The U.S. Food and Drug Administration (FDA) has approved daraxonrasib , an oral multi-selective RAS(ON) inhibitor, for adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy. The approval is based primarily on the results from the pivotal randomized phase 3 RASolute 302 trial comparing daraxonrasib to chemotherapy as second-line therapy for patients with metastatic pancreatic cancer, led by Brian Wolpin, MD, MPH , director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute.
Well, thank you so much for joining me, Doctor Wolpin. Um, it's such a pleasure to have you. Congratulations. Um, a little bit belated at this point, but, um, on the results of the Rasolute 302 trial and the plenary and etc. etc. Um, I, I would love to hear first of all just how you got involved. That's sort of my, my. I, I was writing up the question to ask and I realized I actually am not very familiar with um how exactly industry sponsored trials connect with academic cancer centers. So, I was kind of just an ignorant question of curiosity, but also, you know, how you felt excited about this particular trial and, and chose to participate in it. Yeah, sure. So, um, I've been working in pancreatic cancer for many years. I've been at Dana-Farber a little over 20 years, and all that time my focus has been on pancreatic cancer. So we've been involved in quite a number of different both research endeavors and also uh work to try to identify new therapies. It's been extremely hard to find new treatments that successfully work against pancreatic cancer, but one thing we've known now for many years is that. There is an oncogene that drives growth of pancreatic cancer, and that's the KRAS oncogene, and it is mutated in almost 95% of pancreatic cancers, so it has been a very logical thing that you would want to target that. And in the laboratory, if you do target that by a number of different means, you really can treat pancreatic cancer well if you use a drug that can block that or an approach that blocks that. The trouble is we've not had a drug that can do that in people. So about 12-13 years ago there was a real change in the field where a really outstanding chemist at the University of California San Francisco was able to identify molecules that could stick to RAS and start to show you could start to block the function of RAS, which is really again the driver in almost all pancreatic cancers. That the suite of compounds that came from that work, it turns out were not very relevant to pancreatic cancer. They were very specific for one particular mutation in CRS which you don't see very often in pancreatic cancer, but there were a number of both folks in the academic world but also in the commercial world at biotech and in pharma that were really working hard to identify other ways to block RAS signaling. And it turns out one of those, which was the drug that was ultimately presented direct on RAST targeted drug specifically and then working with them about. Um, working with them in the laboratory to study the drug in the lab, and what became clear is that the, the Diraxin RASIB that we were working with in the lab really blocked RAS signaling well if you use it in a culture dish or you used it in a mouse, but whether it would work in people at the time was unknown. And so we worked with them to open a phase one clinical trial, a first in human, sometimes it's called clinical trial, uh, obviously opened at Dana-Farber but at other sites too. Um, and that's where we really started to see some of the first activity in patients, showing that the drug worked in patients, and then we obviously kept going after that and worked with them on the phase 2 and then the phase 3 trial. Yeah, yeah. I think my question kind of stems from, um, I listened to a recent um like webinar with uh RevMed and um Uh, Tyler Jack was the other person, um, and he kind of gave the history of, uh, the molecule itself. I always butcher it. I, it hasn't cemented in my head, Diraxon racid, weird, uh, emphasis, but, um, and he said that, uh, you know, they actually set out to find, um, a, a more targeted, uh, drug, right, and, uh, Darixon Racid. Specifically it's or it's not specific it's RAS on and so it was a little bit broader than they expected and so I guess I was just wondering, you know, being a pancreatic cancer researcher and knowing that RAS is sort of this open question and like, you know, we want to figure this out and it would have such incredible um impact um like did you have like uh like uh options to choose from? Were you like oh I I. I believe more in this one like did you have sort of that choosing power or was it more like you had this, um, especially even within RevMed I know that they had some like candidates they were working on and maybe this is a little bit too insider knowledge or whatever but just again the curiosity of like were you sitting there being like, OK, I have to choose the one that will go into the clinical trial or was it kind of like this is the first one, let's let's do it. Yeah, so, um, at the time, this is now several years ago, there were not that many RAS inhibitors available that were appropriate for patients with pancreatic cancer, so there were not that many trials, um, but we had been working with the team at Revolution Medicines for a while, so we had seen both from the data they had generated and some data internally. That the drug looked very good, so we would not have gone forward to work with a trial that we didn't think the drug had, you know, potential to be effective, but it's not that there were 20 different, you know, inhibitors out there to choose from. There are now, right, there are a lot more RAS inhibitors there now and actually now we do have, uh, you know, a dozen or more different RAS inhibitors in in trials at Dana-Farber, but