In colorectal cancer, BRAFV600E mutations occur in 10–15% of patients and confers a poor prognosis.1–3 Previous attempts to address this genetic alteration with specific BRAF inhibitors yielded disappointing results, mainly due to the feedback activation of the epidermal growth factor receptor (EGFR), which leads to continued cell proliferation.4–6 To overcome this feedback mechanism, investigators evaluated the effect of simultaneously targeting multiple intracellular signal transduction pathways (including BRAF, MEK and EGFR). In this respect, the BEACON CRC trial evaluated a treatment regimen consisting of the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab, with or without the MEK inhibitor binimetinib in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC). In previous reports of this trial, it was already established that encorafenib and cetuximab with or without binimetinib had a manageable safety profile in this setting with encouraging clinical activity. Updated results of this trial, presented at ASCO 2020, further solidify these initial findings and indicate a significantly improved overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for encorafenib plus cetuximab, relative to the standard chemotherapy-cetuximab treatment in patients with BRAFV600E-mutant mCRC.