RASolute-302 with Daraxonrasib - Game Changer at ASCO 2026 in Pancreatic Cancer

Hello, I'm Roy Gersain, a community medical colleges. Alongside my brother and co-host, Rob will go say, "We are the oncology brothers. We are coming to you right from ASCO 2026. Hours after plenary abstracts have been presented here. Each one of these studies is in fact guiding our practice today. I must say, everyone here would acknowledge that too. The biggest story at ASCO and potentially for 2026 in the field of cancer is around recidibitors in pancreatic cancer. During the presentation, there were tears, hugs, standing ovation, and rightly so. That's exactly what our clinical inside segment would focus on. - We'll have to you referring to the Razzalo 302 study with direct son Rassib in previously treated metastatic pancreatic cancer. And the punchline here is direct son Rassib has doubled overall survival from 6.7 months to 13.2 months. You know what, for years we've not seen much advancement in this devastating field. And this is not just for a small subset of pancreatic cancer. This is for rather majority of our patients with this disease. Do we need to do better than 13.1 months? Come on, yes, absolutely. But this is a huge step in the right direction. To touch on this data and nuances around this drug to make sure we're ready for all our pancreatic cancer patients to start using this, we're excited to have Dr. Raksana Shroff from University of Arizona. Dr. Shobampant from MD Anderson, Dr. Ilene O'Reilly from Memorial Sloan Kettering and Dr. Andrew Coe from UCSF. Thank you everyone for joining us. - Welcome everyone. To set the stage, some background here with regards to pancreatic at Noh Karsanova. This cancer remains one of the most legal cancer sweet treat. Where the five year overall survival for metastatic disease is unfortunately still less than 5%. Off-front treatment options here are modified full pharynx, the leery fox or gem side of being napactyl-pactyl. Given limited options, whatever we have not used up front, we reserved that for second line. Yes, we do look for those particular mutations for two intract and RG1 fusion, but those are rather rare. What's rather common and seen in more than 90% you're in pancreatic cancer space is Rasputation. This brings me to Razzaloo 302, phase three study where we have Razz inhibitor now in second line. Before we get to the data, Eileen, we have different types of Razz mutations. What are they and how common are they in pancreatic cancer? - Thank you so much. Thanks for the opportunity to be here. So the topic is Razz mutations in pancreas cancer and it's a topic dear to all pancreatologists' heart. So Razz mutations are present in almost every individual with this disease or alterations in the napkinase pathway. And basically they're responsible for badness, right? They're responsible for growth, for metastases, for angiogenesis and that's been known forever in this disease. Well, you know, many, many decades, but what's fundamentally changed is that there's now an ability to effectively target this that's been underscored by the Razzaloo 302 study. But specifically to talk about the details in pancreas cancer that we see Razz mutations detectable in about 90 to 95% of people. They occur primarily at codon 12 where we see alterations in the G12 physician, either D, which is present in about 30%, Keras G12V and about 30%, sorry, 4030, and then less commonly G12R, about 15%. We more rarely see alterations at X on three and X on four. They account for about 5% of people with pancreas cancer, Q61, H being one of those. And then a small percentage of individuals don't have a resputation, but they still can have activation and signaling through the MAKKINA's pathway. So that's why the Razzals will discuss them shortly are so profound here because we're not talking about a small subset of this disease. We're talking about applicability to essentially everyone with pancreas cancer. I mean, thank you so much for that background. You know, out in the community, whenever we were talking about precision medicine, lung cancer, Rohecky touched on N-track, historically it's a small subset. That is not the case here. This is for majority of our pancreatic cancer patients. Shibham, directs on Razzab, is the drug here at the center of all this. Can you please touch a little on the mechanism of action? How exactly is this drug working? Again, and I'm not looking for nitty gritty signs behind it, but broadly, how is this able to control the disease? Roheck, so this is a unique drug. This Razz is mostly in the on state essentially. Think about it like a light switch which is always turned on stuck in the on position. So this drug is like a molecular glue. It sticks to cyclophilin A, which is a cellar chaperone, and then that sticks to the Razz on protein. Leads to stereocindrance and cancer cell death. So that's how it acts essentially. Just think about it like a well-crow, just all sticking everything together, leading to cancer cell death. So it sounds very easy, you know what I say? But this is decades of science, really amazing chemistry, which has led to this point essentially. And that binding to Razz on is, I think, essential. The reason why we are seeing such good responses of this agent. - Thank you for walking us through. And that's how the molecular is named directs on