Evidence‐based second‐line treatment in ras wild‐type/mutated metastatic colorectal cancer in the precision medicine era

Target‐oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first‐line treatment and are eligible for second‐line approaches. In such a context, antiangiogenic and anti‐Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second‐line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K‐ and N‐RAS mutations are not eligible for anti‐EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first‐line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR‐based first‐line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its sub-stitution with another anti‐angiogenic agents has been shown to increase survival, whereas anti‐ EGFR monoclonals represent an option in RAS wild‐type patients. In addition, specific molecular subgroups, such as BRAF‐mutated and Microsatellite Instability‐High (MSI‐H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted ap-proaches. This review provides a critical overview about the state of the art in mCRC second‐line treatment and discusses sequential strategies according to key molecular biomarkers.