VALTIVE1: Validation of Tie2 as a response biomarker for VEGF inhibitors In Ovarian Cancer

Background Studies in ovarian cancer (OC) show that the addition of anti-angiogenic VEGFi, such as bevacizumab, to cytotoxic chemotherapy improves Progression Free Survival (PFS) and, in some cases, Overall Survival (OS). Notwithstanding the beneficial effects of VEGFi for OC patients, informative biomarkers could help optimise their use and improve patient selection. We have carried out biomarker studies in ovarian and gastrointestinal cancer trials, in which patients were treated with cytotoxic agents and bevacizumab. Plasma samples were analysed to determine changes in Tie2 concentration during treatment. We have shown that a reduction of at least 25% in plasma Tie2 concentrations on-treatment over 9 weeks predicts a significant PFS benefit from bevacizumab, whereas an immediate increase in Tie2 of over 10% after treatment starts denotes resistance to bevacizumab and hence lack of benefit. In patients who do achieve a bevacizumab response, an increase in plasma Tie2 that is at least 40% above the nadir concentration signifies the onset of resistance. The VALTIVE1 study aims to optimise the frequency and number of plasma samples for a better definition of Tie2 “vascular response” and to evaluate acceptability of a future randomised discontinuation study to evaluate Tie2 as a predictive biomarker, thus completing the CRUK biomarker roadmap. Method VALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, which will enrol 176 adult patients, who are receiving first line platinum-based chemotherapy and bevacizumab for high risk ovarian cancer, from 15 UK centres. VALTIVE1 participants will provide blood samples before and during treatment with bevacizumab and upon disease progression. Cross-sectional imaging of pelvis and abdomen will be performed and reported according to RECIST v.1.1 during treatment until disease progression, death, or withdrawal of consent, whichever occurs first. The primary endpoint is assessment of PFS difference between Tie2-defined vascular responders and Tie2 defined vascular non-responders. Results N/A Conclusion The results of VALTIVE1 will underpin the design of a subsequent randomised study, VALTIVE2, in which OC patients receiving bevacizumab will be randomly allocated to the conventional 12 months of VEGFi therapy or Tie2-guided bevacizumab therapy. Impact statement Validation of plasma Tie2 for clinical decision making around the use of VEGF inhibitors in the NH