RASolute 302 Pancreatic Cancer Study with Daraxonrasib at ASCO 2026 – Dr. Brian Wolpin

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossane here with my brother and co-host Rohit Gossane. In our post-ASCO conference highlights, we often just cover lung cancer, breast cancer, giumiligencies, and GI malignancies. Within GI, we often cover multiple different disease sites. But given the importance of one single study, Razzalut 302 in pancreatic cancer, we want this conversation to focus just on that. And for this, we have a special guest, Dr. Brian Wolpin, senior author on this study and the one who presented this data at plenary during ASCO 2026. When he's not on the biggest podium, Dr. Wolpin is seeing patients as the GI medical oncologist at Dana Farber Cancer Institute. Brian, thank you so much for joining us. Brian, congratulations on your work. This is a win for your team, investigators on quality community and importantly our patients. No, we don't have a cure for pancreatic cancer yet, but efforts here were able to buy us more time for our patients with their loved ones. Anyone listening to this can picture that patient in front of them wishing they had this drug available earlier. Let's get into all this. What we have at hand from study that I'm talking about here is Razzalut 302 in second line pancreatic adenocarcinoma. Before we get into the study itself, Brian, we all now know that Razz mutation is present in more than 90% of pancreatic cancer. Brian, can you touch on different Razz mutations that we see in pancreatic cancer? We're absolutely right that we've known for some time that somewhere between 90 to 95% of pancreatic cancers have a Razz mutation. In pancreatic cancer, that's largely K-RAS, that's mutated. And there's really three hotspot mutations that are most common, G12D, G12V, and G12R. So those make up together, those three, almost 85% of pancreatic cancer has a mutation, one of those three. There are, though, other less common mutations, occasionally Q61 or at G13, and there are some other G12 mutations we see too. But to your point, this is very much a Razz mutated disease almost entirely, meaning almost all patients have that Razz mutation. Indeed, to sum it up, the landscape that we were talking about is the common mutations, G12D, G12V, and G12R, making the bulk of the pancreatic cancer mutation type from Razz standpoint that we see. We have been able to target K-RAS G12C in lung and colorectal cancer. But what we are talking about here is a small subset of the disease. However, here in pancreatic cancer, for that Razz mutation itself, that's almost all our patients. Ryan, could you touch on the trial design and the findings here? Yeah, of course. So Razz Luthorio2 study, as you said, this was a study for patients who had metastatic disease, and they must have had one prior line of chemotherapy before, so this was a second line study. And we did require that they had documentation of their Razz status, meaning they must have had some testing. Could have been on the tumor, could have been from self-read DNA, we allowed either. But there needed to be some documentation of whether a Razz mutation was present or not. That being said, all patients were eligible. You were not required to have a Razz mutation, and you were not required to have a Razz G12 only mutation. Every patient who we could document, they either did or did not have a Razz mutation could enroll. So it does represent essentially the broad population of patients we see in pancreatic cancer. It was a randomized phase three trial, so patients were randomized one to one to either directs unrassive, which is an oral drug with 300 milligrams, once a day orally, or investigator and patient choice of chemotherapy. I think as your audience knows, there's a number of different chemotherapy regimens that can be used in the second line setting, often based in part on what you got in the first line setting and the choices that were made there. We didn't want to be restrictive. We really wanted to allow people to use whatever chemotherapy they thought was most appropriate for their patients. So you can see here there were four different choices that are all standard of care. And then the primary endpoints there were two dual primary endpoints were overall survival and progression-free survival. This to start with was in the Razz G12 population as the primary endpoint. And that's because Razz G12 mutations as we talked about are so common. We wanted a more homogeneous population to start with for the primary endpoint. And then the secondary endpoints were for the entire population and patients that were evaluated. So the overall survival was the primary endpoint. And you can see that there was a statistically significant and substantially improved overall survival for patients who received directs-unresive compared to chemotherapy. Directs-unresive being the green line, chemotherapy being the gray on the Kaplomire curve. And you can see the median overall survival was 13.2 months. If you received directs-unresive 6.6 months, if you received chemotherapy in the Razz G12 population, hazard ratio of 0.4 and very statistically significant. If you look at the curve on the lower part of the slide, you'll see that's now in the overall population. So this allows the less common Razz mutations, including Q61, G13. It also allows patients who we were not able to identify a Razz mutation. And the results were very similar. Again, a substantial improvement in overall survival for directs-unresive compared to chemotherapy. And then the upper left of your side, you can see objective response rate. This was done by blinded independent central review. And you can see a substantial higher objective response rate if you received directs-unresive compared to chemotherapy. To the left is the Razz G12 population. To the right again is the overall population. And over 30% response rate for directs-unresive, about 11% for chemotherapy. Brian, when these results were popped up, this is when during plenary, we all got really excited. We're talking to Dr. Shubin Pant, another author on this study. And he made a point, which is so