**6.3 Aflibercept**

Aflibercept is a recombinant fusion protein that binds to VEGF-A, VEGF-B and placental growth factor (PLGF), all of which have been implicated in angiogenesis and/or the survival of newly formed blood vessels [54]. As it binds to additional pro-angiogenic targets (compared to bevacizumab which binds only VEGF-A), aflibercept may provide further anti-angiogenic effects compared to targeting VEGF-A alone. In preclinical studies, it demonstrated a broad range of anti-tumour and anti-angiogenic activity both alone and in combination with chemotherapy, which was also observed in phase I clinical trials [55]. Recently, a large randomised phase III clinical trial (VELOUR) in advanced CRC patients, receiving second line therapy, demonstrated that the addition of aflibercept to systemic chemotherapy significantly improved outcomes compared to chemotherapy alone [56]. Based on this data, aflibercept was recently approved for use in the second line setting in mCRC when given in combination with chemotherapy. Importantly, results from a subanalysis of VELOUR showed that there was no significant impact of prior exposure to bevacizumab, illustrating the benefit that it provides as a multiple angiogenic factor trap, in a setting where resistance to bevacizumab may have developed [57].
