Triple therapy prioritized

Roughly 1 out of 10 colorectal cancer patients have a BRAF mutation and a relatively poor prognosis. BRAF inhibition with a drug is not effective in those patients, in contrast to melanoma patients with that same mutation. In 2012 René Bernards and his colleagues at the Netherlands Cancer Institute discovered that colon cancer cells are insensitive to BRAF inhibition because of taking a detour through the epidermal growth factor receptor EGFR (see illustration). Give colorectal cancer patients a combination of such a BRAF inhibitor and a EGFR inhibitor, they advised.

Triple therapy

Following a first, successful clinical trial at the Netherlands Cancer Institute a large international study is currently being carried out by over 200 hospitals. In the context of this study physicians treat patients with metastasized, BRAF mutated colorectal cancer with three medicines simultaneously: encorafenib, binimetinib and cetuximab. The first two inhibit the BRAF and MEK kinases, the third blocks the EGFR receptor (see illustration).

The promising interim results of this triple therapy  made the American Food and Drug Authority FDA give the treatment a so-called breakthrough therapy designation, which means they'll speed up the registration process of the drug combination once the study is finished. In Europe the EMA agency is in charge of registration.

Intelligent combinations

"These patients respond well to the triple therapy", says Bernards. "This shows that drug combinations that are chosen intelligently, based on a solid scientific knowledge about how cells function, works not only in cells and mice but in patients as well."

The Netherlands Cancer Institute is one of the participants of the international study. The study includes patients with metastasized colorectal cancer and a BRAF mutation, who receive either standard treatment, or BRAF inhibitor encorafenib in combination with EGFR inhibitor cetuximab, or triple therapy. At the Netherlands Cancer Institute the study is expected to run until the end of 2018.