Targeted therapy for metastatic colorectal cancer: role of aflibercept

Worldwide, colorectal cancer (CRC) is the third most commonly diagnosed cancer in male individuals and the second most commonly diagnosed cancer in female individuals. Survival outcomes are less than optimal for patients with metastatic disease, with a 5-year survival in the 5% to 8% range. The development of new chemotherapeutic agents and effective combination regimens for metastatic colorectal cancer (mCRC) has increased median overall survival (OS) to the 24- to 28-month range. Because of the recognition that vascular endothelial growth factors (VEGFs) and their receptors are primary regulators of physiologic and pathologic angiogenesis and lymphangiogenesis, leading to neovascularization and tumor growth, the targeting of the angiogenic pathway has become a focus of key therapeutic strategies in mCRC. Therapeutic regimens that include bevacizumab, an inhibitor of VEGF-A, in combination with cytotoxic chemotherapy, have resulted in improved response rate (RR) and survival in mCRC. However, the effects of VEGF-A inhibition are often temporary, with resistance and disease progression developing in most patients. Proposed models include intrinsic and adaptive resistance, mediated by factors other than VEGF-A. Aflibercept (known as ziv-aflibercept in the United States; Zaltrap®, Regeneron Pharmaceuticals; sanofi-aventis), a novel recombinant fusion protein, is an angiogenic factor trap that blocks the binding of VEGF-A, VEGF-B, and placental growth factor. Phase I/II clinical trials have demonstrated effective activity in mCRC, with acceptable safety and tolerability. A recent phase III randomized double-blind trial in patients previously treated with oxaliplatin reported significant improvement in OS, progression-free survival (PFS), and RR with aflibercept compared with placebo when administered in combination with irinotecan and fluorouracil. Adverse events were consistent with anti-VEGF therapy. Thus aflibercept represents a potential new treatment option for patients with mCRC.