8, 10, 12, time to growth (TTG)) as well as baseline prognostic factors were tested in a multivariate log-normal model of OS. Model performances were evaluated by posterior predictive check of the OS and hazard ratio distributions. Results: TTG was the best TGI metric to predict OS (days), but Week 8 ETS, an earlier measure, had satisfactory performance, and was employed due to its ease of clinical utility. The parameter estimates of the model with Week 8 ETS are: Parameter Estimate (SE) p-value Intercept 8.07 (0.270) TS ratio at week 8 -1.99 (0.135) Baseline hemoglobin (g/L) 0.133 (0.111) Baseline ECOG = 1 -0.400 (0. 048) Baseline ECOG = (2, 3) -0.163 (0.077) 0.033 Log(# baseline metastases) -0.209 (0.032) Baseline cor. calcium (mg/dL) -0.104 (0.019) Time from diagnosis (day) 8.0E-5 (1.7E-5) Baseline LDH (U/L) -3.7E-4 (9.2E-5) Lung metastases (yes) -0.138 (0.046) 0.002 Log(scale) -0.107 (0.020) This model was then used in simulation mode to define a clinically relevant ETS target for future Phase II studies with investigational treatments. Conclusions: A TGI-based OS model is proposed for patients with RCC. The model demonstrates good performance when fitted to data from 10 different Phase II and Phase III clinical trials. Simulations with this model help with identification of relevant ETS targets in clinical trial design. Disclosure: F. Mercier:is employed by Pharsight Consulting Services (a division of Certara, L.P.), a company that received financial support from Pfizer to complete this work; B. Houk: is employed by Pfizer; L. Claret: is employed by Pharsight Consulting Services (a division of Certara, L.P.), a company that received financial support from Pfizer to complete this work; P. Milligan: is employed by Pfizer; R. Bruno: is employed by Pharsight Consulting Services (a division of Certara, L.P.), a company that received financial support from Pfizer to complete this work.