The Evolving Treatment Landscape in -Mutated Metastatic Colorectal Cancer

Between 8% and 12% of patients with metastatic colorectal cancer (mCRC) harbor a mutation in their tumors, which is associated with a poor response to standard chemotherapy and short overall survival. Moreover, nearly 30% of 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 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 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 mCRC after at least one previous line of systemic therapy. Novel approaches for managing 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.