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The PancChat Podcast is a collaborative effort from Let’s Win Pancreatic Cancer and the Pancreatic Cancer Action Network (PanCAN), inspired by the long-running #PancChat Twitter/X chat.
Hosted by award-winning journalist Alisyn Camerota, each episode features conversations with leading researchers, clinicians, patients, and advocates who are shaping the future of pancreatic cancer care and research. Together, we deliver expert insights, personal journeys, and the latest breakthroughs—bridging the gap between science and lived experience.
Whether you’re a patient, caregiver, healthcare professional, or simply want to learn more, join us to connect, be inspired, and learn how you can help to accelerate progress in the fight against pancreatic cancer.
Cindy Gavin: Hi everybody and welcome back. I'm Cindy Gavin, CEO and Co-Founder of Let's Win Pancreatic Cancer. On today's episode, we are going to take a closer look at the KRAS mutation. Over to you, Alisyn.
Alisyn Camerota: Hi everyone, welcome to PancChat. I'm your host, Alisyn Camerota. Before we get started, we want to thank our sponsor Revolution Medicines. So today's episode focuses on KRAS, which you've probably heard a lot about. That is a gene that is present in pancreatic cancer as well as other cancers.
And up until now, KRAS has generally been considered undruggable, but that's changing. Our guest today is Dr. Eileen O'Reilly. Dr. O'Reilly holds the Winthrop Rockefeller Endowed Chair in Medical Oncology at Memorial Sloan Kettering Cancer Center in New York City.
She is a clinical scientist whose research involves integration of molecular and genetic-based therapies for pancreatic cancer along with the development of treatments and the identification of biomarkers for therapy selection. Great to have you, Dr. O'Reilly.
Dr. Eileen O'Reilly: Thank you so much, wonderful to be here. Look forward to our discussion.
Alisyn Camerota: Yeah, we've been looking forward to it. So today we're talking about KRAS which occurs in as I understand it about 90 to 95 percent of pancreatic cancer diagnoses. Let's just start by defining it. What is KRAS?
Dr. Eileen O'Reilly: Yes. So I think it's a great place to start and to level set in terms of our discussion. RAS is a gene and RAS is switched on in pancreas cancer. It's involved in signaling. It's involved in growth and it's involved in metastasis.
And we've known this historically for a long period of time. About 20 to 25 percent of cancers will have this gene switched on. And the most common version of it being switched on is in pancreas cancer is in KRAS. But also we see alterations in NRAS and HRAS. They occur more commonly in melanoma and other malignancies.
Alisyn Camerota: So in other words, all of us are walking around with the RAS gene, but those of us without cancer, it's not switched on.
Dr. Eileen O'Reilly: Correct. Yes. And we have, for example, and we'll discuss this, I'm sure today as we go, we have RAS in our skin and some of the side effects from the new agents that we're now using in the clinic affect the wild type RAS in our skin.
Alisyn Camerota: That's interesting. I was wondering why we've seen the rash with the new groundbreaking drug, it often comes as with a side effect of that face rash or skin rash and I didn't know the connection until you just explained that. So thank you. Okay so why, historically, has RAS or KRAS been so difficult to treat?
Dr. Eileen O'Reilly: Yeah. So this has been a focus of treatment targeting for many, many years. And there's been lots of very thoughtful and grounded scientific approaches that have tried to address KRAS. But it's been difficult. Partly, it's been difficult to have drugs bind to the altered version of the gene and have them stick and be able to exert their effect.
And almost now it's going back almost 13, 14 years in one of the labs in UCSF that an observation was made in a small subset of altered RAS and G12C, which we see occasionally in pancreas cancer, for example, that the switch to pocket was identified and some drugs were able to target that. And that's really where the story started along, you know, with parallel discovery efforts across multiple labs around the country.
Alisyn Camerota: So it was undruggable, as we said, or it was considered undruggable and now with the advent of this new drug, it binds to, explaining it to us, a protein that surrounds this gene?
Dr. Eileen O'Reilly: Yeah. So it's a pocket. It's a fold in the DNA and that was considered difficult to access and considered, what's the word I'm looking for, that non-adherent and that people have described it as a greasy ball, right? And I think it's a very good description. That's just nothing sticks to it.
And that observation was made for a small subset and then from there. And this new class of drugs, right, the class that have just received the first approval, the tri-complex inhibitors, they also have a very interesting mechanism. They bind a protein that's very highly present in cells called cyclophilin. And for example, daraxonrasib binds cyclophilin. That combination then binds the RAS gene and that switches off the signaling and turns off this growth metastasis and downstream consequence of an activated RAS gene. And that's thought to be how it exerts some of its effects.
