The BRAF V600E mutation is found in approximately 8% to 15% of patients with metastatic colorectal cancer (mCRC) and is a marker of poor prognosis. Patients with this particular mutation have typically been treated with standard first-line therapy regimens for RAS wild-type mCRC, which even with intensified regimens, still produce poor results. After failure of initial therapy, subsequent treatment with second and third-line therapy provides limited benefits, with reported overall response rates (ORRs) of less than 10%, median progression-free survival (PFS) times of approximately two months and median overall survival (OS) times ranging from four to six months.
Unlike in other tumour histologies with BRAF V600E mutations such as melanoma and non-small cell lung cancer, inhibition of BRAF alone in BRAF V600E-mutant mCRC produces minimal clinical response. This is due to the rapid feedback activation of epidermal growth factor receptor (EGFR) which allows prolonged MAPK (mitogen-activated protein kinase) activation and continued cell proliferation. However, when combined with targeted inhibition of EGFR, inhibition of BRAF results in synergistic inhibition of tumour growth in BRAF V600E-mutant CRC xenograft models. Additionally, even more profound inhibition of the MAPK signalling pathway and greater anti-tumour activity could be achieved with the addition of a MEK inhibitor, as has been clinically validated.
Triplet Therapy of BRAF, MEK and EGFR-inhibitors
The BEACON CRC open-label phase III clinical trial aims to clinically evaluate the triplet combination of encorafenib (Braftovi®, a BRAF inhibitor), binimetinib (Mektovi®, a MEK inhibitor) and cetuximab (Erbitux®, an EGFR-targeted monoclonal antibody) in patients with BRAF V600E–mutated mCRC who had disease progression after one or two previous regimens. 665 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 doses used in the clinical trial, as part of a 28-day cycle, are as follows:
- Encorafenib 300mg orally daily
- Binimetinib 45mg orally twice daily
- Cetuximab 400mg/m2 initially then followed by 250mg/m2 intravenously weekly
The results of the study were very promising, as the median OS was 9.0 months in the triplet-therapy group (95% CI = 8.0 – 11.4 months) compared to 5.4 months (95% CI = 4.8 – 6.6 months) in the control group. The objective ORR was 26% (95% CI = 18 – 35) in the triplet-therapy group and 2% (95% CI = 0 – 7) in the control group (P<0.001). The median OS in the doublet-therapy group was 8.4 months. 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.
The most frequently reported adverse effects included predominantly gastrointestinal and skin toxicities such as diarrhoea and dermatitis acneiform, as well as fatigue and nausea. Higher grade (grade 3 or 4) skin toxicities were rare and were less common than the 12% rate of grade 3 or 4 rash reported for cetuximab monotherapy. This suggests that BRAF inhibition may ameliorate this cetuximab-related adverse effect. Some patients experienced known MEK inhibitor class-related adverse effects such as serous retinopathy (also referred to as retinal pigment epithelial detachment), increased creatine phosphokinase, and reduced left ventricular ejection fraction. However, these are generally reversible and manageable with dose interruption, with or without subsequent dose reduction. The triplet combination regimen appeared to be well tolerated and the safety profile manageable.
Administration and Pharmacokinetic Properties of Braftovi® + Mektovi®
Both encorafenib and binimetinib should be swallowed whole with water. Both drugs are mainly cleared by the liver. Encorafenib has many potential drug interactions as its metabolism involves cytochrome P450 (CYP) 2C19, 2D6 and 3A4. Strong inhibitors of CYP3A4 such as clarithromycin and itraconazole, and grapefruit juice should be avoided. Liver disease will increase the concentrations of both drugs. A reduced encorafenib dose is advised in mild hepatic impairment (Child-Pugh Class A) and the combination should not be used in patients with greater impairment. The terminal half-life is about nine hours for binimetinib and six hours for encorafenib. Little active drug is excreted in the urine. Dose reductions are not required in mild to moderate renal impairment. However, there is no data regarding use of the combination in severe impairment. Animal studies have shown foetal toxicity. Therefore, the combination should not be used in pregnancy. Women of child-bearing potential should use effective contraception during treatment and for at least one month afterwards.
In conclusion, a combination of encorafenib, binimetinib, and cetuximab targeted therapy regimen 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, and may soon become a new standard of care. To maximise the potential for benefit to patients, additional investigation of this regimen in the first-line and potentially the adjuvant settings is warranted. A clinical trial to investigate the triplet therapy regimen in the first-line setting (ANCHOR-CRC [Encorafenib, Binimetinib, and Cetuximab in Subjects With Previously Untreated BRAF-Mutant Colorectal Cancer]) was recently initiated.
- Van Cutsem E, Huijberts S, Grothey A, Yaeger R, Cuyle PJ, Elez E, et al. Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAFV600E–mutant metastatic colorectal cancer: safety lead-in results from the Phase III BEACON colorectal cancer study. J Clin Oncol. 37: 1460-69.
- Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019; 381: 1632-43.
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