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 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 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 V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
Related Questions
Would you choose to use IO or BRAF directed therapy based on BEACON? Or would you continue to use cytotoxic chemotherapy?
New answer by (March 6, 2020)
I agree with @Anita Turk and would utilize IO in the second line for BRAF-mutant MSI-H colorectal cancer, and cetuximab + encorafenib in the third line setting. I also favor f...
Of note - the tumor tissue biopsy NGS did not show KRAS or BRAF mutations. Microsatellite stable. Patient received first line FOLFOXIRI + Avastin .
New answer by Medical Oncologist at Mary Lanning Healthcare Morrison Cancer Center/University of Nebraska Medical Center Adjunct Faculty (January 9, 2022)
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 ...
G1 neuropathy and G3 neutropenia were observed with cycle 12 FOLFOX + bev.
Would you reintroduce oxali at a lower dose or switch to irinotecan+EGFRi ...
New comment by Medical Oncologist at Mayo Clinic ( January 24, 2022)
You are right. I would give FOLFIRI with panitumumab for RAS/BRAF WT left sided disease.
To re-challenge with oxaliplatin, no life time dose limit so it is really based on to...
Would you consider the BEACON regimen (i.e., encorafenib/binimetinib + cetuximab) in this setting?
New answer by Medical Oncologist at Mayo Clinic (July 6, 2022)
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 o...