New breakthroughs in pancreatic cancer treatment and research  

Shubham Pant, M.D. Hi, I'm Dr. Shubham Pant, and I'm a professor of GI Medical Oncology at UT MD Anderson. And joining me today is Dr. David Hong, who's a professor of Investigational Cancer Therapeutics at UT MD Anderson. And this is the Cancerwise podcast. David, welcome to the show. 

David Hong, M.D. Thanks for inviting me, Shubham. 

Shubham Pant, M.D. So today, David, we're gonna talk about something which has been in the news all over the place. We're gonna to talk about advances in pancreatic cancer in treatments and research. And David, you are like the key of the key of the key opinion leaders of KRAS targeting overall. So, let me start with, tell us a little bit more about KRAS, like tell us about the gene, tell us why is it so important? 

David Hong, M.D. Thanks for asking that question. We've known about this KRAS gene for close to over 40 years. And just like any other gene in our body, when it's not mutated, not mutated, it functions to be turned on and off to allow for regular cells to replicate. But we recognized almost 40 years ago that mutations that arise in the KRAS genes can lead to cancer and drive cancer. We now know close to 35% of all cancers have this mutation. In some subsets of cancers like pancreatic cancer, it's almost 98%. In colorectal, for example, it's close to 45%. In non-small cell lung, close to 30%. And so, it is a significant driver of cancer pathogenesis in many, many different tumor types. So, it is significant target that we have for almost 40 years known has existed, but it's had, really not had much success targeting. 

Shubham Pant, M.D. So, what you're saying is science takes time, right? So, it kind of takes time. It was always for these 40 years when I was in fellowship, a long, long time ago, it was considered undruggable. It's been considered undruggable for a long time. So, why is this mutation protein so hard to drug? 

David Hong, M.D. And when you look at any molecule, obviously, it's complex. It's not as just simple as, hey, the gene eventually becomes a protein. And what they found was that the protein itself is GTP-bound. That means a molecule called GDP and GTP bind to RAS to turn it on and off. And so, traditionally in drug development in cancer, we've had what are called tyrosine kinase inhibitors, which are ATP-bound, and we've been able to target those relatively easily because they're very deep pockets that organic chemists and biochemists can figure out a way to developmolecules that block that. 

Shubham Pant, M.D. And slink in like the GFR Like slink in and bind on? 

David Hong, M.D. The GDP pocket itself is a very shallow pocket. And so, there are many times that they tried developing these targets for RAS and just were not successful. People in the early 2000s developed drugs that are called farnesyltransferase inhibitors that tried to alternatively block the activation of RAS through something called prenylation or farneseylation. And they did develop some of these molecules, but what we didn't realize then was that just like many processes in nature, although you can block farneseylation, there's another pathway called geranylation that still activates RAS. 

Shubham Pant, M.D. So, what are you telling me, David, is like if we're on a highway, let's say in Houston, like 45, blocked the highway, they find a way around it, like a side road, like car starts running. 

David Hong, M.D. Yeah, absolutely. Absolutely. And so, you could block one highway, but then the-. 

Shubham Pant, M.D. Finds an alternative route. 

David Hong, M.D. Alternative route. 

Shubham Pant, M.D. Got it. 

David Hong, M.D. And it wasn't until sometime in 2013, a physician scientist figured out a structure that could lock into a region near that very shallow kind of space called the GDP pocket that locked RAS into what's called an "off" state. And that was the first paper and the first discovery that really launched this KRAS targeting revolution. 

Shubham Pant, M.D. And as I understand it, KRS is not just one gene, right? It's got all these different alphabets associated with this. KRAS G12D, V, R, C is what you were talking about. So, tell us a little bit about this KRAS G12-C. What is the percentage in pancreatic cancer, and what you are trying to say is like, am I right to say it's like a shiny ball, you can't stick anything to it, right, and they found something to kind of stick to it and kill the cancer cell? But tell me a little about the start of the KRAS G12C, but how has the RAS revolution, as we call it, dramatically changed with a new drug called daraxonrasib, though it's hard to say. Daraxonrasib. So, tell us a little bit about that evolution from the Cs and why it's so important, and what's the difference between these C inhibitors and these, what we call as a pan-RAS inhibitors. 