at the time there were many, many less, right, because it just. Things had not progressed far enough to get to that point yet. Yeah, yeah, that's wonderful. Well, I, I might skip ahead. This was a later question, but I would love to hear a little bit more about sort of that like, you know, what's next question? What does it look like now question? Because, um, obviously the push has been how incredible this news is and it is, period, you know, um. And the outcomes are still really terrible, um, and so I guess I'm just wondering, um, especially because there's so much like I've even, and I have a lot to learn, but, um, I even saw recently about a KRAS vaccine, you know, it's, I, I feel like this, there's a huge boom that I'm getting like just through my email, you know, and so I can't imagine what it looks like on your end, um, and I'd love a little sneak peek if you could. Yeah, so I think you're definitely right that this feels like uh the time at which things are really going to accelerate and change, right? We historically have almost entirely used chemotherapy to treat patients with pancreatic cancer and as opposed to some other cancer types, you really just can't use one medicine alone. One medicine is not strong enough, so a single chemotherapy drug does very little. So it ultimately means you need to combine chemotherapy drugs together and that gets hard for patients because they each have their own side effects and then you put them together and there's more side effects and so it hasn't been the easiest right because the chemotherapies have a lot of side effects that make life more difficult for patients and they don't tend to work for very long so they they do work we have used them for years and they they do help patients. But the durability of how long they help patients isn't nearly as long as what we would want. And I think the way that I have thought about it is that chemotherapy essentially deals with the consequence of the cancer, right? It's sort of killing cells that are dividing a lot. And the problem is there's many other cells in your body that divide too, and it, it causes side effects by hurting those cells. Whereas KRAS is really. The founding of the cancer, right, so that we think one of the first things that happens that leads to a pancreatic cancer is you get a gene, this one gene, KRAS, that gets a mutation in it. So if you block that, you're really sort of blocking the foundation of the cancer rather than trying to deal with the consequences later on of a more rapidly dividing cell. So I think what Direxon RASIP has done. Is it really has been a proof of concept that that really works, right? If you go after the root of the cancer, the mutant gene that starts the cancer, you really can do better even than the chemotherapies we've been using for a long time, and that really has opened uh all new doors, right, to help think about new treatments, and to your question, some of those new treatments will be things combined with RAS inhibitors, right? We. Know that RAS inhibitors work, but in the setting we tested they weren't a cure then either, right, they helped people live longer. But people still then pass away from their cancer. We would like to obviously prevent that. And so I think part of what is coming is, well, are there RAS inhibitors that are better than Dirax on RASIB that may work even more effectively, but I think even more important than that are there also new medicines we can add to these RAS inhibitors that will make them profoundly treat the tumor so that you get even deeper reductions in the tumor and maybe cure more people from their cancer. There are also then as you alluded to, there are things beyond sort of small molecule inhibitors, which is what this sort of class or targeted therapies. There's vaccines and immune therapies and a whole host of other things that are also being tested. And I think there's a lot more going on now than there has been in the past, and I am hopeful that some of these things will also break through and turn out to be useful, and we were gonna have to then figure out well what are the right combinations for the patients that help them the most. Yeah, gotcha, gotcha, that's wonderful. Um, if you had to give just like a. Couple of the, like, the next things that we should be looking out for. Um, I feel like probably maybe a combination. Um, is there like a specific combination that's like about to read out results you're excited for? Yeah, it's pretty early days, so I'm not sure I can tell you exactly what's gonna win that race, but, um, you know, there have been some data reported recently, one. Set of data was two RAS inhibitors together. One of them was DAXARASID, which, as you mentioned before, binds to and blocks a host of different mutations in RAS, and one was a mutin allele specific inhibitor, so it binds to and blocks only RAS when it has a very particular mutation. It's early data, but it suggested maybe the combination will be better than each one individually. That we will have to test in a larger study, and there is a phase 3 trial plan to open it towards the end of the year to ask that question. Um, there was another small data set that was released combining a RAS inhibitor with a PRMT5 inhibitor, it's a different kind of drug. Um, that drug is trying to block a different vulnerability. In pancreatic cancer, um, about a third of pancreatic cancers seem to be susceptible to PRMT5 inhibitors, and so that was a combination also with Diraxone Racib with one of the PRMT 5 inhibitors in, in that case made by a company called Tango, um, but there are others, um, and that data also looked quite interesting, um, I think there will be many more. Those are two that just happened to release data in the past few weeks, but. I think this really is the