Abstract A36: Plasma biomarkers predicting outcome in patients with advanced RCC: Results from the sorafenib phase III TARGET trial
Authors: Pena Carol , Shan Michael , Bukowski Ronald M. , Escudier Bernard , Lathia Chetan 
Published: June 2012

Abstract
Background: The pivotal phase 3 Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) demonstrated sorafenib (SOR) to be effective and safe for patients with advanced RCC, in whom 1 prior systemic therapy had failed. In this trial, SOR doubled progression-free survival (PFS) and significantly improved overall survival (OS) with a manageable safety profile (Escudier et al., 2007). SOR is a multikinase inhibitor with activity against RAF kinase and a number of receptor tyrosine kinases, including VEGFR-2, VEGFR-3, PDGFR-β, c-KIT, FLT-3, and RET. An additional (exploratory) objective of the TARGET trial was to examine plasma biomarkers potentially predictive of clinical outcome.
Methods: Patients (N=903) with advanced clear cell RCC, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR or placebo (PBO). A planned, independently assessed analysis of PFS showed significant benefit for SOR over PBO, permitting the crossover of patients from PBO to SOR treatment. Plasma VEGF, soluble VEGFR-2 (sVEGFR-2), CAIX, TIMP-1, and p21 Ras were measured by ELISA at baseline (BL) and after 3 and 12 weeks of treatment. Correlative analyses were performed to examine the relationship between biomarker levels and outcome (PFS/OS).
Results: BL VEGF and sVEGFR-2 data were available from ∼79% (712 and 713, respectively) of the 903 patients randomized. An exploratory subset analysis of CAIX, TIMP-1, and p21 Ras yielded BL data from ∼14% (128, 123 and 125, respectively) of the study patients. Correlative analyses of BL VEGF have been described in part elsewhere (Escudier et al., 2009), but are also included here for completeness. Using the median BL level of each biomarker to define high vs low levels, elevated VEGF (HR=1.65, P=0.002), CAIX (HR=2.26, P=0.034), TIMP-1 (HR=3.34, P=0.001), and p21 Ras (HR=2.49 P=0.016) correlated with poor prognosis (OS) in univariate analyses of PBO patients. Although BL VEGF (P&lt;0.0001), CAIX (P=0.027) and TIMP-1 (P&lt;0.001) correlated with MSKCC score, TIMP-1 (P&lt;0.001) remained significantly prognostic in a multivariate analysis of the subset of PBO-treated patients with CAIX, TIMP-1, and p21 Ras data. Mean VEGF levels increased significantly in the SOR cohort at 3 weeks (P&lt;0.0001) and at 12 weeks (P&lt;0.0001), while sVEGFR2 and TIMP-1 decreased in the SOR cohort at these timepoints (sVEGFR2, P&lt;0.0001 for both timepoints; TIMP-1, P=0.002 and 0.006 for 3 and 12 weeks, respectively). There was no correlation between SOR benefit and BL levels of sVEGFR-2, CAIX, TIMP-1, or p21 Ras, or between outcome and change from BL at 3 or 12 weeks for VEGF, sVEGFR2, CAIX, TIMP-1 or p21 Ras in this exploratory subset analysis.
Conclusions: BL CAIX, TIMP-1, p21 Ras, and VEGF levels were prognostic for OS in patients with advanced RCC, and among these, TIMP-1 offered independent prognostic value.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A36.