One of the reasons BRAF inhibitors may not be effective in BRAF-mutated mCRC is due to the strong feedback activation of the EGFR receptor upon BRAF inhibition. Thus, a study was initiated to evaluate the safety and efficacy of encorafenib (a highly selective BRAF inhibitor) plus cetuximab, with or without the PI3K inhibitor BYL719 in patients with advanced BRAF-mutant/KRAS?wild-type mCRC (Van Geel R, et al. ASCO 2014. Abstract 3514). Of 18 patients recruited into the study, there have been 3 partial responses (including 1 in the triple arm), and prolonged disease stabilization was frequently achieved. Grade 3 toxicities to this combination included vomiting and QTc prolongation, but fatigue and vomiting were the most frequently observed adverse events that could be managed appropriately. This triplet therapy holds promise for patients with advanced BRAF-mutated mCRC who have failed standard treatments. Whether there is overall value in this regimen in prolonging survival or disease stability will be determined with further study.
