Abstract
334 Background: PAZO is a multikinase inhibitor approved for the treatment of mRCC. From phase II study of PAZO in mRCC (VEG102616), plasma CAF analysis from 3 different platforms (cross platform correlation r >0.70) revealed several candidate CAFs including HGF, IL-6, IL-8, TIMP-1, VEGF, E-Selectin and OPN were found to be significantly correlated with clinical benefit (Tran ASCO 2010, #4522). To validate these findings, plasma were analyzed for CAFs from mRCC pts enrolled in phase III randomized, placebo controlled trial with PAZO where progression-free survival (PFS) of 9.2 months of PAZO and 4.2 months of placebo (hazard ratio:0.46 p<.0001) and overall response rate 30% was observed (Sternberg, JCO, 2010). Methods: Plasma samples (n=344) from phase III randomized, placebo-controlled trial (VEG105192) were analyzed for candidate CAFs by a CLIA-certified laboratory (Aushon Biosystems, MA). These markers of PAZO and placebo arms were correlated with PFS by Cox regression and plotted in Kaplan Meier by using median concentration of each marker as a cutoff. Results: Higher levels of IL-8 (p<0.006), HGF (p<0.01), OPN (p<0.001) and TIMP-1 (p<0.006) were associated with shorter PFS in PAZO treated pts. Higher levels of all these markers except HGF were also associated with shorter PFS in the placebo arm (IL-8 (p<0.002), OPN (p<0.001), IL-6 (<0.001), TIMP-1 borderline at p= 0.052) and were therefore prognostic. Only IL-6 was predictive of PFS benefit; pts with high IL-6 had a greater relative benefit from PAZO compared to placebo with a HR of 0.32 in the high IL-6 group and 0.57 in the low IL-6 group (p value for interaction 0.009). Conclusions: This study validated HGF, IL-8, OPN, and TIMP-1 as markers associated with clinical benefit with PAZO treatment. IL-8 and OPN were confirmed as prognostic markers in the placebo arm and IL-6 was both a prognostic marker and predictive marker for pazopanib therapy. [Table: see text]
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