Alisyn Camerota: And when you say this new class of drugs, is it just daraxonrasib and am I pronouncing that correctly? It's the Revolution Medicines drug that has gotten so much attention. Is there a panoply of this class of drugs? Is it just that one that's gotten approval?
Dr. Eileen O'Reilly: Yes. So this is a first in class and a major and significant breakthrough, I would say, in pancreas cancer and in terms of what it means for cancer in general. And it's really a start point of much to come. But in parallel, there are multiple other agents in development. Maybe going back to where we were starting this discussion, what does RAS look like?
So RAS comes in several different flavors. And for example, in pancreas cancer, the most common version of the mutation or alteration of the gene that we see is called G12D. And it's basically a single substitution of an amino acid, a building block in our DNA that's switched out that causes this version to be altered. That's G12D. And then similarly, the next most common is G12V.
And then the third most common, which is about 15 percent, is G12R in pancreas cancer. And they have when we see these in almost every single individual with this disease, they're the G12 point on the DNA building blocks where this change has occurred.
Alisyn Camerota: But this new drug treats the various G12 mutations? Yeah.
Dr. Eileen O'Reilly: So daraxonrasib is broad in its scope and it targets the abnormal version of RAS, so the wild type version sorry, the mutated version and that's G12D, V, or R. But also we see other alterations, Q61, G12S, G12A. These are rarer alterations. But it also targets the wild type version of RAS. And in a small subset of people with pancreas cancer, we won't identify a RAS mutation, but this drug also, potentially, has activity.
And that was identified both in preclinical models, so before we get to people, but also to some degree in the RASolute 302 trial. So yeah, it also targets not so relevant to pancreas cancer but other diseases where development is going to happen: HRAS and NRAS.
Alisyn Camerota: And what are those diseases?
Dr. Eileen O'Reilly: Melanoma is a common one. Some of the leukemias have HRAS and NRAS.
Alisyn Camerota: Well, that's great. I mean that is great. That's a great development and great discovery. And can you tell us what your role has been in this process of this drug's approval and development?
Dr. Eileen O'Reilly: Yeah. So I've been very privileged to be involved in the early to mid to late stage development of this in terms of the phase 1 and then help design the phase 3 with multiple colleagues across the country and of course with the support of Revolution Medicines who sponsored and funded the study and also to be part of the steering committee with Dr. Wolpin and Dr. Wainberg who oversaw the trial as it was conducted and provided insights and then involved in the dissemination of the outcome from the RASolute 302 trial and continuing to develop this drug and related drugs in pancreas cancer in various different disease settings. There's just huge interest in building on this in every setting in pancreas cancer, right, in the resected setting.
So people have undergone surgery, people who are potential candidates for surgery, people who don't have metastatic disease and keeping in mind that the recent FDA approval is focused on metastatic disease. But there's about 50 percent of people with this diagnosis that don't have, at the time of their diagnosis, metastatic disease. So we need to understand where this and related drugs fit as either a single agent or a combination agent. And what's the best time point to integrate a RAS targeting approach.
Alisyn Camerota: And Dr. O'Reilly, on a personal note, I mean I know that you treat people with pancreatic cancer every day and have for many years and it's such a bleak diagnosis. And so, with the advent of something like this, how does it change your job and your outlook?
Dr. Eileen O'Reilly: Yeah, thank you. I think that's a very nice question. Well, I think it's very validating, right? You have a target in the tumor. You have a drug that's effective for that target and you see a successful outcome.
So that's huge. And to see this pivotal point in pancreas cancer is even more, I think, significant for what it means. And to your point that this disease is extraordinarily challenging in many, many ways. And I think it's very heartening for many, most of all patients and families. This is why we're here.
This is why we do what we do. That there's an avenue forward. That there's something to build upon and expand upon. But I think even beyond that, it's significant in the fact that targets that have been recognized and have forever been designated as high priority that with amazing science, right, successful drug development, bioengineering, you name us as part of this mathematics, physics, modeling, All of this contributes to what is a successful drug in the clinic that there are other genes, many of them, that now are within potential reach based on the development pathway that's been observed here.
Alisyn Camerota: Amazing.
Dr. Eileen O'Reilly: And I'll give you one other thing that's lovely to see.
People now want to work on pancreas cancer, right? It draws people from wide fields and that's one of the lovely things in the last six months as the data was starting to emerge and emerged is the amount of people who are reaching out to learn more and hear more from very different fields in life. And I think it brings funding, it brings interest, right?