future of the field, I think, which is KRAS is sort of the director of the orchestra in pancreatic cancer. Once you inhibit that, you can then go after so many other. Aspects of pancreatic cancer biology and use it, use these new medicines in a way that if they were given by themselves they wouldn't work as well and so I think you're right that these combinations likely are the future. What exactly is gonna be the winner we're gonna have to see. I hope there are multiple winners, right? Multiple ways we can do this and we will figure out for each individual patient what the best one for them is. Yeah, yeah, that's wonderful. Thank you. I gotta get back to where I was in my, in my list here, um. Yeah, I, I wanted to talk to you specifically about this, um, because you work with patients, right? You're, you're a clinician and you're, and I, um, I guess I was just wondering what your sense was, uh, from the patients about the trial and about KRAS and about, cause obviously from my perspective and, um, obviously I think I speak to. And hear from patient advocates and sort of those uh institutions but um you know I I don't talk I haven't spoken with someone like directly who was like either on the trial or heard about the trial or whatever um and I guess I just was wondering what sense you got from them and how they felt about it if you can I know they're not a monolith obviously but if you got a general sense um about about that. Mhm, sure. So, you know, first I would say patients are very brave, right? They go on trials with us when we don't know if the drug will work and sometimes we don't know what the side effects could even be, right, when we do these first trials in patients, it's never been given to a person before, so we really don't know what we will see. So it, it really shows you the bravery and dedication of patients to go through and do that with us. Um, you know, I think the drug has some advantages over chemotherapy and that it's not an IV infusion, right? Uh, most of the therapies we use in pancreatic cancer are IVs. Some of the medicines we use require hours to deliver, so they're in the infusion room for most of the day in some instances. Um, and then some of the programs we use, you actually have to wear a pump at home, so you carry a pump with you that has chemo in it and it gets delivered over 48 hours and that's inhibiting for a patient's life, um, and then again, the more side effects it causes, sort of the less of a normal life people can lead, and so I think Diraxin Recib is a pill you take it once a day, there's no IV infusions, there are no pumps, you don't spend all day sitting in the infusion room, you take it at home, right? And the side effects tend to be less, so your life is more normal. So I think, you know, one theme that I would say from the patients that I treated who were on these trials is that their life felt more normal, right? They didn't feel as tethered to the clinic and kind of being constantly reminded about their cancer and they were able to do things like. Go on trips and take bike rides and do things that they want to do and be less sort of always reminded of what is lurking there, which is the cancer. And so I think that was a big improvement over what we've been able to do with IV chemotherapies. And then the medicine does have side effects. Every medicine has some, right? It's, it's not that it has none. So Diraxin recip can cause rash and sometimes inflammation in the mouth, um, but overall, again, people tend to feel better than when they're on chemotherapy, so their life feels more normal. And I think ultimately what we would like to do, right, is find the right set of medicines that people can take as pills and live as normal a life as we can have them live, right? And really be more living with the cancer instead of the cancer taking over so much of their day to day activities. So I would say um most patients who went on these trials really felt like it was substantially better than being on chemotherapy. They had all received chemotherapy before, because that was mandated in these trials, so they all knew what chemotherapy was like. Yeah, yeah, well, that's wonderful. Um, and I mean, This is a little bit of a um of a switch up here apologies just out of order um but uh. And I can honestly, it was kind of related, to be honest. It was, you know, are you hearing from patients the excitement that's in the field? You know what I mean? It's like the, the field is like, oh my God, this like, it's the tipping point, it's such celebration, and I guess I wonder about the patients themselves. That's I guess sort of my question. It might be a hard question, it might not be um the right thing to focus on at this moment, but I, I, I just can't help but wonder, I guess. Yeah, I think the results from the trial uh made it into quite a bit of media and so patients have um very commonly now heard of this. They definitely are excited and you know are interested in participating in either studies or receiving the medicine. You know, I, I think another thing that's come up is this is a US based program, so, uh, the trial was worldwide, right? The trial was not only open in the US, it was open in Europe and also in Asia, um, but the expanded access program currently is only in the United States and the review for the FDA is a US review. So there really needs to be still quite a bit of work to make this drug also more broadly available outside the United States. Gotcha, gotcha. Good to know. Honestly, I feel like uh I didn't understand that necessarily, even though I know that it's not approved yet and that it's You know, just the expanded access program, it's um helpful to hear. I feel like what that actually means in practice. Um, uh, so yeah, this is the question, this is again more just like a