PCN8 - A Lesson Learnt from Avastin®: - Bevacizumab Induced Hypertension as a Predictive Biomarker of Patient Response in Overcoming Regulatory and Health Technology Assessment (HTA) Hurdles

Abstract

The high cost of VEGF-targeted anti-angiogenic therapies within a financially strained health-system, makes reimbursement decisions a potentially limiting factor for new compounds. Failure to demonstrate adequate clinical benefit and cost-effectiveness in HER-2 negative metastatic breast cancer resulted in significant regulatory and health technology assessment (HTA) challenges. There is increasing expectation for new drugs to have companion diagnostics that identify likely patient responders, with growing support for using biomarkers to inform treatment decisions The purpose of this study was to critically examine published literature on trials incorporating biomarkers related to VEGF inhibition across different cancer indications, to explore their value as predictive, prognostic, pharmacological or surrogate response biomarkers A search with a strict set of inclusion criteria was used to review the current literature. Information was gathered for 13 biomarkers that have been explored for anti-VEGF therapy and a database was compiled housing raw experimental data for comparison. Each biomarker was critically evaluated and ranked accordingly, to validate their potential as predictive, prognostic, pharmacodynamic and surrogate endpoint markers for bevacizumab-based therapies, with consideration for likely regulatory, clinical and payer acceptance. A total of 222 published studies were incorporated into the analysis. Plasma VEGF-A, PlGF and soluble VEGFR-1/VEGFR-2 demonstrated value as pharmacodynamic biomarkers with limited prognostic value. CECs and CA19-9 showed prognostic and predictive value under restricted indications. Blood pressure demonstrated superiority in its ability to predict response to bevacizumab. The evidence suggests the incorporation of biomarkers in clinical trial design must be tailored to the drug and the cancer indication to which the therapy is applied. The potential for blood pressure as a biomarker of response to bevacizumab has been highlighted. Bevacizumab-induced hypertension should therefore be considered as a key candidate for future biomarker-driven trials, increasing the likelihood of test-treatment acceptance by key regulatory and HTA stakeholders.