Cytokine and angiogenic factor (CAF) profiling for identification of markers associated with response to cediranib in metastatic renal cell carcinoma (mRCC).

Abstract

362 Background: Cediranib is a highly potent and selective signaling inhibitor of vascular endothelial growth factor (VEGF) receptors−1, −2, −3 and c-Kit. In a phase II trial, patients (pts) with mRCC were randomized 3:1 to treatment with cediranib or placebo to primarily assess the difference in change in tumor size at 12 weeks. Cediranib resulted in a significant reduction in tumor size vs. placebo (Mulders et al. ESMO. 2009). Here we investigated soluble biomarkers in serum and concentration changes during treatment. Methods: Pts received cediranib 45 mg/day PO or placebo for the first 12 weeks on treatment. At that time (or upon progression if earlier), treatment was unblinded and pts on placebo were given the option of receiving cediranib. Serum was collected from 61 pts at baseline (BL; cediranib 46, placebo 15), from 50 pts on day (D) 28, and from 45 pts on D84. Multiplex bead suspension arrays and ELISA were used to measure CAF concentrations including VEGF, placental growth factor (PlGF), sVEGFR-2, PDGFbb, HGF, MMP-9, multiple chemokines and interleukins (IL). The objectives of this exploratory analysis were to assess whether baseline CAFs were associated with changes in tumor size after 12 weeks of treatment and whether CAF levels changed while on treatment. Results: Of 39 CAFs available at BL, lower than median (‘low') concentrations of IL-10, VEGF, PlGF, stem cell factor (SCF), and monokine-induced by interferon-gamma (MIG) were associated with larger decreases in tumor size than high concentrations (independent of treatment arm), whereas the opposite trend was observed for IL-5 and TRAIL. Consistent with inhibition of VEGF signaling, cediranib treatment resulted in changes over time in VEGF (increase), sVEGFR-2 (decrease) and PlGF (increase) concentrations. In addition, SCF, a c-Kit ligand and M-CSF decreased, while VCAM-1 and TRAIL increased during cediranib treatment. Conclusions: Candidate CAFs associated with response to cediranib in mRCC such as IL-10 and VEGF were identified. Patients treated with cediranib showed distinct CAF changes compared with placebo. These results require independent validation in a larger trial. [Table: see text]