David Hong, M.D. C inhibitors, or the C stands for cysteine. So, as you mentioned, KRAS is the most common isoform of RAS, but it's, also there's something called HRAS and also NRAS, but KRAS the most isoform or protein isoform of RAS, but within those there are different mutations, like you said, C, D, V, R, S. This molecule could block KRAS G12C and lock in the "off" state. Your question about how prevalent is it in pancreatic cancer, it's actually very non-prevalent. That means it's not, we don't see a lot of it. It's only probably one to 2% of all pancreatatic cancer. But what was really stunning is that in lung cancer, which is, it's prevalent in about 13% of all lung cancer and also about 5% of colorectal cancer, if you can block KRAS in both lung and pancreatic, you could definitely see evidence of clinical benefit. And this was really the first drugs that showed clinical benefit targeting RAS. 

Shubham Pant, M.D. Tell me about this new pill that we talk about that's there everywhere all over the news, daraxonrasib. Tell me a little bit about that. 

David Hong, M.D. So, daraxonrasib works differently than the OFF inhibitors. It binds to another protein called cyclophilin A, and then it binds to KRAS when it's fully on and essentially prevents other molecules such as RAF and MEK to really propagate that signal to turn the whole process on. And, you know, it was a risky bet that this would work. Nobody thought that, many people... 

Shubham Pant, M.D. Including you and me! 

David Hong, M.D. A lot of us felt like, wow, we don't know what really RAS does fully in adult human cells. 

Shubham Pant, M.D. Healthy skepticism. That should be there in science. 

David Hong, M.D. Healthy skepticism. And many people felt that if we blocked all of RAS, which this also blocks normal RAS, that we would cause major problems. Well, it didn't. And what we did see was these incredible responses, particularly in pancreatic cancer, particularly in lung cancer. Now this drug, unlike the C molecule, can target all these different variants: C, D, V, R, and S of KRAS. It's a pill that you take every day. The main side effect that we're seeing with this is rash. It's acneiform rash that occurs on the face. And it's similar to another drug that we already have approved, which is called cetuximab. In most patients, it's really very mild, a little bit of acne here and there, but in some patients, it can get more severe. It can bleed. It can cause an infection, or it can be painful. But we've learned now over many, many months how to manage these rashes. And so, I think once daraxonrasib is approved, we have kind of algorithms and ways to mitigate this rash, that I think we'll be able to implement for many patients who get daraxonrasib. So, Dr. Pant, you are an expert in pancreatic cancer, and why is KRAS so relevant in pancreatic cancer? 

Shubham Pant, M.D. David, thank you so much. As you mentioned, you know, KRAS is in 90% of patients with pancreatic cancer. So, this is kind of the main driver of pancreatic cancer. And though the Cs is very low, it's one to 2%, the main ones are KRAS G12D as in Delta, V as in Victor, R as in Romeo, that's the way I remember it. Or you could think about it as digital video recorder from the 1980s. That's a way I think about. But I think the challenge is exactly as you said. That this RAS is always turned on. It's stuck in the "on" position. So, the way I think about it is like a light switch, which should be turned off in the body, but it's turned on and it's stuck in the "on" position, right? And you cannot flip it off. So, that's been a challenge in targeting pancreatic cancer. The other challenge is not just the RAS. Pancreatic cancer to target, even with chemo, has been challenging because it's almost like a, it's like a shield. It's, you really cannot penetrate it. So. So, we really have worked hard. We've tried multiple trials, immunotherapies, but they have not worked in this disease just because of the nature of the tumor. It's a lot of stroma, something called stroma. You can think about it like, that we had one of my colleagues describe it like a chocolate chip cookie. So, you have the little chips which are inside it, now nobody can eat chocolate chip cookies anymore, but you have like the little chocolate chips inside it and that's the tumor cells and the whole, the dough is kind of the stroma So, just think about it's hard to get any therapy inside the tumor cell. And that's why it's been so hard to target. 

David Hong, M.D. Obviously, daraxonrasib has been in the news. Tell us about this study that was recently reported at the American Society of Clinical Oncology, RASolute 302. 

