The presence of a BRAF mutation is associated with poor prognosis in metastatic colorectal cancer (mCRC) and results in unique clinical characteristics, as demonstrated by retrospective series I published with my team. I was the first to report on the limited activity of BRAF inhibitors in mCRC, and subsequently explored this unique biology in in vitro and murine combination studies in mCRC models. Based on this preclinical work, we have completed multiple clinical trials leading to Food and Drug Administration (FDA) approval of encorafenib and cetuximab.
I have been involved in establishing molecular subsets of CRC, with an emphasis on integrating ribonucleic acid (RNA) profiling into clinical practice. This effort is focused on moving consensus characterizations into clinical practice, both through retrospective interrogation of existing cohorts, but also including prospective clinical trials planned and underway. I have encouraged biomarker-enriched clinical trials and am a leader at the national level in development of these studies in the US cooperative groups.
Microsatellite instability in CRC has been associated with expression of multiple neoantigen and a unique molecular subtype. Based on my investigator-initiated concept with Dr. Michael J. Overman and his Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) clinical trial screening framework, program death cell protein 1 (PD-1) inhibition with nivolumab was evaluated in high microsatellite instability (MSI-H) CRC, which demonstrated meaningful activity alone, or in combination with ipilimumab, resulting in FDA approval for both agents.
Biomarker enrichment studies have demonstrated the potential limitations of findings from CRC primaries, including potential discordance. Development of circulating cell-free DNA assays have allowed improved interrogation of contemporary molecular findings. Dr. Kopetz has demonstrated the heterogeneity associated with many driver mutations in CRC, including mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibitions. These findings are being prospectively integrated into current clinical trials.