Razz on because it's affecting that on effect. So again, Razz mutation is present in more than 90% of pancreatic cancer patients. Let's get through the study. Rochner, can you touch into study design of Razzalut 302? - Sure. So Razzalut 302 was a large phase three randomized open label study that was conducted internationally in multiple countries. And it involved patients with metacetic pancreatic cancer who had received one prior line of chemotherapy. Patients were randomized one to one to directs on Razz at as a single agent taken daily versus investigators choice of chemotherapy. It was one of four different options. The traditional things that we think of of Gempsideomy Nampakla Taxel, a modified Fulfurinox, Maliri with five FU or Fulfox. The study had a dual co-primary endpoint of overall survival and progression free survival, specifically in the Razz G12 population. All patients in the second line setting were allowed to be enrolled, as long as they had documented tumor for Razz's mutational status testing that could be done locally. The key secondary endpoints included the overall survival and progression free survival in the entire intention to treat population, as well as some other important efficacy endpoints like overall response rate. And importantly, there was also a patient reported outcomes collected as well. And so like you mentioned at the plenary session, the data came out as well as the New England Journal publication and kudos to some of our co-authors who were on this call today, but it really did. It made us blush. So out of the 500 patients, the majority as Eileen alluded, 92% of patients had Razz G12 mutations. In the primary endpoint of median overall survival in the Razz G12 population, the median OS was 13.2 months with directs on Rassib and 6.6 months with chemotherapy, which is striking, we're seeing a doubling in median overall survival. And in the intention to treat overall population very similar, median overall survival of 13.2 months versus 6.7 months with a hazard ratio of 0.4 and similar doubling scene with median progression free survival in both the G12 population, as well as the overall population. And overall response rate that was about 30% compared to about 11% in the chemotherapy arms. Really impressive checking all the boxes in terms of some of the important clinically meaningful efficacy endpoints. Importantly, there was also really notable RO data, notable quality of life data that supports the fact that not only was directs on Rassib providing improvements in survival and response, but there was improvements in terms of time to deterioration, overall quality of life. The site effect profile was given a lot of attention before this data came out. But even then, the AED profile was the expected profile that we talk about with as inhibitors, including Rassian, Stomatitis, being some of the more notable ones. I know we're going to touch on that later, but really just powerful, like you said, powerful to be in that room and to watch those Kaeplin-Mayer curves pop up on that screen. Indeed, the study definitely made a splash and it was very palpable. Doubling of the overall survival, we'll get a chance to dive into the site effect profile. But thanks so much, Rassian, for sort of laying that foundation where we stand today with the data. This is in second line settings. And we have trial on this going on going for first line setting that is Rassimlo 303. And this is rather an overall agent. And the dose here is 300 milligrams overall daily. Andrew, what are clinical implications for this data? Broadly, at the end of the day, with pancreatic adornocardinoma, we will have our patient exposed to in first line at clinical trial for now. Or second line, this is an important step ahead. But would you not consider this therapy for it? What I not consider it for. - Yeah, 'cause I would think that road, that's a fair question. 'Cause broadly, we're gonna be using it for everybody. - Well, no doubt this is a game changer. And I was actually thinking that very question in terms of who would not be a candidate for it. If didn't wanna see the data in terms of starting with what this only be for Jeet, with folks with a quote on 12 mutation, but it looks like the all-comers population really benefited. So even in those folks who might be Rass Wild, I think still would be candidates for this drug. And one thing I'm thinking about is that a lot of patients who would not even be candidates for further treatment beyond frontline therapy because of deterioration. I think we're going to be now able to capture and treat a much larger swath virtually all patients who are able to be able to take this easier oral medication will be able to really treat a lot more than we would previously have when we were just dealing with chemotherapy. I think it'll be tempting to treat earlier. I will wait a little bit until we have some first line, more first line data. And there actually are some first line data in terms of showing some quite impressive monotherapy. I have to see with this. But given that the initial indication will be for second line plus, I've been with the most part reserved for that setting and say it's your question. I think it will be on virtually. Everyone even up to a certain level of declining performance status, which is obviously an issue with this patient