What we're doing today is speaking to that topic. And it's encouraging our younger colleagues who are thinking about their career and their focus to think about pancreas cancer, which hasn't necessarily been the way for a long time.
Alisyn Camerota: I am so happy to hear that and I can imagine exactly what you're talking about. You had to be a certain type of dogged, I would say, saint in order to go into pancreatic cancer treatment, you know treating it – like you are – because I can only imagine you know for most patients the treatment hasn't been successful, let's be honest, over these decades. And so to keep soldiering on through that must be very hard and take its emotional toll. So I'm happy that you all in this field have this good news to hang your hat on now.
Dr. Eileen O'Reilly: Yes. And with this development already, there are multiple other promising directions that are being sensed in the clinic. Some of these concepts are now in late stage clinical trial testing, sort of building on the story, right, combining RAS with chemotherapy. That's a promising avenue and there are a good number of phase 3 trials addressing that question in terms of both the pan-RAS inhibitor with chemotherapy or the allele specific, so the more narrowly focused G12D in particular targeting drugs combined with chemotherapy.
But even beyond chemotherapy, we see opportunities for people that weren't candidates or chose not to consider chemotherapy now having a treatment option within scope.
Right? And I think that's a big unrealized area for many, many years. I think it's going to build a lot of development there. And also there are some other pathways in the cancer cell for which signaling is aberrant and targeting that signaling with the RAS inhibitor has shown promise.
So for example, a class of drugs called PRMT5 inhibitors.
They address MTAP loss, which is a gene that's involved in a metabolic pathway in pancreas cancer. So all of this is kind of starting now to evolve rapidly. I think we hope for the pace of change, while it can't catch up for 20 years of historical modest progress, but it can certainly hopefully change very much in the next three to five years.
Alisyn Camerota: That's wonderful. And so when you use the term successful, you're seeing a successful outcome now with this. Define that. I mean, what does this drug allow for patients' longevity?
Dr. Eileen O'Reilly: So it's an oral agent that's attractive, right there. And the phase 3 data comparing daraxonrasib to chemotherapy showed that the ability to shrink the cancer, to control disease and extend life was better for longer.
And integrated in the phase 3 trial, the RASolute 302 trial, were several quality of life analysis of which some of the data have been presented and quality of life was maintained better for longer for people on daraxonrasib relative to chemotherapy. And so they're some of the key points. And I think that resonates well with patients and with the oncologic community.
There's certainly a lot we have to learn here. And I think – I don't mean to minimize in any way the side effects. And the side effects for some people can be uncomfortable in terms of the rash and some mouth irritation and to a lesser extent the gastrointestinal side effects in terms of nausea and diarrhea. But I do think strategies will continue to be optimized and we'll learn how to optimally dose these medications and maximize the benefits and hopefully for most who can benefit that the trade offs and the side effects are acceptable and manageable.
Alisyn Camerota: And so far in terms of longevity, does it double life expectancy? I've read that. But is that too good?
Dr. Eileen O'Reilly: Yes. So that's what the data from the phase 3 showed that the four people with pancreas cancer on average had a doubling of their cancer control on daraxonrasib relative to chemotherapy. And that's our current best standard chemotherapy in the setting of which this drug was tested. And that's a significant increment. I think we all agree it's not enough.
But by relative magnitude, compared to other studies that have been conducted in this disease, it's substantial. And I think most people see this and certainly as I do is the first major breakthrough in pancreas cancer in a long period of time. But we can't stop today, right? Goal is as we're discussing is integrating this and hopefully allowing as many people that can benefit to access the medication and then to build on this and related drugs in this disease.
Alisyn Camerota: How is a person tested for KRAS for the KRAS mutation and generally speaking they have it, right? I mean generally speaking you see this in what 90 percent, 95 percent and once you do, how does that change the next steps?
Dr. Eileen O'Reilly: Yeah. So thank you. You bring up some important points here. When should we do testing and how are we using testing and what does it mean for daraxonrasib and other related medications? So testing is done both on tissue and on blood.
Sometimes the quickest and easiest way is to use a circulating DNA assay. And typically one can get an answer, at least for individuals who have metastatic disease, where there's a reasonable disease burden. The yield is high from circulating DNA of blood tests within about a week. Tissue based analyses also have a high chance of picking up a RAS mutation presuming there's adequate tissue and adequate DNA, which can be a challenge sometimes in this disease. But the turnaround time can be a bit longer, two, three, four weeks for next generation sequencing results.
