The results of a new clinical trial published today in the New England Journal of Medicine show that using a combination of three drugs that target a specific BRAF gene mutation in patients with metastatic colorectal cancer (mCRC) effectively boosts the overall survival (OS), an important indicator of treatment success. The BEACON CRC Phase III trial was reported by researchers at The University of Texas MD Anderson Cancer Center. The drugs tested were encorafenib, binimetinib and cetuximab.
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Colorectal cancer, which affects the large bowel and rectum, is a major killer among cancers. It is the second most deadly cancer in men and women combined, with just over 51,000 deaths in 2019 alone. Even when examined separately, it is also the third most common cause of death in both sexes.
Targeted therapy specifically targets the cancer’s proteins or genes. In this case, the triple-gene therapy targets the BRAF and MEK mutations, in the 15% of CRCs that have a mutation called the BRAF V600E in the BRAF gene. This makes up over 90% of BRAF mutations in patients with mCRC, and is a powerful driver of the malignant process. Thus, its presence indicates a poor outcome, the median survival being less than 12 months from diagnosis. Most such patients are female and over 70 years of age, never under 60. It is associated with poorly differentiated tumors, faster spread throughout the abdominal cavity and larger tumor size.
How this triplet combination works
The cells within the human body constantly communicate on a host of issues with each other. One such very important pathway of crosstalk is the RAS/RAF/MEK/ERK or MAPK (mitogen-activated protein kinase) signaling cascade. It regulates the multiplication, maturation, survival and end-of-life of the cell in a normal organism, and is in turn regulated by feedback from stress pathways, the cell’s own DNA, changes in the concentrations of various proteins, and signals from growth factors and from other cells. When this pathway goes out of control, the cell can develop malignant behavior – uncontrolled proliferation, failure to go into its programmed nontoxic cell death (apoptosis) mode, and lack of differentiation into a mature (and typically non-proliferating) form.
The enzyme called RAS initiates this pathway, activating a succession of downstream protein kinase enzymes, including the one called BRAF. The RAF family, in turn, acts primarily upon MEK1 and MEK2, enzymes of the MAPK/ERK group. These activate a number of transcription factors, enzymes that drive the downloading of messages from DNA in the form of RNA, which in turn regulates the production of specific proteins within the cell in response to the cell’s needs. These include the epidermal growth factor receptor (EGFR) proteins.
Among all molecular changes that lead to cancer in human beings, RAS and RAF mutations predominate. Located on chromosome 7 (q34), the BRAF gene that encodes the BRAF enzyme has been found to have over 30 mutations so far, and in 90% of cases, it is the V600E variant – the most powerful cancer-producing mutation of them all. This V600E mutation renders the BRAF gene independent of the need for activation, and increases its level of activity tenfold.
The problem with using BRAF inhibitors to silence this mutated gene is that the tumor rapidly adopts other pathways to achieve the same goals, bypassing the silenced gene. This leads to a very poor response to treatment. To avoid this, multiple drugs blocking different pathways were used in the current trial. Encorafenib is an RAF inhibitor that is very selective for the enzyme. It is used with bimetinib, an MEK1/ MEK2 inhibitor, and cetuximab, which is an EGRF inhibitor.
Encorafenib was given Breakthrough Therapy Designation in August 2018 by the US Food and Drug Administration (FDA) in mCRC patients with BRAF V600E who had progressed with one or two courses of standard treatments. This means that early clinical evidence could indicate the drug is much better than standard existing therapy, either in terms of longer survival or reduction of irreversible symptoms and signs of the disease. This approval puts the drug on the fast track for development and review and ensures that the FDA works with the researchers to take its development forward as efficiently as possible.
Importance of this trial
The BEACON CRC trial was performed at over 200 centers all over the world, so its results can be considered generally applicable. These findings were first reported in the ESMO World Congress on Gastrointestinal Cancer 2019. This is the only phase III clinical trial to look at the success rate with combined targeted therapies.
In this open-label trial, which means that patients knew which drugs they were getting, there were 665 patients with BRAF V600E mCRC, all of whom had received one or two courses of standard treatment for metastatic cancer. All were switched to alternative therapies after they progressed on conventional treatment. They were randomly assigned to one of the following arms:
- Triplet regimen (encorafenib, binimetinib and cetuximab)
- Doublet therapy (encorafenib and cetuximab)
- A combination of either irinotecan with cetuximab, or folinic acid, flurouracil and irinotecan (the FOLFIRI regimen), and cetuximab. These patients received either of these regimens according to the researchers’ discretion.
The median OS with triplet therapy was nine months compared to 5.4 months for the treatment that is currently considered the standard of care (the doublet regimen). Moreover, the objective response rate (ORR) was 26% - or in other words, over a quarter of patients who had mCRC had a decrease in tumor size that met a preset criterion in terms of amount and duration of response after being treated with the triple-drug combination. This is in contrast to only 2% with standard treatment.
There were no unforeseen adverse events with the triple-drug combination. The rate of adverse events of grade III or higher was 58%, 50% and 61% with triplet, doublet and standard therapy respectively. About 11% of those on standard therapy stopped treatment because of adverse events, compared to 8% and 7% in the doublet and triplet groups respectively.
The results of this trial will support attempts to gain full approval for the use of this drug in this group of patients. In this group of patients, the triplet therapy seems to confer a survival advantage in terms of months over standard therapy. Drugs which inhibit the BRAF pathway, called BRAF inhibitors, are already a new option in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of both colon and rectal cancers within the US.
This study builds on a decade of research into the tumor biology of BRAF-mutated colorectal cancer, and reflects a rational combination to address the vulnerabilities unique to this tumor. We are encouraged to see a meaningful improvement in outcomes with this new regimen for our patients. This targeted therapy combination should be a new standard of care for this patient group.”
Researcher Stephen Kopetz
Future work will try to throw light on the question of whether this combination may also benefit those with less advanced disease or as a first-line treatment. Also, triplet and doublet therapies must now be tested on different patient groups to find out which one has the greatest impact on each condition. Meanwhile, other scientists are already carrying out the ANCHOR-CRC trial to look at how triplet therapy works if given as first-line treatment to these patients, instead of as a reserve drug combination after the failure of earlier therapies for metastatic cancer.
Kopetz, S., et al. (2019). Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. NJEM. https://www.nejm.org/doi/full/10.1056/NEJMoa1908075