The presence of BRAF V600E mutations in metastatic colorectal cancer (mCRC) has long been known to be associated with an extremely poor prognosis with a median survival of about 12 to 15 months in clinical trials. In contrast to melanoma carrying the very same mutation, single-agent BRAF inhibitors, or combinations of BRAF and MEK inhibitors, have not shown relevant clinical activity in mCRC. The randomized phase II trial presented at ASCO GI now explored a triplet combination of the BRAF inhibitor vemurafenib added to the regulatory standard of care, cetuximab and irinotecan. The triplet combination met the primary endpoint of the trial in the form of a clinically relevant improvement in progression-free survival with higher response and disease-control rates. It is of note that, in the triplet combination, cetuximab likely serves to counteract feedback-loop activation of EGFR after BRAF blockade. It will remain to be seen if regulatory agencies or guideline committees will regard the results as practice-changing.
