Metastatic
colorectal cancer (mCRC) is incurable in patients with unresectable disease. For most patients, the primary treatment is palliative systemic
chemotherapy. Genomic profiling is used to detect specific genetic mutations that may offer selected patients a modest survival benefit with targeted
therapy. Patients with mCRC with KRAS/NRAS/BRAF wild-type left-sided
tumors may benefit from
epidermal growth factor receptor (EGFR) inhibition with either
cetuximab or
panitumumab, in conjunction with
chemotherapy. EGFR inhibitors can extend survival by 6 months compared with
chemotherapy alone. The
vascular endothelial growth factor (
VEGF) inhibitor
bevacizumab can serve as an alternative to EGFR inhibitors in right-sided
tumors or second-line
therapy. Many patients will have RAS mutations, and targeted
therapies will not provide any benefit. The PRIME trial demonstrated that the addition of
panitumumab to FOLFOX was associated with reduced overall survival. Patients with BRAF mutations do not benefit from targeted
therapy unless a BRAF inhibitor supplements treatment. Triple combination
therapy with
cetuximab, the BRAF inhibitor
encorafenib, and the
MEK kinase inhibitor
binimetinib has extended overall survival by about 3 months compared with
chemotherapy alone. Finally, for the minority patients with
microsatellite instability (MSI) high/mismatch repair (MMR) deficient
tumors, either due to
Lynch syndrome or sporadic mutations,
immunotherapy is recommended as first-line treatment. The KEYNOTE-177 trial demonstrated that
therapy with single-agent
pembrolizumab improved progression-free survival by 8 months compared with FOLFOX or FOLFIRI and with or without EGFR inhibition. At this time, targeted
therapy should only be used in patients with unresectable metastatic disease.