population. No, with more than 7,000 abstracts that have been presented here at Asco, I've heard game changer twice this weekend. One when, right now you and I were talking about resolute 302 and now Andrew, you brought this up and we're not using this likely. This is paradigm shifting. This is indeed game changing. I lean when looking at the efficacy is direct sonrasse working well in all the rest mutations. Or is this selectively doing better in one mutation over another? And what about that non-mitated disease? Just echo the game changer, right? This is a fundamental paradigm shift in terms of how we think and approach pancreas cancer. So to answer the question, 92% of people in the study had an alteration at the G 12th position. So it was very robust and adequately more than adequately empowered to see that signal that we all saw. But I think the benefit is directly very consistent in the non G 12. So in the rare individual who had a G 13 mutation in the small percentage of people who had a Q 61 mutation. And even in the wild type group, I think there were 9 and 7 people respectively on the direct sonrasse of arm who didn't have a respitation on 7 people on the chemotherapy arm. And again, directly very consistent. We need to have a detailed breakdown of the genomics in terms of a little specific response. And that's the next big analysis that will be coming on these data, just a little an outcomes, but not just that commutational profiles, what it means if you're H. R. D. positive and then as you pointed out, detailed understanding if you have a non G 12 mutation, what that means. Based on the data that we saw yesterday, I think it's pretty clear to me that this is an open and active consideration right now for every individual with this disease. There's some pre clinical data that's suggesting if you have a B-Raff, 600 E mutation, which is extremely rare in pancreas cancer, maybe the benefit isn't there, but that's a tiny, tiny fraction. So I think for all practical purposes, we ignore that and we embrace this and understand as time evolves whether some refinements on our approach maybe need this. At the end of the day, we'll be utilizing this for all pancreatic had no personal patient in second line. And should we have not used this drug out in community and we will store adopting to this, but could you go or the side effect profile because managing those along with clinical pearls are going to be the key. So I think, as Roshan was saying, your side effect profile has been talked about. So the main side effect that we see is a rash. It's mostly grade one or two, but it could be in 15% of patients, it's higher than that. One of the unique things about the rash that comes on the face. So when this gets out in the community, the main thing is you have to tell them to use sunscreen, really the sun, it's really sensitive to sun. So that's very important. I think prevention is better than cure in that sense. So sun is very, very important in this drug. The other things that are important are that we do start these patients prophylactyl on doxycycline and some steward creams. Some of the rashes do get bad enough that they get super infected. So you need to maybe be best friends with a dermatologist or, you know, my parents always want me to be dermatologist. I'm just kidding. But maybe we're all on dermatologist now. In a way, but I think it's good to have some dermatological help because sometimes the patients need a little bit more care antibiotics, more other antibiotics for their rash. So it's end on college community. We've always adapted. When Sitaxima came out, I remember like people are getting rashes, infusion reactions, especially in the Midwest. So I think oncology community is very good at figuring it out. The thing about this drug is the benefit is just exponential. You know, if this was like a month, one month benefited would be a very different conversation. But, you know, we all have seen in our practices that this exponential never in my life had so many patient requests to get this drug. It's just that the expanded access also. It's a lot. I'll tell you, sometimes I have to actually fight my patient because they don't want to stop the drug, even though they're never ash and that side effects, they're like arguing with me back and forth. And they don't want me to stop the drug, you know, because they feel better. Other ways just as Roshna said, the patient related outcomes, they feel better with pain, they're eating better. So clinically, they feel better, you know, they have these other manifestations. So it's not nothing. You have to watch out for it. You've got to try to get ahead of it. And you might need dermatological help. The second thing about stomatitis patients can get mouth wash, we give them kind of like magic mouth wash or other things. And sometimes if it gets bad enough, then you have to hold the drug. And the interesting thing is that the half life is not very long. And in my practice, mostly I've seen in two weeks patients get better, like everything resolves. And then maybe we can start them at the same dose or maybe we have to dose or just some of the patients. So I think as this gets out, we'll use this more and more. And I think we'll figure out how to do this, how to give this drug to our patients. And at least from medical oncology sample, and that's exactly what you've