Current Status of Angiogenesis Inhibitors as Second-Line Treatment for Unresectable Colorectal Cancer

SIMPLE SUMMARY: Colorectal cancer is the third most common disease and the second most common cause of death around the world. The drug for second-line treatment is determined by the type of drug used for first-line treatment and the biomarker status. As biomarkers, the RAS gene, BRAF gene, and dMMR (mismatch repair deficient)/MSI-H (microsatellite instability-high), TMB-H (tumor mutation burden-high), and HER2 statuses have been evaluated in clinical practice, and the corresponding molecularly targeted therapeutic agents should be selected based on the biomarker status. If all of these biomarkers are negative, an angiogenesis inhibitor is often used as second-line treatment. Although no useful biomarkers have been established for the selection of bevacizumab (BEV), ramucirumab (RAM), or aflibercept (AFL), which are the angiogenesis inhibitors used in second-line treatment, previous biomarker studies have suggested that VEGF-A and VEGF-D might be potential predictors of their therapeutic efficacy. The rationale for selecting these three angiogenesis inhibitors in second-line treatment should be clarified. ABSTRACT: Colorectal cancer is the third most common disease and the second most common cause of death around the world. The drug for second-line treatment depends on the drugs used in first-line treatment and the biomarker status. As biomarkers, the RAS gene, BRAF gene, and dMMR/MSI-H, TMB-H, and HER2 statuses have been established in clinical practice, and the corresponding molecularly targeted therapeutic agents are selected based on the biomarker status. Given the frequency of biomarkers, it is assumed that when patients move on to second-line treatment, an angiogenesis inhibitor is selected in many cases. For second-line treatment, three angiogenesis inhibitors, bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are available, and one of them is combined with cytotoxic agents. These three angiogenesis inhibitors are known to inhibit angiogenesis through different mechanisms of action. Although no useful biomarkers have been established for the selection of angiogenesis inhibitors, previous biomarker studies have suggested that angiogenesis-related factors such as VEGF-A and VEGF-D might be predictors of the therapeutic efficacy of angiogenesis inhibitors. These biomarkers are measured as protein levels in plasma and are considered to be promising biomarkers. We consider that the rationale for selecting among these three angiogenesis inhibitors should be clarified to benefit patients.