Targeting KRAS in NSCLC: Recent Progress and New Approaches

MedPage Today brought together three expert leaders for a virtual roundtable discussion on lung cancer: Moderator Roy Herbst, MD, PhD, is joined by Anne Chiang, MD, PhD, and So Yeon Kim, MD, all from the Yale Cancer Center in New Haven, Connecticut.

This third of four exclusive episodes examines current emerging options for patients with KRAS G12C-mutated non–small cell lung cancer. You can see other videos in this series here.

Following is a transcript of their remarks:

Herbst: Next topic. Let’s talk about KRAS. I’m probably the most senior member of this trio here, And I’ll tell you, I grew up hearing we can’t target KRAS, those patients don’t respond to chemotherapy, immunotherapy, targeted therapy — actually there was no immunotherapy. But now we have these agents, two approved agents, but now there’s an ODAC [Oncologic Drugs Advisory Committee] meeting and there’s some concerns about these drugs. How are they going to be used? And there are these newer agents. Tell us, how often do you use adagrasib [Krazati] and sotorasib [Lumakras], So Yeon? Where do you use them? And just give us some thoughts.

Kim: Yeah, so there’s currently two FDA-approved KRAS inhibitors, sotorasib and adagrasib. And I would say that the response rates from the trials are very similar to each other. So, 30% to 40%. And recently there was a publication in NEJM about the new KRAS inhibitors, the G12C inhibitor divarasib. That’s also demonstrated about 50% or so overall response rate. Whether that’s better than the currently approved, it’s hard to tell. And they all work by similar mechanisms. So they lock KRAS G12C in its inactive state. And I would say that generally for the KRAS inhibitors that are being evaluated, the response rates have been 30% to 40%, and we definitely have to do better.

Herbst: Absolutely. So Anne, I know you’ve been involved with this. We’re studying these in the Lung-MAP trial. Are we going to be able to move those two agents we talked about into the front line? Right now we have the CodeBreaK trial of sotorasib. It met its endpoint in PFS [progression-free survival], but there wasn’t a survival benefit. Any thoughts on that?

Chiang: Yeah, I mean I think that it would be great to move those into the front line. I think that’s the natural path of how we develop drugs. But I think we’ll have to see. I do think that the toxicities of these drugs are sometimes…they’re a little bit harder for our patients to handle. They do have side effects and so perhaps waiting until second line isn’t the right thing because they have better performance status upfront. So I think we’ll have to wait and see.

Herbst: Now we’re very fortunate we have So Yeon Kim here, and Dr. Kim works with Dr. [Patricia] LoRusso here at Yale in our Phase I group, and out of the Phase I group I keep hearing about the new generation of KRAS inhibitors. It’s just like Generation X and baby boomers, I don’t know when the new generation starts. But I know there are agents, there was just a publication of a drug in New England Journal of Medicine from Genentech. I know you’re working with drugs from Eli Lilly, Revolution [Medicines] and others, without betraying any confidences, what’s new about this new generation? What’s the excitement?

Kim: So, typically, I think how we can do better with targeted therapy is we either see them in combination. So for example, we could combine sotorasib with immunotherapy, which has already been evaluated. And I don’t think that the response rate happens substantially better with combination immunotherapy. And there have been concerns about potentially also immunotherapy, like side effects and the combination, especially if they’re given in combination together without a lead-in phase.

Another way that we could improve upon the efficacy with monotherapy is looking at different mechanisms. So the G12C inhibitors that are currently out in the market, they’re locking the G12C in its inactive state. And there’s different ways that we could look, think about resistance mechanisms and also think about how we can target KRAS G12C. So KRAS G12C, really it’s an equilibrium between its on and off state, and it’s regulated by other proteins such as SHP2, SOS1, and there’s different drugs that are currently looking at blocking KRAS 12C in its on stage to try to minimize the feedback mechanism that’s pushing towards KRAS to its on state when you’re actually blocking the off state of KRAS G12C. There’s mechanisms of trying to inhibit both the on and off states of KRAS G12C.

And then there’s also PROTACs [proteolysis targeting chimeras]. So, PROTACs are mechanisms at which you’re actually bringing an E3 ligase to the KRAS G12C. So, what happens is that the tumor is ubiquitinated and destroyed. So that’s being also looked at, and I think PROTACs are very unique in its way is that it’s not only targeting KRAS 12C itself, but there’s other KRASes that you can target with mechanisms of PROTACs. So for example, KRAS G12D is a PROTAC that’s being evaluated right now.

Herbst: How often do we see 12D in lung cancer versus 12C? I guess always the time you want to use a 12C, it’s not the right mutation, right?

Kim: Yeah. So 12C is seen in about 14% of patients and I would say 12D is actually more common in pancreatic colorectal patients. But in lung cancer patients, there’s about 4% of patients.

Herbst: Anne, what’s your experience been with the toxicity of these agents? I do think we need to move them to the earlier stage and 12% of KRAS patients with adenocarcinoma are going to have G12C and we’ll probably want to combine with IO [immunotherapy]. The problem is the toxicity, the hepatotoxicity I know has been a concern.

What’s your experience been just with the agents alone? And then of course there could be the anecdotal effects you see if you’ve had someone who’s been on IO and then you add the KRAS agent, do we see any toxicity there because the half-life of the checkpoint inhibitor might still be in play?

Chiang: I think in the latter case, we’re really worried about toxicities — in particular interstitial lung disease, hepatic toxicity — that’s something that we’re trying to avoid. And usually we allow a washout period before we start the sotorasib or adagrasib after an IO therapy. And you’re always crossing your fingers hoping they do well.

I think being able to use that combination upfront, perhaps with chemo, learning how to use IO and KRAS G inhibitors would be really helpful. I agree with you that right now whenever we see a KRAS G12C, we’re so excited and then we see a KRAS G12D or some other number and our attitude sort of deflates and we need to find other options for that. Although So Yeon, I know you have slots open right now for those patients on trial.

Herbst: So it speaks to putting patients still on clinical trials. My take on this whole area is it’s great progress. Like anything else we’re learning, it’s a learning model. You would expect that KRAS being such a driver of so many signal transduction pathways would be very prone to resistance loops, and it is. So combinations with other agents are in play. We do have to look at the toxicity there.

And then newer drugs, as we heard about from So Yeon, that might have slightly different mechanism, might block…be more pan-RAS agents. Maybe the on/off — don’t completely believe that that will make that much difference, but certainly it’s worth testing. All these things need to be tested in clinical trials.

And now in this world, where we’re recovering from the last few years where clinical trials were hit a great deal by what happened in the world, I hope that we’ll see more studies at the meetings as we move forward.

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