The Evolving Treatment Landscape in <i>BRAF-V600E</i>–Mutated Metastatic Colorectal Cancer

Abstract

Between 8% and 12% of patients with metastatic colorectal cancer (mCRC) harbor a <i>BRAF-V600E</i> mutation in their tumors, which is associated with a poor response to standard chemotherapy and short overall survival. Moreover, nearly 30% of <i>BRAF-V600E</i> mCRC tumors also have microsatellite instability. Transcriptomic signatures suggest a strong immunogenic biologic background for most of these tumors. In contrast to the melanoma context, single-agent BRAF inhibition does not achieve clinical benefit in <i>BRAF-V600E</i> mCRC. Different preclinical/translational studies have elucidated that, in this context, upon BRAF inhibition, there is immediate signal upregulation via the EGFR, and therefore an anti-EGFR treatment should be added to the BRAF inhibitor. Several phase II studies have confirmed the activity of BRAF inhibitors combined with EGFR-directed monoclonal antibodies in patients with <i>BRAF-V600E</i> mCRC. The role of other mitogen-activated protein kinase inhibitors, such as mitogen-activated protein kinase kinase or PI3K inhibitors, remains unclear. The phase III BEACON clinical trial confirmed the BRAF/EGFR inhibitor combination of encorafenib/cetuximab as the new standard of care for <i>BRAF-V600E</i> mCRC after at least one previous line of systemic therapy. Novel approaches for managing <i>BRAF-V600E</i> mCRC include, among others, triple combinations of BRAF inhibitors and anti-EGFR antibodies combined with immune checkpoint inhibitors in the microsatellite instability population and evaluation of the encorafenib/cetuximab treatment in combination with standard chemotherapy with bevacizumab in the first-line setting.