BRAF mutations are detected in up to 20% of patients with metastatic colorectal cancer (mCRC) and portend a very poor prognosis. Now, data from the phase III BEACON CRC trial, recently reported at the ESMO Congress 2019 and in the New England Journal of Medicine, demonstrate the promising efficacy of a rational combination of targeted agents.

“BRAF inhibitors as monotherapy have failed to improve the outcomes of patients with BRAFV600E-mutated mCRC,” states corresponding author Josep Tabernero. This finding is contrary to the results obtained in other BRAFV600-mutated cancers, particularly melanoma, and is explained by rapid activation of bypass signalling via EGFR in mCRC. “Thus, we sought to potentiate BRAF-targeted therapy with an EGFR inhibitor, with or without a MEK inhibitor,” explains Tabernero.

Accordingly, 665 patients with previously treated BRAFV600E-mutated mCRC were randomly assigned (1:1:1) to either triplet therapy with encorafenib, binimetinib and cetuximab, doublet therapy with encorafenib and cetuximab, or control treatment with cetuximab and irinotecan-based chemotherapy. The median overall survival durations were 9.0 months, 8.4 months and 5.4 months, respectively (HR 0.52 for the triplet and 0.60 for the doublet versus the control treatment; P < 0.001 for both comparisons). The objective response rates were 26%, 20% and 2%, respectively. Importantly, the novel combinations had favourable toxicity profiles, with a lower rate of grade ≥3 adverse events with the triplet (58%) and with the doublet (50%) than with control treatment (61%).

“Our findings point to a paradigm shift in the treatment of BRAF-mutant mCRC and warrant further investigation to better define the benefits of both the triplet and doublet therapies,” opines Tabernero. Indeed, the study was not powered to compare the triplet and doublet therapies; for some patients the doublet might be sufficient. “These novel combinations are certainly showing promise in reverting the resistance of this disease to therapy and must be pursued swiftly,” concludes Tabernero. Notably, the ongoing ANCHOR-CRC trial will provide insights into the efficacy of the triplet in patients with treatment-naive mCRC.