Role of aflibercept in the treatment of advanced colorectal cancer

SUMMARY Colorectal cancer is the third most common cancer in men, representing 10% of cases, and the second most common cancer in women, representing 9.4% of cases, worldwide. It is estimated that 50–60% of patients will develop metastases during the course of their disease, while 15–25% will present with synchronous metastatic lesions, reducing the probability of 5-year survival to 12%. Colon cancer represents the fourth most common cause of death from cancer worldwide and the second most common cause in developed countries. First-line therapy of advanced or metastatic colorectal carcinoma (mCRC) usually consists of the administration of oxaliplatin or irinotecan in combination with leucovorin and 5-fluorouracil. In the first- or second-line settings, monoclonal antibodies can be added to chemotherapy. Bevacizumab (anti-VEGF monoclonal antibody) is utilized with fluoropyrimidine-containing regimens in combination with oxaliplatin or irinotecan. Cetuximab can be administered in combination with irinotecan or as a single agent in patients who have wild-type KRAS. Panitumumab has also been approved for third-line single-agent therapy in KRAS wild-type patients and recently in first- and second-line therapy in combination with chemotherapy. There are no standard second-line treatments of mCRC specifically used in combination with FOLFIRI, and no drugs have been approved for patients with prior bevacizumab treatment. Aflibercept is a new angiogenesis inhibitor with a unique mechanism of action. Aflibercept is a recombinant fusion protein consisting of VEGF-binding portions from extracellular domains of the human VEGFR1 and 2 fused to the Fc portion of human IgG1. Aflibercept acts as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as the related ligands PIGF and VEGF-B. Aflibercept interferes with the biological actions of VEGF by ‘trapping’ VEGF and preventing it from interacting with its receptors on endothelial cells, blocking the activation of VEGFRs and the subsequent proliferation of endothelial cells; this results in inhibition of the growth of new vessels. The role of aflibercept in the management of mCRC was studied in the VELOUR trial, which showed that its addition to the FOLFIRI regimen resulted in a survival benefit, giving a statistically significant log-rank test with p = 0.0032 (hazard ratio: 0.817; 95.34% CI: 0.713–0.937). This benefit was supported by subgroup and sensitivity analyses, the increased median progression-free survival, and improved response rates observed in the aflibercept arm. Aflibercept toxicity is acceptable, manageable and within the established range of other VEGF inhibitors.