stated, we have adapted to new of these. We just saw about five drug tools within about just among. So yes, it's exciting times and we will adapt to this. But to watch you what you mentioned, oncodermatologist, our community folks who are working in our rural areas, they are their dermatologist. You're all a just GI positions along with other hats that they put on. But we'll have to learn some of these management strategies. But now we also know that there are concerns about any role of the modium here upfront or rather being proactive. Yeah, you know, I think it's like Shobam said, right? Reemptive and prophylactic is always better than reactive and trying to catch up. And you know, the two of you and I have definitely talked about, you know, the quality of life impact when it comes to things like grade two diarrhea, right? And so with the rash, just being on top of it with anti-diarrhea, anti-diarrhea management is really critical. I also just want to reiterate exactly what he mentioned about a learning curve. We use targeted therapies in all kinds of spaces and the investigators on this call who are critical in the original study help educate the nursing population, the dermatology population, they all help educate us on how to do this. And so the diarrhea just like the rash, it's going to be really trying to be prophylactic and to be really kind of aggressive with anti-diarrhea and managing it as well as patients closely with anti-diarrhea management and the treatment is going to be really important to how they do and adjusting as necessary. And I will just underscore exactly what Shobam said. I mean, even in the publication right, they talk about treatment discontinuation rate and the treatment discontinuation rate was pretty small in the directs on rasset bar, especially compared to the chemotherapy arm. And you know, I think it just speaks to the fact that when patients are benefiting, they want to stay on the drug that is providing that benefit. And so, you know, the drug is really important to you. And so, I mean, it's funny. I was talking to Dr. Wolben to Brian about this. And it does seem like, again, just good oral hygiene. These mouthwashes, all of this layering in from the beginning is the right way to approach this. I mean, obviously, Eileen and Shobam, I'm sure you all have comments as resolute investigators, but that's what Brian and I were talking about at one of the times that he and I were chatting. So again, I think it's really, how can we stay ahead of it? Eileen, can I bring you into this conversation as well? Any other clinical roles that we should keep on our way to some of the side effects? Yeah, then I'll just echo everything. Everyone said, maybe a couple of additional points. We sometimes see the GI issues early and we do recommend pre-medication with antibiotics for the first couple of weeks. I think that really helps get people true and that gets better. And sometimes we'll see the diary early. So occasionally, even in the first day or two, we just cancel patients hydrate well, quick with the abodeum, if it happens. And most of all, not to get discouraged, right? I think a big part of this is education and setting expectations and guiding and supporting people. We want people to be able to stay on this drug to maintain as full benefit for as long as possible and supporting everybody. The mucusitis tends to curve a bit later and usually there's time to intervene on that. And we're all as oncologists who've looked after people for many years with chemotherapy, right, and other medications. We have a good handle on that with magic mouthwash or dexamethasone mouth rinse. And my senses in people who are less well nourished, they're a little bit more vulnerable to mucusitis. So they're the people I keep a close eye on and have a low threat. for those hold to help that settle because it can for some people be a bugbear. But overall, and not to minimize side effects here, I think we put it in the context of the bigger picture, right? And the bigger picture, again, is profound. And we do the best we can with all the support of tools that we can make it as manageable and as comfortable as possible for people. You know, I will say I think a lot of folks were barmed when some public figures appeared with such severe rashes and things like that. It tends to actually be very variable, I will say. And we're typically able to treat through it for the majority of patients as was pointed out earlier, folks who had a very severe rash. I've only had to really hold it intimately for up to a week at a time before those symptoms subside and you're able to, overall in my experience, I've been quite pleased in terms of the tolerability or able to manage with maximum support of care. When you were resuming to retreat these patients, are you dose reducing at that point in time? I initially tried to maintain them on the same dose at 300 milligrams daily. For recurrent episodes, it seems like we're having to peedently fold, then I might drop the dose. This drug cannot come fast enough for us out in the community settings. But Andrew, you had alluded to this. I speculate that this is going to be used all over the place in that borderline, resectable disease for a patient that is not fit for surgery or even in frontline settings for that fail patient where single agent chemotherapy has poor