Advanced colorectal cancer and BRAF mutations: triplet combination improves survival

The three-drug combination of encorafenib, binimetinib, and cetuximab significantly improved overall survival (OS) in patients with BRAF-mutated metastatic colorectal cancer (mCRC), according to results of the BEACON CRC phase 3 clinical trial.

Prof. Scott Kopetz (MD Anderson Cancer Center, Houston, USA) presented the international collaboration, which included >200 centres worldwide in this open label, three-arm randomised clinical trial. A total of 665 patients with BRAF V600E-mutant mCRC who had progressed after one or two prior regimens in the metastatic setting were randomised to receive triplet therapy, doublet therapy (encorafenib and cetuximab), or the investigator’s choice of irinotecan or folinic acid, fluorouracil and irinotecan (FOLFIRI) and cetuximab [1]. BRAF mutations are estimated to occur in up to 15% of patients with mCRC, with V600E being the most common mutation and representing a poor prognosis for these patients.

The treatment combination resulted in median OS of 9 months (95% CI 8-11.4) for the triplet combination therapy compared with 5.4 months (95% CI 4.8-6.6) for current standard-of-care (HR 0.52; 95% CI 0.39-0.7, P<0.0001). Objective response rate (ORR) for the triplet-targeted therapy was 26% (95% CI 18-35) compared with just 2% (95% CI 0-7; P<0.0001) for standard therapy.

Median OS for the doublet combination was 8.4 months (95% CI 7.5-11) compared with standard therapy (HR 0.6; 95% CI 0.45-0.79; P<0.0003). The study was not powered to compare triplet and doublet therapies, but future analyses will explore which patients are most likely to benefit from triplet vs doublet combinations.

BRAF V600E targeted treatment was well tolerated, with grade 3 or higher adverse events seen in 58% of patients on triplet treatment, 50% of those in the doublet group, and 61% of those in the standard therapy group.

In conclusion, BEACON CRC is the first and only phase 3 trial designed to test BRAF/MEK combination targeted therapies in patients with mCRC and the BRAF V600E mutation, and the study reported clinical benefit for those selected patients. An ongoing study (ANCHOR-CRC) is evaluating the effect of triplet therapy in BRAF-mutant mCRC.

1. Kopetz S et al. ESMO Congress 2019. Abstract LBA006.
2. Kopetz S et al, N Engl J Med. 2019 Oct 24;381(17):1632-1643.



Posted on 26 November 201917 May 2024