Shubham Pant, M.D. Thank you for that question. So, RASolute 302 built on the work, the Phase 1 work, all right, that was done with the daraxonrasib, which showed an improvement, like you, as you said, in pancreatic cancer. These patients were getting responses. These responses were durable. They were living longer. But as you know, we have to confirm this, right? And the way we confirm any finding in Phase 1 is through a Phase 3 trial, in which means we compare the drug to standard of care. So, this was a global trial which randomized patients who had already failed one previous line of chemotherapy, and it could have been anything, something called 5-fluorouracil-based or gemcitabine-based, and they were randomized to either daraxonrasib, just a pill, right, as you said, a pill versus standard of care chemotherapy. And investigators like me could choose any standard of chemotherapy for the patient, which was appropriate. So, if they receive gemcitabine-based frontline, we give them 5-FU-based therapy second-line. If they got 5-FU-based therapy frontline, they got gemcitabine-based therapy second-line. I'm an optimistic person, right, by nature. But, you know, when you do a lot of pancreatic cancer and you've participated in a lot of negative trials, you're always cautiously optimistic. But what I saw with the hazard ratio of 0.4 and the trial, it was just remarkable. So, just to put in context, any drug which has been approved for pancreatic cancer, chemotherapy, and we don't have a lot.  We just have a handful. The benefit has been two months, 2 1/2 months, three months maybe. There was a drug, erlotinib, which was for lung cancer. We did a frontline study in the 2000s in pancreatic cancer. It had a two-week survival benefit, and it still got approved. So, I'm just telling you how challenging the disease is. And in this trial, RASolute 302, patients who were on the daraxonrasib, that doubled their survival. So, patients who received the chemotherapy, their survival was 6.7 months. And the patients who received daraxonrasib, their survival was 13.2 months. And again, it's not a cure. So, we want to be careful about what we say. It's not a cure, but again, it's another like summer you get to spend with your children or grandchildren. It's another holiday that you get to spend. Another graduation. So, it's truly meaningful, I think, for patients. And I had a number of patients on this trial. So, I think it was truly meaningful for these patients. And I think this is just the beginning. We take this and we develop further therapeutics, how to further improve this survival benefit. So, I think for our patients, it's truly remarkable. 

David Hong, M.D. Tell me a little bit more about KRAS G12D in pancreatic cancer. Why is that mutant allele so important? 

Shubham Pant, M.D. Yeah, so, you know, as we said, KRAS G12D is in 40% of patients with pancreatic cancer. And we have a lot of KRAS G12-D inhibitors. So, daraxonrasib, as you said, is a pan-RAS inhibitor, and it does have side effects. So, the side effects are rash, as you said, mouth sores, also called stomatitis. Patients can get nausea, diarrhea. Those are the side effects. Now, these new generation of inhibitors that are KRAS G12D inhibitors, and some are ON inhibitors. Just similar to daraxonrasib, some bind to that GDP and GTP both in the "on" and "off" state. So, switch it off, both. We have an inhibitor, which is a protein degrader. That means a KRAS protein which is formed. It degrades the protein. So, we have a number of agents in this indication and the interesting thing about this, these agents, David, is that they really do not tend to have a lot of side effects. They're what we call as relatively clean drugs as far as side effects are concerned. And why that is important to you and me in drug drug development, is that we can combine it with chemotherapy or with any kind of chemotherapy. And that's what we're doing. We're launching multiple Phase 3 trials in treatment-naive patients with pancreatic cancer. That means patients who have never seen chemotherapy for their stage 4 disease and combining the D inhibitors with chemotherapy to try to improve patient outcomes. So, I'm really excited about the next steps in development of these compounds. 

David Hong, M.D. So, when you think of pancreatic cancer and the treatment landscape in the next five to 10 years, what do you envision? 

Shubham Pant, M.D. I can envision a lot of things. I can be really creative. But I think it's a truly, you know, this is, I think we've burst the dam, or we've at least, I think, taken a big chunk out of the dam of the treatment for pancreatic cancer. And I think the tsunami is coming in a good way, right? Not in a bad way, in a really good way. So, we have KRAS G12D inhibitors. We have KRAS G12V inhibitors, which are coming out. Now what we are doing with a drug like daraxonrasib is we're moving to the frontline setting. That means patients who are treatment-naive, why not give them the benefit? Try to do these clinical trials to see if it works in a frontline setting as it worked in a second- line setting. So, we've recently launched a trial called RASolute 303, 303 comes after 302. RASolute 303 in which there are three arms to this trial. Patients will either get daraxonrasib single agent as a pill, daraxonrasib in combination with chemotherapy called gemcitabine and nab-paclitaxel, or chemotherapy gem and nab-paclitaxel. And if you asked me like five years ago, will I be able to give a pill to a patient with treatment of pancreatic cancer? I would have scoffed at you. I would be like, David, that's not possible. But who knows, we are going into that era. We are also launching a trial called RASolute 304, which is in the adjuvant setting. That means after resection for pancreatic cancer, and after the patients finished chemotherapy, and these are patients with no evidence of disease. So, the tumor's been taken out. This is the 20% early-stage pancreatic cancer. Even those patients, they have a 50 to 70% chance of the pancreatic cancer coming back. It's a truly tough disease. So, in that, if you're able to show that daraxonrasib, we had a vaccine trial recently that we did a KRAS-targeting vaccine trial. If we think we can change the outcomes in these patients, we can truly get more cures. So, I'm really hopeful for the way forward.