outcomes. But again, right this minute, Razzle 3.02 is in second line. Shibham, can you touch on ongoing trials with directs on Razzab? That should be on our radar. Which ones do you want me to touch on? No, no, no. So this is the Razzle 3.02. We have the Razzle 3.03 where we're moving to the frontline. Really exciting. It's single agent, Razzle 4. Or Razzle 4. Gem napacletaxe or Gem napacletaxe. You have Razzle 3.04, which is the adjuvant setting. Remember, this is how we achieve the cures. We take out the micrometastatic disease even after a recession, you know, 50 to 70% of pancreatic cancer patients can have relapse. So we have Razzle 3.04, which is after finishing off your adjuvant therapy patients are randomized to either Razzle 4. Razzab or a schedule follow up like we would do normally. And there are two other, you know, that's another hour long discussion of elite specific agents, especially Keras G12D, which is in 40% of patients at pancreatic cancer. And there are two other studies which have been announced, which is Razzle 3.05 and 3.09. 3.05 is chemotherapy, whether without a Zoldone Razzab, the other Razzab, and 3.09 is Zoldone Razzab plus the Razzab and you know, versus chemotherapy. However, there are other agents also, which are clinical trials, which are being launched. Just to give a full balance is there's another one called 734, INCB 734, which is very similar chemotherapy, whether without. It's a Razz on-off inhibitor and sety-degressive, which I can never say properly, but it's a protact. So that's a clear adjuvant deep protact, which is also in the clinical trial in the front line setting, with or without Nellity Fox or Fortfarer and Ox. So what an exciting time for pancreatic cancer. So we are excited to see how this is going to all play out in front line setting and also in adjuvant setting. But this is all confined to pancreatic ethnocortinoma. We know that Razz also is a concern in colorectal space and lung cancer space, and often associated with poor prognosis. Any ongoing trials in other pathological sites like colorectal in lung cancer that we need to be watching out for? Yeah, thanks for asking me the easy question, but there, I mean, it's there in colorectal and in lung, right? So those trials are ongoing in colorectal and lung. The magnitude of benefit colorectal in the earlier data said maybe has not been that great, but in combination therapies. So I think folks are working on that. So it's just like I said, it's just an amazing time. I feel like, you know, more plenaries on the way for pancreatic cancer, you know, this is just the beginning. We can't wait. Wow, these are certainly exciting times and date as we start to close, I lean any final thoughts here. Just summing up, right? Just on Razz, new 302. This is a very rigorous perspective randomized study with an outcome on the control arm that was as predicted and as we use every day in clinical practice and supported by progression free survival, the significant magnitude of overall survival by response rates and by quality of life. So it hit all the benchmarks and leaves really very little to question here in terms of the significance of the bindings. So now, our goal and our hope is to get this to as many patients as we can as quickly as we can and as my colleagues have alluded to to look to see how we can integrate Razz directed therapy into every setting in pancreatic cancer. Here at Asco this weekend, more than 7,000 studies were presented. One got standing innovation. This one. And that is because for years, we've not seen much advancement in pancreatic cancer. And now we're finally seeing doubling of that overall survival based off Razz, new 302 study with direct son Razz. I lean, Wachna, Shubham, Andrew. Thank you so much for walking us through this data shortly after this was presented at Asco plenary. For our listeners, let's go over a quick recap. From thousands of abstracts here at Asco 2026, quite a few are practice changing. But there is one that has created a lot of buzz and that is Razz, 302 where direct son Razz has doubled the overall survival for pancreatic cancer in second line from 6.7 months to 13.2 months with has a ratio of 0.40. With doctors O'Reilly, Pant, Shroff and Co, we touched on this study and what this means for our clinical practice. Oh, what we are talking about is doubling of overall survival. That is impressive. Few other things that we covered here during the conversation was that Razz mutation is present in more than 90% of pancreatic cancer patients. As a result, we're not talking about the benefit in a small subgroup, but rather most patient with this devastating disease. Also, this is an oral medication which helps with time toxicity that our patients face with chemotherapy. Then we also touched on some of the common side effects that we see. That is Razz. That is where we have to be very proactive with doxycycline, which is going to be very helpful. With this drug, we also talked about stomatitis and diarrhea for us to keep on the radar. Well, what did I miss? Right, we need to get comfortable in appreciating and managing these side effects given all pancreatic cancer patients will get exposed to this drug. Thanks for joining. Make sure to tune back in for more conference highlights, treatment algorithms, and challenging cases. We're alive from ASCO, the oncology brothers.