personal, I would love to know what it felt like to give a plenary. I just cannot imagine speaking in front of that many people. Maybe you were just so prepared, um, but one, I guess the proper reporter question is, you know, how did you come to be the one to give the plenary? Was it like, uh, you know, were you like, I wanna give this, whatever, um, or, uh, and then also, uh, yeah, how did it feel and just was that such a crazy moment. I just can only imagine, so it, it seems really neat to me. Mhm. Yeah, sure. Um. So when clinical trials, large trials like this are done, there are generally a small number of investigators who help design and lead the trial, and uh there often is a steering committee of people who do that, and the chair of the steering committee is usually the one who will present um the data at meetings, so I was in that role, um. So, um, yeah, it's, it's probably one of the biggest, uh, forums that I will ever, you know, present in terms of a live presentation with almost 10,000 people in the room, so, um, a bit intimidating for sure, um, even having given quite a lot of talks over the years, um. The lights are very bright. You can only see the first few rows, so it's not like you can see all 10,000 people. So, but I have never given a talk where um I've been interrupted in the middle like that. That that is an unusual scenario, um, and so, um. You know, just first a bit overwhelming, you know, it's just the, you know, I've taken care of so many patients with pancreatic cancer over the years that um I just feel like the presentation was mostly for them, right, to show that we did it right. We finally have cracked the armor a bit and there's now a new future ahead again, not that we figured this out yet, but we really have made uh a dent in a way we haven't in the past, um. So, um, that it already was sort of overwhelming to give the talk in that way, um, but also I was only, I wasn't even halfway through, so needed to pay attention, otherwise I was gonna lose my train of thought and then the next half of the talk was not gonna be so well performed, so just trying to keep my, my wits about me, um, and then, uh, you know, just I, I think what it shows you is, um. Just how much all of us want this, right, how patients, families, physicians, this cancer has such a bad reputation and it is so hard to treat that we have all been desperate for something like this, and there are so many people who have worked so hard to get here to finally see it. You know, I think people saw the initial data and and just didn't want to wait to show that that's amazing and um and it is and I I think it's gonna really change how we treat the disease going forward. Yeah, absolutely, and I'm, I'm sure you seemed like you had it all together in the second half from, from my perspective, and I'm sure even if you didn't, the audience would have forgiven you. I mean, this is, uh, this is the like most exciting or most rousing, um, I feel like oncology news, uh, clinical oncology news that I've, I've had the pleasure to cover. So it is, um, such a pleasure. What's next for you in particular? Like what are you working on? What is your next sort of question? Yeah, so I, as you said, see patients and I have a laboratory and we study pancreatic cancer, we obviously have a whole host of different projects going on. I think a lot of projects in the therapeutic space over the past few years have pivoted towards understanding how RAS inhibitors work. So I, I really think that what we will see in the next few years is that instead of chemotherapy being the base treatment all patients get and trying to add things to that, which we've been trying to do for a while. I think RAS inhibitors will become the base treatment all patients get, and we will figure out what we add to that to make them work better. So a bunch of the work we do in the lab on the therapeutic side have shifted, has shifted over the past few years to really understanding, well, when you give a RAS inhibitor, what does that do to the tumor? How does the tumor adapt to that? How does it try to develop resistance to that? And what are the things we can do to prevent that adaptation or that resistance from developing. And I think that's where we're gonna spend a lot more time also in the next few years really trying to decipher the mechanisms of that because I think that's really what in the clinic we will then need because I, I do think RAS inhibitors will become standard. I think probably. All settings for for patients with pancreatic cancer. Again, we don't have trial data to support that yet. I can't say that that has happened, it hasn't yet, but I think that's where we're likely going. So if, if you think that's true, then you really gotta understand resistance and adaptation. And then also part of the lab works on early detection. Um, I think we should not lose sight of the fact that 80% of patients present with advanced disease that we know we cannot cure because it's already too progressed to cure. And so if we're going to use these RAS inhibitors to their fullest potential, I think we need to find the disease earlier to give us a better chance to cure patients. And so a good portion of the lab works on questions around that, how do you identify people to screen, how do you find it earlier, and I think that's also an important thing for us to be working on and obviously others in the field work in that space too. Yeah, yeah, absolutely. Well, I would love to hear more, but we have to run. Is there anything I missed in the last minute that I have you? No, sounds great. Thank you for featuring this. I appreciate it. It's nice to have some good news about pancreatic cancer to talk about, so I appreciate you doing that. Yeah, well, thank you so much and talk to you soon. I'm gonna stop.
