Circulating angiogenic factors as predictors of benefit from bevacizumab (bev) beyond progression in metastatic colorectal cancer (mCRC): Traslational analyses from the phase III BEBYP trial.

Abstract

3603 Background: TML and BEBYP trials demonstrated that the strategy of prosecuting bev beyond progression is effective in mCRC. Previous analyses from phase II studies showed that a modulation of plasma angiogenic factors occurs during 1st-line treatment with chemotherapy (CT) + bev and a wide variability in soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) levels was observed at the time of progression. Moving from preliminary analyses in murine models we selected a pool of candidate ligands to be tested in the clinical setting. Methods: sVEGFR2, Placental Growth Factor (PlGF), Platelet-Derived Growth Factor-C, basic Fibroblast Growth Factor, Angiopoietin-2 and soluble Tie-2 were assessed by ELISA on plasma samples collected at baseline in a cohort of 59 patients enrolled in phase III BEBYP trial of 2nd-line CT ± bev beyond progression to a bev-containing first-line regimen. Plasma levels were defined high or low adopting the median values as cut-off. Results: A significant interaction between treatment arm and baseline sVEGFR-2 levels was observed (p=0.036). Among 30 patients with high sVEGFR-2 levels, the prosecution of bev was associated with a significant benefit in terms of PFS (median: 10.4 vs 3.4 months, HR 0.37 [95%CI 0.10-0.58], p=0.0015), that was not evident among 29 patients with low sVEGFR-2 levels (5.4 vs 5.0 months, HR 0.98 [95%CI 0.45-2.11], p=0.956). Despite a trend towards a greater benefit from bev among 30 patients with high PlGF levels (HR 0.45 [95%CI 0.13-0.86]), no interaction between treatment arm and baseline PlGF levels was observed (p=0.210). Combined analysis of sVEGFR-2 and PlGF showed that prosecuting bev provided a substantial benefit in PFS in the subgroup with high levels of both ligands (10.5 vs 2.3 months, HR 0.25 [95%CI 0.01-0.45], p=0.043). Conclusions: sVEGFR-2 levels at the time of first progression may predict benefit from prosecuting bev. Interesting results from simultaneous analysis of sVEGFR-2 and PlGF may be affected by a pronounced subgrouping and should be considered cautiously. Given their potential clinical value, these data need prospective confirmation. Clinical trial information: NCT00720512.