One of the advantages in a way for daraxonrasib is that while it is a RAS targeting drug, the FDA approval has been agnostic to the actual specific mutation. That's not to say here that we don't want to test. We definitely do want to test because we have a lot to learn about which mutations the drug may work best in and to understand how resistance is emerging and how to tackle resistance. But it does make it somewhat easy to access and to use in that by virtue of a diagnosis of adenocarcinoma of the pancreas with metastatic disease that's now within label for utilization.
Alisyn Camerota: You've referred a couple of times, a few minutes ago, to the KRAS wild type. What is that?
Dr. Eileen O'Reilly: Thank you. I should be clear on my definitions here.
Alisyn Camerota: It's such an intriguing modifier connected to KRAS. I've never heard before. So, what is that?
Dr. Eileen O'Reilly: Yeah. So, most people with pancreas cancer will have a mutation. So, they'll have an abnormal version of RAS. And as you mentioned, that's in 90 to 95 percent of people. There is a small percentage of people where we won't be able to detect a RAS mutation.
And there are two explanations there. The more common explanation is it's there but our tools are limited in terms of the ability to detect it. So for example, a person has a low burden of disease and we're not able to pick it up, just limits of detection don't allow that in terms of circulating DNA or the tissue specimen is not adequate. Again, a low DNA quality or just a limited epithelial actual malignant cell component to actually do the testing on. So that's probably the biggest reason why we don't see a RAS mutation.
But there is a small subset where there truly isn't a RAS mutation. And then there can be other genes that are altered that are what we call the drivers. So in pancreas cancer, we think is the main mutational signal that's underpinning the cancer as RAS. There can be rarely no RAS mutation and these other drivers. And then there can be, not to make it more complicated, but a small additional subgroup where we'll see the pathway active, this RAS, RAF, MAP kinase pathway activated, but we don't see again a specific mutation in RAS or one of these rare fusions which tend to occur in younger people.
So that's the RAS wild type. It's kind of a mishmash of several different subgroups. But mostly the RAS wild type is - the mutation is there, we're just not detecting it.
Alisyn Camerota: It's so complicated, Dr. O'Reilly, with all the things that you have to deal with, all the various elements that you have to sift through.
Dr. Eileen O'Reilly: Well, for many things, there are multiple examples in the drug development world that we start broadly in terms of the application of a medication. But as it gains use in practice, we understand where the maximum value of a particular medication is. And it may be that we'll see this over time in certain versions of KRAS that are best suited to a pan-RAS inhibitor or a tri-complex inhibitor like daraxonrasib. And it may be settings, to go back to your other question, where using a more narrowly focused drug, an allele specific inhibitor which can have some virtues in terms of less side effects or different side effects rather than less side effects and that might be a better fit for a person in a certain disease setting. So all of this we'll have to figure out and that's the excitement and the challenge and what clinical trials will help us inform over these next few years.
Alisyn Camerota: What else, doctor? What have we missed?
Dr. Eileen O'Reilly: I think you've picked up on key points. What's RAS? What does it mean, for this disease? You know, what's the significance of daraxonrasib? And to put it in one word, I think it's huge in terms of the change that's coming for pancreas cancer, for other cancers and refuting this notion that we can't target this gene successfully.
But we're just still, at the same time, at the beginning of learning how to optimally utilize these drugs. And I think for patients, having more choices is also huge and having the ability to help control their cancer and hopefully live better for longer is what we want to do and ultimately to try to cure this disease and not to be naive about it. We're a ways from that. But I think with change comes optimism.
Alisyn Camerota: It's beautiful. Anything else?
Dr. Eileen O'Reilly: It's great to chat with you today and thank you very much for the invitation and thank you.
Alisyn Camerota: Thank you, Dr. O'Reilly, for being here. It's wonderful to get your expertise. I know that our listeners will get a lot out of it.
We also want to thank our sponsor Revolution Medicines and our listeners for tuning in. I'm your host, Alisyn Camerota and I hope you'll join me next time on PancChat.
Julie Fleshman: Hi, I'm Julie Fleshman, President and CEO of PanCAN. If you or a loved one has been diagnosed with pancreatic cancer, navigating this journey can feel overwhelming, but you don't have to do it alone. You can explore the many resources we have about the KRAS gene mutation, tumor testing, clinical trials, and treatments. You can find PanCAN at pancan.org and Let's Win at letswinpc.org. Together, PanCAN and Let's Win are committed to guiding you through every step of the pancreatic cancer journey, offering support, information, and hope.
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