Dynamics of circulating VEGF-A predict benefit from anti-angiogenic cediranib in metastatic or recurrent cervical cancer patients

Abstract

BACKGROUND AND PURPOSE: There is a need for predictive and surrogate response biomarkers to support treatment with anti-angiogenic VEGF inhibitors. We aimed to identify a minimally-invasive biomarker predicting benefit from cediranib pre-treatment or early during treatment in patients with recurrent or metastatic cervical cancer. EXPERIMENTAL APPROACH: Blood samples were collected before treatment, during treatment and upon disease progression where appropriate from patients enrolled in CIRCCa, a randomised phase II trial of carboplatin and paclitaxel with or without cediranib. Plasma concentrations of VEGF-A, VEGF-R2, Ang1 and Tie2 were measured using multiplex ELISA. Pre-treatment and temporal changes of the biomarkers were investigated using proportional hazard regression and unsupervised clustering analysis. KEY RESULTS: Samples (n=556) from 52 patients were analysed. VEGF-R2 (p=0.0006) and Tie2 (p=0.04) were down-regulated following cediranib, while VEGF-A (p=0.0025) was up-regulated. High ECOG performance status (p=0.02, HR=2.15, 95%CI 1.13-4.09) and low pre-treatment Tie2 concentrations (p=0.003, HR= 0.57, 95%CI 0.39-0.83) were independent prognostic factors associated with reduced progression-free survival. Two patterns of changes in VEGF-A following cediranib were identified. Patients with elevated VEGA-A in the first 3 treatment cycles, regardless of magnitude, had reduced progression-free survival in the placebo arm but improved survival with the addition of cediranib (p=0.019, HR= 0.13, 95% CI 0.02-0.71). CONCLUSIONS AND IMPLICATIONS: Patterns of early elevation in plasma VEGF-A should be studied further as a potential biomarker to predict treatment benefit from cediranib.