Efficacy and Safety of Aflibercept and Its Role in the Treatment of Metastatic Colorectal Cancer

Abstract

Vascular endothelial growth factor (VEGF) and related pathway elements are critically important in the pathogenesis, growth, and development of solid tumors. Inhibiting the VEGF signaling pathway is being investigated as a therapeutic strategy for cancer, either by blockade of VEGF ligand binding or inhibition of the VEGF receptor. Aflibercept is a VEGF inhibitor that has been approved by the US Food and Drug Administration for the treatment of macular degeneration and metastatic colorectal cancer (mCRC). A search of PubMed and MEDLINE from January 2000 to August 2013 was performed using the following terms (or combination of terms): VEGF, colorectal cancer, mCRC, aflibercept, ziv-aflibercept. Studies were limited to those published in English. Phase 1 and 2 clinical trials of aflibercept in advanced non-hematological cancer showed acceptable safety and provided justification for further investigation. Four phase 3 clinical trials were conducted to evaluate aflibercept for the treatment of different cancers. The VELOUR trial evaluated aflibercept with FOLFIRI in patients with mCRC. The addition of aflibercept resulted in improved median overall survival (OS, 13.5 vs. 12.1 months, p = 0.0032). The VITAL trial evaluated docetaxel plus aflibercept vs. docetaxel plus placebo in patients with non-small cell lung cancer (NSCLC) who had progressed after first-line platinum-based chemotherapy; there was no significant difference between the two treatment groups in terms of OS. The VANILLA trial in patients with metastatic pancreatic adenocarcinoma was terminated because addition of aflibercept to gemcitabine failed to demonstrate improved OS in an interim analysis. In patients with metastatic androgen-independent prostate cancer, the VENICE trial also failed to demonstrate an increase in OS when aflibercept was combined with standard first-line chemotherapy. The most common adverse events associated with aflibercept in these trials were hypertension, venous and arterial thromboembolic events, hemorrhage, and proteinuria. In patients with mCRC, aflibercept demonstrated an improvement in OS when added to FOLFIRI. However, it has failed to show similar benefits in other tumor types. Further investigation is needed to improve patient selection and to distinguish patients who may benefit best from aflibercept from those who will require other anti-angiogenic agents.