Combination drug development in BRAF mutant colorectal cancer

Despite recent therapeutic advances, the management of patients with BRAF V600E mutant colorectal cancer (bmCRC) remains an area of clinical need. It is associated with a unique clinical phenotype, including its proximal tumor location, poorly differentiated histology, as well as peritoneal and nodal spread. Chemoresistance is often attributed to bmCRC, although this does not always manifest in progression- free survival (PFS) differences compared with its wild- type counterparts. However, overall survival (OS) remains universally poor irrespective of the therapy [1]. Furthermore, molecularly targeted therapy approaches to improve survival outcomes in these patients with BRAF inhibitors have been disappointing relative to the impressive responses observed in melanoma. In selected molecular basket clinical trials, the overall response rate (ORR) to these strategies in bmCRC was 0-5% and median progression free survival (PFS) was 2.1 months [2]