Association of circulating cytokine and angiogenic factors (CAFs) with outcomes to second-line FOLFOX plus bevacizumab or cediranib in metastatic colorectal cancer

406 Background: Chemotherapy combined with inhibitors of VEGF signaling is associated with improved outcomes, but biomarkers of therapeutic benefit have been elusive. Cediranib (Ced) is an oral VEGFR tyrosine kinase inhibitor that has been investigated as a treatment for metastatic colorectal cancer (mCRC). Methods: 215 patients with progressive disease and no prior VEGF inhibitor therapy were enrolled in a randomized phase II study of FOLFOX + Ced 20mg/d, Ced 30mg/d or bevacizumab (Bev) 10mg/kg (Cunningham D, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4028). 36 CAFs were analyzed at 3 time points (baseline, wk 4, wk 8). Groups were dichotomized by median CAF value. Hazard ratios (HRs) were estimated from a Cox model with a single term. Results: Data were available for > 85% patients for each CAF. When pooled across all arms, several baseline CAFs including VEGF, interleukin (IL)-2Rα, IL-8 and PDGF were associated with improved PFS (Table). Low and high baseline CAF subgroups were evaluated for potential predictive CAFs. Pts with elevated baseline IL-8 did better with Ced 30mg/d than Bev (HR 0.6 for PFS, CI 0.3-1.0) while low IL-8 was associated with greater benefit from Bev than Ced (HR 2.1, CI 1.0 to 4.2). For Ced 20mg/d, PFS HRs were 0.9 (CI 0.5, 1.6) and 1.7 (CI 0.9, 3.2) for elevated and low baseline IL-8 respectively. Hepatocyte-growth factor (HGF) demonstrated a similar relationship, while a trend for the inverse association was seen with IP-10. Distinct patterns of cytokine modulation were seen between Ced and Bev during the 8 wks, including decreases of sVEGFR2, IL-13 and increases in osteopontin. Conclusions: Several potential prognostic factors for second-line mCRC therapy were identified including VEGF and IL-8. Further work in larger placebo-controlled studies is required to further evaluate predictive markers for VEGF signaling inhibitors. [Table: see text] [Table: see text]