Triple down.

The 5-10% of metastatic colorectal cancer (mCRC) patients whose disease harbors a BRAF V600E mutation have a poor prognosis. That is because they tend to have a poor response to initial systemic therapy, quick progression, and poor response to subsequent targeted therapy. In particular, they don’t respond well to BRAF-targeted therapy. Why? If you comb through the EGFR-signalling pathway, you’ll see a laundry list of proteins involved in colorectal cancer pathogenesis (including Raf). So what if you attacked the EGFR pathway at multiple points? In BEACON CRC, patients who progressed on first or second-line systemic therapy and who had BRAF V600E mutation were randomized to receive either [1] triplet therapy with encorafenib (BRAF), binimetinib (MEK), and cetuximab (EGFR); [2] encorafenib and cetuximab; or [3] cetuximab and either irinotecan or FOLFIRI. Triplet therapy had a much higher response rate (2 → 26%), and also significantly improved median overall survival from 5 → 9 months. TBL: Triplet targeting of the EGFR pathway improves survival over standard therapy in patients with progressive mCRC with BRAF V600E mutation. | Kopetz, N Engl J Med 2019