The evolving landscape of BRAF inhibitors in BRAF mutant colorectal cancer and the added value of cytotoxic chemotherapy

Our understanding of the molecular profile and associated targeted therapies has revolutionised the approach to treatment of metastatic colorectal cancer (mCRC). Approximately 10% (range, 8–21%) of mCRC carry a BRAF mutation which occurs primarily (>90%) at the V600E codon and leads to overactivation of the RAS/RAF/MEK/ ERK signalling [mitogen-activated protein kinases (MAPK)] pathway (1). BRAF mutant (MT) mCRC are renowned for their poor prognosis with a median overall survival (OS) inferior ranging from 10 to 20 months with resistance to standard systemic therapy, often not even reaching secondline treatment (2,3). The exception is the subset of MSI-H/ dMRR patients (up to 30% of BRAF MT CRC) who benefit from immunotherapy with checkpoint inhibitors (CPI) following the recent Keynote-177 trial (4). Unlike melanoma, previous trials with BRAF inhibition monotherapy (or combination with MEK inhibition) for BRAF MT mCRC show only minimal activity. This is due to feedback upregulation of epidermal growth factor receptor (EGFR) that re-activates the oncogenic pathway bypassing BRAF. Benefit of combining BRAF and EGFR inhibitors to overcome this pharmacological escape has been seen in several trials now. The BEACON phase 3 trial (5) is the pivotal study of this approach showing that the combination of the BRAF inhibitor encorafenib with anti-EGFR treatment (cetuximab) with or without a MEKinhibitor (binimetinib) led to significantly better OS and overall response rates (ORR) compared to irinotecan (FOLFIRI) or irinotecan with cetuximab. One strategy to ameliorate outcomes of these patients might be to combine multiple mitogen-activated protein kinases (MAPK) targeting agents with cytotoxic agents. Encouraging preclinical data combining irinotecan with anti-BRAF molecules (6,7), led Kopetz et al. (8) to explore the addition of the BRAF inhibitor vemurafenib to a backbone of irinotecan and cetuximab in previously treated BRAF MT mCRC.