In 2012, researcher René Bernards and colleagues at the Netherlands Cancer Institute discovered why colon cancer cells are insensitive to BRAF inhibition. They showed that the growth signals in cells take a detour, which means that they can continue to function. This detour goes via the epidermal growth factor receptor EGFR (see illustration). Their recommendation was to give bowel cancer patients both a BRAF inhibitor and an EGFR inhibitor, and in this way blocking the detour.
Following the first successful patient study at the Netherlands Cancer Institute, a large international study was set up for patients with metastatic bowel cancer and a BRAF mutation: the BEACON study. The standard treatment for these patients is chemotherapy in combination with an EGFR inhibitor. The BEACON study compares this standard treatment with two experimental treatments that combine BRAF and EGFR inhibitors and exclude chemotherapy. Some of the patients also received a MEK inhibitor. The Netherlands Cancer Institute also participated in this study, under the supervision of PhD student Sanne Huijberts, among others.
The results show that patients who receive the smart combination treatments now survive longer: 8 to 9 months compared with 5 months for standard treatment. In addition, in this group it takes longer for the disease to start growing again: 4 months versus 1.5 months. Oncologist, Neeltje Steeghs from the Netherlands Cancer Institute: "This is a unique combination of medicines for patients with a tumour that has not responded well to any drug at all until now. Ultimately, these tumours will also become insensitive to this combination treatment, but it does give patients a few extra months of time."
At the end of last year based on the promising intermediate results, the American medicines agency FDA gave the combination therapy a so-called breakthrough therapy designation. This means that the FDA has promised to accelerate the registration of the combination therapy as soon as the study is completed. The EMA is the equivalent body in Europe. Until the treatment is approved it is unavailable.
In the future, this new treatment will be standard care. The situation is quite unique in that this treatment not only originated in the laboratory of the Netherlands Cancer Institute, but also in that it was tested in clinical trials in patients under the same roof. Researcher René Bernards who discovered why bowel cancer patients don't respond to BRAF inhibitors: "It is gratifying to see that intelligently chosen combinations of medicines that are based on solid scientific knowledge of how the cell works, not only work in mice and cells but also in patients."
About the BEACON study
Treatment: three treatment schedules: 1) chemotherapy and EGFR inhibitor, 2) BRAF inhibitor and EGFR inhibitor, 3) BRAF inhibitor, MEK inhibitor and an EGFR inhibitor
Patients: 665 patients with metastatic colorectal cancer, a BRAF mutation and disease progression after 1 or 2 other treatments
Status: this study is closed, no new patients can take part
The research by René Bernards and colleagues was published in 2012 and was financially supported by the Dutch Cancer Society, NWO, the EU and the European Research Council. The BEACON-study was financed by Array BioPharma.