We're Finally Beginning to Crack the KRAS Nut in Colorectal Cancer

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine at University of Oxford. If one were to define me narrowly — I would argue too narrowly — I could be described as a colorectal cancerologist. I spent a career looking at the therapeutic options and studying the biology of colorectal cancer. Today I'd like to talk about an article that popped up in The Lancet Oncology by Per Pfeiffer and one of his colleagues from Copenhagen, in which they discuss the "drugability" of KRAS.

We know that colorectal cancer is the valley of death for many, many drug-development programs. It's a tough nut to crack. And KRAS has been among the most intriguing of targets for the past 20 years or so. It's been extraordinarily difficult to find drugs that are active against it. KRAS is one of the earliest oncogenes identified. I remember when I was a youngster doing my PhD at Beatson Cancer Centre with Allan Balmain, who was one of the early discoverers and worked with KRAS extensively. And here we are 30 years later, at last, with some potential drugs that may work.

We know that 30%-40% of all colorectal cancers are KRAS mutant. But only 3% of those harbor the highly specific codon 12, G-to-C mutation. It's a minority of KRAS mutations. In 2013, there was a chemical breakthrough, For the first time, we had small molecular inhibitors that would bind fiercely and irreversibly to that specific KRAS mutant. Those drugs have proven effective in the treatment of non–small cell lung cancer; they've gone into an accelerated approval pathway as monotherapy. Two of the agents that have done very well with non–small cell lung cancer are sotorasib and adagrasib.

We know and we've talked about this before: We need to consider mutants contextually in terms of the tissue and the microenvironment from which they come, and of course, the different carcinogens at play in terms of the ontogeny and development of that tumor. No mutant is an island unto itself. Well, sometimes they are, but it's unusual.

Now, back to KRAS codon 12, G-to-C mutation. These drugs have been tried as single agents and they've fallen short, with response rates less than 10%. But some interesting new data, generated initially by biology, show that one of the resistance mechanisms to inhibition of this KRAS pathway, perhaps not surprisingly, is through EGFR signaling.

We know how to deal with that. We have cetuximab, we have panitumumab, and some recent basket-style trials are being reported that show that the addition of these specific KRAS-mutant blockers, with either panitumumab or cetuximab, are giving us response rates in the order of 30%-40%.

This is very encouraging. Now, it's a tiny minority of colorectal cancer, but nevertheless, if we are to follow a personalized-medicine approach, it leads us to have biomarkers to identify patients who will benefit, understand the biology that allows us to put rational combinations together, and to exploit these in the clinic.

A nice story, but more data are needed and larger numbers of patients studied. Watch this space for an interesting new addendum to the therapeutic compendium, the cupboard of drugs that we use to treat colorectal cancer. A further step, a small step, but a step nevertheless in the right direction toward personalized medicine for colorectal cancer.

Thanks for watching and listening, as always. For the time being, Medscapers, over and out.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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