Development of novel inhibitors of KRASG12C

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Published: 4 Nov 2020
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Dr Kevan Shokat - University of California San Francisco, San Francisco, USA

Dr Kevan Shokat speaks to ecancer about the development of novel inhibitors of KRASG12C: a topic that was discussed at this year’s ENA 2020 virtual meeting.

Dr Shokat starts with talking about what kind of cancers can we find KRASG12C mutations in and why the development of these inhibitors is an important leap in the world of targeted therapies. He then gives recent updates regarding the development of these drugs, especially with regards to what was presented at the ENA 2020 meeting.

He says currently there is no drug out there but a lot of drugs are in phase I and II clinical trials right now. Dr Shokat winds it up explaining how these inhibitors can impact the future of cancers treatment and translational research.

Dominantly in lung cancer, non-small cell lung cancer, about 30% of lung cancer has KRAS mutations and the most common KRAS allele that is observed is the G12C allele. Then the next largest is colon cancer where G12C as well as G12D and V are found mutated. There’s a significant G12C population, although it’s not the highest frequency, in colon. Then there are various rare sets of pancreatic cancer mutations that have the KRASG12C mutation.

Why is the development of KRAS(G12C) inhibitors important?

The main reason is that we know from the twenty years of history of targeted therapies, for example the kinase inhibitors, is when we can get a drug to bind to the oncogenic mutation and inhibit the actual driver oncogene the tumours have a chance to melt away and have a very strong response. But if we inhibit another step in the pathway that is activated by the oncogenic mutation sometimes we don’t get a very good therapeutic response. So the highest priority of the targeted therapies is for every driver oncogene we need a drug that inhibits that protein. That’s where we interrupt the cancer signalling the best.

At the meeting we heard updates from Mirati. Pasi Jänne gave a beautiful talk on I believe it was Sunday morning about the Mirati G12C inhibitor in lung cancer, the frequency of response, the durability and the rather well tolerated nature of the drug. And another talk in a later session was given about the effect of the G12C drug in other cancers like colon cancer and pancreatic. So right now we’re seeing every month another large chunk of clinical data. Since last summer, or two summers ago, where Amgen reported their first phase I clinical trial data it has been very, very promising news.

So it looks to me like one or several KRASG12C inhibitors will be approved in the coming years and there are a large number of patients that would qualify for the trials that are looking good.

Are there any approved drugs of this nature yet?

No, none of these have been approved yet. They are all now in the efficacy trial stage. Some are in phase I – Genentech announced they put a new entity into phase I and Amgen and Mirati are in phase II, phase III. So those are ongoing trials, they have received promising news from the FDA about likely criteria for approval so everything is looking quite good. But no approvals yet.

How will these inhibitors impact the future of cancer treatment?

The first thing they do is they tell us what happens when we make a drug against KRAS. The data I was telling you looks quite exciting. Now, the narrowness of these drugs, in other words they only work on the G12C mutation, means that many KRAS mutant patients would not benefit from this drug. So we need new drugs to target the G12D allele and the V allele. So what this drug tells us is the signal finding of the potential if we drug KRAS and many, many patients will benefit. But the next opportunity will be to go after the other alleles and in particular the G12D allele which is the most frequent in pancreatic cancer which is such a lethal cancer.

So, if we can say it, I look at it this way, that the G12C drugs were a chemical achievement that enabled us to see a clinical benefit. Now that takes the biological question of whether a drug for KRAS is going to be valuable out of the equation. Now there is very little biological risk. Now the G12D allele is the chemical challenge. That’s the mountain we need to climb. There is emerging data I presented at the meeting of some of our G12D data but this has now mobilised everybody to go all in on the chemistry and the structure. I’m very hopeful that in the coming years we’ll hear some really exciting new molecules for these other KRAS alleles. As a total they represent about 30% of cancer so this is a great opportunity to finally treat these kinds of tumours.