David Hong, M.D. Yeah, it's pretty exciting, it is pretty exciting. 

Shubham Pant, M.D. So, David, you know, tell me single-agent daraxonrasib, we've discussed has shown these responses in patients with pancreatic cancer, but tell me about combination. Like how do we, you know, 13.2 months is good, but we want more, right? So, how do we, where do we go? Do we combine it with immunotherapy, with other targeted therapy? Tell me a little bit about the landscape out, you know, next five or 10 years, what you see as far as a Phase 1 clinician. 

David Hong, M.D. I think there are going to be very, very powerful and effective combinations with RAS because RAS, I think, can cooperate with other mutations or other pathogenic pathways. For example, recently there was a report of daraxonrasib in combination with what are called PRMT5 inhibitors, and some of that data was, was kind of almost unbelievable. 92% of patients having significant tumor shrinkage. And we'll see, you know, it was a small number of patients. I think it was... 

Shubham Pant, M.D. 12 patients, yeah. 

David Hong, M.D. 12 patients. But I think that suggests that there could be other very powerful combinations with, for example, immunotherapy. There will be other combinations, I think, beyond just standard chemo, with other immunotherapy checkpoint inhibitors, such as pembrolizumab, and probably in lung cancer. Other very unique pathways with some of these new drugs, perhaps, what are called antibody-drug conjugates, which are an antibody linked to a chemotherapy, which have shown some early efficacy in pancreatic cancer and other cancers. And I think there will be many, many combinations, and many of those, I do think, will have really profound evidence of efficacy. 

Shubham Pant, M.D. That's amazing, David. So, what you're saying is we're just getting started. 

David Hong, M.D. We're just scratching the surface. 

Shubham Pant, M.D. So, for the PRMT5 inhibitors, again, it's for patients who have something called MTAP loss. And that's about 20% of patients with pancreatic cancer, but truly remarkable. I think exactly how you, the way I see it, David, is it's like a pie, right? And we are slicing it into different things. So, you have a, I envision a future in pancreatic cancer in the frontline setting, that means treatment-naive setting, that patient comes to me and I test them for all this. So, the important thing is we should do next-generation sequencing, find that target, right? You know, if they have a KRAS mutation, then they could get a pan-RAS inhibitor or pan-KRAS inhibitor. If they have KRAS-G12-D, they could get that pan-RAS inhibitor, but maybe in combination with the D inhibitor or maybe a D with combination of chemo. They have, you know, or maybe, you know, combination of immunotherapy. You have a MTAP deletion, you could get PRMT5 inhibitor. And then we haven't talked about something like, what you said, ADCs, like Claudin, 18.2 is a target in pancreatic cancer. ADC along with the RAS inhibitors. So, a lot of work to do, a lot of combinations to do. But I think the big thing is that it all benefits our patients. So, it's truly, and for something like pancreatic cancer, which has been just a tough disease, it's just a truly remarkable time, I think, in that. What do you think about that? 

David Hong, M.D. I agree with you. It's actually just a remarkable time in drug development in oncology. Beyond just pancreatic cancer. I think these RAS inhibitors will have wide impact across multiple cancers, not just pancreatic, lung, colorectal, but other tumor types. And so, it's an exciting time. 

Shubham Pant, M.D. David, this was a great conversation. Thank you so much for being here today. 

David Hong, M.D. Thanks for inviting me, Shubham. 

Shubham Pant, M.D. And thank you for tuning in today. If you enjoyed this episode, be sure to follow or subscribe on Apple Podcasts, Spotify, YouTube, or wherever you get your podcasts. And don't forget to comment or review. For more information or to request an appointment, call 1-877-632-6789 or visit MDAnderson.org. Thanks for listening to the Cancerwise podcast from UT MD Anderson.