N. Engl. J. Med. 2019 Sep 30
Encorafenib, Binimetinib, and Cetuximab in V600E-Mutated Colorectal Cancer.
Abstract
Background
Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.
Methods
In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.
Results
The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.
Conclusions
A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
Related Questions
What are your top takeaways from ASCO GI 2025?
1. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. This ambitious phase 3 randomized trial is an initiative of project frontrunner to attempt to allow access of targeted therapy in earlier lines of treatment for advanced ca...
How would you treat a young patient with metastatic colorectal cancer who initially tolerated 12 cycles of FOLFOX + bev with disease progression after cycle 3 of maintenance 5-FU + bev?
TRIBE and TRIBE2 studies showed convincing evidence of triplet chemotherapy FOLFOXIRI/bevacizumab has PFS, and more importantly, OS benefits for patients with metastatic colorectal cancer (mCRC) and now, this regimen has been used in our routine clinical practice more and more frequently especially ...
Would you use encorafenib with cetuximab vs encorafenib alone as second line therapy in a patient with metastatic colon cancer with concomitant KRAS G12V and BRAF V600E mutations identified on liquid biopsy?
I would rather state this question as, "Would you use encorafenib with cetuximab or cetuximab with encorafenib plus binimetinib (triplet regimen), or cetuximab in combination with irinotecan based chemotherapy?"Based on the available data, it seems like KRAS mutation was not relevant. BEACON trial (...
How would you treat metastatic colon CA with BRAF non-V600E mutation?
BRAF mutated metastatic colorectal cancer is about 7-10% of all metastatic colorectal cancer. When we discuss BRAF mutated metastatic colorectal cancer, we mainly/only focus on BRAF V600E mutated metastatic colorectal cancer, however, about 22% of BRAF mutations are Non-V600E which means about 2% of...
For a patient with metastatic colon cancer who tested positive for MSI (i.e. MLH1 hypermethylation etc) and BRAF mutation, what would be your preferred choice in the second line setting?
Approximately 15% of colorectal carcinomas demonstrate mismatch repair deficiency. The majority of these are MLH1/PMS2 deficient due to MLH1 promoter hypermethylation (MLH1ph). BRAF V600E mutations occur in approximately 50% of colorectal carcinomas with MLH1ph. The role of immunotherapy in patients...