Advanced NSCLC: Rationale Behind KRAS Inhibition

David R. Gandara, MD: For many years—as a matter of fact, I’ve written editorials on this—KRAS has been called the undruggable mutation, and for many years it has been. Ben, why was it described as undruggable, and what has changed to make it now druggable with a therapeutic agent?

Benjamin P. Levy, MD: I just want to throw out a disclosure that I am not a card-carrying molecular biologist, but I have certainly learned a great deal about the undruggability of KRAS as these new novel therapies have come into play. What we know historically about KRAS is that there are specific features of the molecular structure of this protein that have shown a high resistance to small molecular modulation, and small-molecule modulation is how we’ve moved the field forward for EGFR and ALK and other receptor tyrosine kinases. We’re learning more about why this is. Just getting down to some details, the mutated KRAS protein has a smooth, shallow surface that makes small-molecule binding very challenging. GTP, which you talked about, almost exclusively occupies that pocket with a high degree of affinity and locks it into the “on” state, where the pedal is put to the metal and the gas is on and is constitutively activated and you have this downstream signaling. If you can’t have interference with a small-molecule inhibitor, coupled with the idea that GTP is exclusively locked in that pocket, you’re going to have uncontrollable cell growth.

The G12C mutation has lent itself to some therapeutic vulnerabilities. We know now that altered protein, and unfortunately other KRAS mutations, may not have an altered protein that lends itself to therapeutic vulnerability, but this altered protein does have a potential pocket located near the GTP binding pocket that can be accessed by a small-molecule inhibitor. Once that small-molecule inhibitor binds to that altered site, it can essentially lock that protein in its GDP-bound state. If you can get that protein to lock into GDP, it essentially renders it inactive or not constitutively active, so you shut down all the downstream signaling.

That’s the basic overview. David, you’ve been very well versed in this field. I don’t know if you have anything to add. But that’s my take on the undruggability of KRAS and how we’ve been able to exploit some of the therapeutic vulnerabilities given the shape or the protein pocket of the altered mutated protein overall.

David R. Gandara, MD: That’s a very thoughtful explanation, Ben. I like it. Would it be fair to say, then, that the reason KRAS mutation has been called undruggable is both structural and biological or functional, because it’s also high-affinity binding that makes it hard to displace it?

Benjamin P. Levy, MD: Yes, I think that’s a good category to think about in terms of the undruggability.

David R. Gandara, MD: For the same reason, then, why haven’t drugs been able to be developed for these other variants, such as G12V and G12D? Is it just because of these structural and affinity characteristics?

Benjamin P. Levy, MD: That’s my understanding. They don’t have the binding pocket that has lent itself to small-molecule modulation. Again, I’m not a card-carrying molecular biologist, but I hope there will come a day when we do develop some drugs that can get into these spaces a little better than they do now and mirror some of the successes we’ve had with KRAS G12C.

David R. Gandara, MD: It’s very interesting. I get a lot of consults or second opinions or calls from oncologists. Everybody is aware that there is something going on with KRAS. This week, I got 2 requests to see patients with a KRAS mutation, both from the same oncologist. I asked, “What do they have?” They have KRAS. I asked, “Which one?” They said, “I have no idea.” Everybody is learning that it’s important, but the purpose of an interchange like this between you and me is to try to shed some light on why it’s important.

Benjamin P. Levy, MD: It’s important for someone like me, who is a dedicated thoracic medical oncologist. For patients we are screening for potential trials, they’ve gone on to immunotherapy. We’ll talk about potential immunotherapy utility for KRAS alterations and coalterations that may impact outcome. But it’s forced even me to say, “We did the molecular testing about a year ago, but we now have some studies looking at specific KRAS G12C inhibitors. It’s time to go back and look to see exactly what KRAS mutation you have, because it is so important to parse that out.” That’s a very good point.

Transcript edited for clarity.