Sequencing of antiangiogenic agents in the treatment of metastatic colorectal cancer.

Significant advances have been made with respect to our understanding of the critical role of agents targeting angiogenic pathways in the treatment of metastatic colorectal cancer (mCRC). The approval of 3 agents that target angiogenic signaling, bevacizumab, ziv-aflibercept, and regorafenib, provides strong evidence that angiogenesis is an important process in mCRC. The addition of bevacizumab to combination chemotherapy in the first- and second-line treatment of mCRC has resulted in meaningful improvement in overall and progression-free survival. The standard of care for mCRC has evolved to incorporate cytotoxic chemotherapy as the backbone regimens (eg, FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin], FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]) with or without bevacizumab, and epidermal growth factor receptor-targeted therapies (eg, cetuximab, panitumumab) in the setting of wild-type KRAS. The development of ziv-aflibercept in combination with FOLFIRI has improved clinical efficacy in the second-line treatment of mCRC. Regorafenib, a small-molecule multikinase inhibitor, has recently been approved by the US Food and Drug Administration as single-agent therapy in the treatment of refractory and progressive mCRC. Each of these agents has been integrated into an evidence-based-albeit, still evolving-treatment continuum for initial treatment, treatment after first progression, and treatment after second progression. However, the most effective strategy for the use of these agents, and others in development remains unclear. This review provides an overview of the current clinical evidence for the use of antiangiogenic agents targeting in the treatment of mCRC.