Section of a human colon. Credit: Winton lab
A new chemotherapy-free drug combination for people with a rare type of bowel cancer has been approved for NHS use in England.
The combination of encorafenib (Braftovi) and cetuximab (Erbitux) will be the first approved bowel cancer therapy to target cells containing specific defects. It will now be an option for people whose cancer cells contain a rare error in a gene called BRAF, after they’ve had chemotherapy, and if their disease has spread to other parts of the body.
The approval comes months after the drug was initially rejected due to uncertainties surrounding the cost-effectiveness of the treatment.
“This drug combination has been 20 years of hard work in the making and it’s great to see it enter the clinic.” – Professor Richard Marais, a genetics expert at the Cancer Research UK Manchester Institute.
A ‘step change’ in bowel cancer treatment
Bowel cancers with a particular DNA error (known as BRAF V600E-positive cancers) produce faulty growth-promoting proteins and are more likely to come back than other types. For decades, treatment for recurrent bowel cancers has generally been chemotherapy.
Rather than the ‘broad-spectrum’ killing of all fast-growing cells offered by chemo, the new combination precisely targets 2 proteins found in cancer cells that are known to be involved in driving cancer growth. One drug – encorafenib – targets the faulty BRAF protein. The other, cetuximab, targets a second protein, known as EGFR.
Clinical trial results have shown that people taking the new targeted duo lived for 9 months on average, compared to 5.4 months for those taking one of two different combinations of chemotherapy and cetuximab.
In the initial National Institute of Health and Care Excellence (NICE) committee meeting, clinicians called the combination a ‘step change’ in the treatment of BRAF V600E-positive bowel cancer, being the first combination to effectively target cells bearing the mutation. The treatment also provides a welcome treatment option for a type of bowel cancer that’s seen little improvement in survival in recent years, despite overall improvements in bowel cancer survival.
“These drugs have transformed my disease”
Podcaster and writer Deborah James was diagnosed with advanced (stage 4) bowel cancer in 2016. She’s been taking the targeted combo for the past 16 months and was one of the patients who sat on the NICE committee for this decision.
“These drugs have transformed my disease. I’m fully aware that they won’t cure me, but I’m coming up to 4 years post-diagnosis with metastatic bowel cancer and the fact that I’m in that position is thanks to the drugs I’m taking.”
James says that she’s had a number of side effects while taking the targeted combination. “I had a bad skin reaction to the drugs, as well as problems with my eyesight, but we were able to manage the reaction with other treatments.
“It’s been a rollercoaster with the side effects, but the drugs have massively improved my quality of life overall – I ran a marathon a few months ago and I just wouldn’t have been able to do that on chemotherapy.”
For James, the next step is to get the treatment option into the system as quickly as possible.
“The drugs are targeted towards a very specific subset of bowel cancer, so not everyone with bowel cancer will benefit. It’s about speaking to your oncologist to see if they could be an option for you.”
NICE decisions are usually adopted in Wales and Northern Ireland as well as England, so the drug combination should now be available to patients in all 3 nations. Scotland has a separate process for reviewing drugs.
The story of the targeted treatment combo began in 2002, when Professors Richard Marais and Mike Stratton first linked a faulty version of the signalling protein BRAF to melanoma. Funded by Cancer Research Campaign, a forerunner of Cancer Research UK, the team showed that this DNA error (mutation) drove cells to become cancerous.
Two years later Marais and Professor David Barford pieced together the 3D structure of the faulty BRAF protein, a vital step towards designing drugs that could target it.
Although much of the early work focused on melanoma – in which BRAF-targeted drugs have proven effective – BRAF errors are not exclusive to this type of cancer. “About half of melanomas have BRAF mutations, but about 10% of bowel cancers also have the same BRAF mutations” says Marais.
Marais adds that initially researchers trialled treating bowel cancer patients with BRAF drugs on their own, but that approach didn’t really work. “Nobody at the time really understood why it worked in melanoma, but not in bowel cancer.”
After digging deeper into the faulty molecule ‘wiring’ of bowel cancers, Professor Rene Bernards in the Netherlands came up with a plausible explanation. The results showed that when drugs interfered with the growth signals sent by mutant BRAF proteins, bowel cancer cells – unlike melanoma cells – were able to rely on growth signals from a different protein, called EGFR. Bernards showed that by targeting BRAF and EGFR at the same time he could stop bowel cancer cells growing, paving the way for combination therapies like the one approved today.
“It’s an excellent example of a drug that is based on an understanding of cancer biology, but when you start using the drugs they don’t work as expected, but it reveals new biology that forces you to rethink your approach,” says Marais.
“Better understanding of the biology leads to testing of new combinations of drugs to find the best treatment for patients who have specific DNA faults in their cancers. It really does speak to the concept of precision medicine.”
NICE (2020) Encorafenib in dual or triple therapy for previously treated BRAF V600E mutation-positive metastatic colorectal cancer [ID1598]