Beyond EGFR Inhibitors in Advanced Colorectal Cancer: Targeting BRAF and HER2.

The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.