true. If this was like old days, and this was the first time we ever saw this data, I really think we all would have lost our minds. The doubling of overall survival here is commendable. But I do want to touch in two things. First, how is directs-unresive working? And then what side effects do we need to worry about in our clinical practice? Brian, let's start off with the mechanism of action here. How exactly is this drug working? So directs-unresive is what's called a RAS-On inhibitor. So RAS sits in two different states. It sits in a GTP bound state, which is the on state, and a GDP bound state, which is an off state. The on state is the state that sends the signals that tells cancer cells to grow. We have wanted to try to be able to block the on state for a while. Some of the inhibitors we use now, like soda-resive and adagressive, those are actually off state inhibitors. But the thing that is different about directs-unresive is that it's an on state inhibitor. So it's actually blocking the state of RAS, that's the one doing the damage, the one that keeps sending these signals to grow. It is also a multi-selective inhibitor. So again, if we do the comparison to soda-resive and adagressive, again, these are G12C specific inhibitors. They find only to G12C, and you wouldn't use them if you found another mutinal leal in RAS. That again is not what we see for directs-unresive. This is a multi-inhibitor. It actually inhibits multiple different mutinal leals, and the thing that's made it so relevant to pancreas cancer is it blocks G12D, G12V, G12R, the three that we're just talking about is most common, and it also blocks the less common. I think another unique feature about directs-unresive is it actually also binds wild-type RAS. So it's not only in the mutant state, but also in the wild-type state that directs-unresive works, and that may be why it actually works in RAS wild-type tumors. It's a little counterintuitive when we're thinking about RAS inhibitors, but almost all pancreas cancer signals through RAS and MAP-Kinease pathway. And so even when you don't have a RAS mutation, there's still a lot of flux through that pathway, and because directs-unresive works to block wild-type RAS, it actually blocks that signaling, even when there's not a RAS mutation, but there's still increased flux through the MAP-Kinease pathway. So again, it does have a number of these features that are somewhat unique compared to prior RAS inhibitors. And then the last thing I'll say, because I know we only have a certain amount of time here. There's a lot of mechanistic things about this drug and how it's working, but it's also what's called a tricomplex inhibitor, meaning that it doesn't bind directly to RAS on its own. It actually binds to a chaperone protein called cyclophilinae, changes the confirmation of cyclophilinae, and glues it to RAS. And this is a class of molecules that are sometimes called molecular glues, because it's a sense of taking the drug, finding another molecule, and gluing that molecule to your target. When you glue a big bulky cyclophilinae to RAS, RAS can't bind to then the effectors it needs to bind to to do its signaling work. So I think there's a number of really sort of interesting features of this drug, RAS on inhibitor, multi-selective, and this molecular glue kind of mechanism. This is exciting, because again, when we're talking about our G12C and pancreatic, it's a very small subset. We are using in lung cancer and colon cancer already, as you had initially touched on. Again, just to recap, the on state is very important, but as if now the data shows that this is working for all comers. I do want to take some time to touch on side effects. Here, Brian, what can we do on RAN to help our patients to get through this safely. Be it that rash, diarrhea, or mouse source. How common are these side effects and how can we mitigate some of these on our end? - I think that's gonna be really important. As we hope this becomes an FDA approved drug that we all can start to use in our clinics. So there really are four side effects that we saw most often. And this has been very consistent all the way back to the phase one trial through two phase two and now in the phase three resolution through two trial. So rash, stomatitis, diarrhea, nausea. And we think that some of this is because it is a RAS wild type binder, RAS wild type does a lot of signaling in the GI track and in the skin. So if you block some of that, you get some of these side effects. So I think the two that are a bit easier to manage, I would say overall, are the diarrhea and nausea. We have medicines for that. We usually can treat patients reasonably well and that usually is not a huge issue. Sometimes patients need to take an anti-emitic some composing or zoophran before they dose with thorax unrassev. If you had a couple patients, we ended up dosing them at night because then they're asleep with the effects of some of the nausea and that has on occasion been helpful. But those things are usually things we can work around and help manage relatively easily with medicines. The rash and stomatitis have been a little bit harder and that's what we have been spending quite a bit of time trying to think about how to do better in terms of management. You can see from the plot here that about 10% of patients get a pretty substantial rash and it often is on the face over the bridge of the nose can be in the scalp. Those are the areas that I think are the most bothersome to patients. It can also be on the chest and back. It looks a bit like an EGFR antibody rash but often if it gets to be more severe, it has a more severe look than that. It can actually have some bleeding associated with it. It's not so common to see with EGFR antibodies. So what we've started to do and we sort of picked this up along the way is we've started to do prophylactic treatments like we do for EGFR antibodies. So we've been giving patients a tetracycline family antibiotic like minocyclin or doxocyclin. I've tended to use doxocyclin. We've also used prophylactically some steroid creams for the face and for the chest and back. We've usually used hydrochlorosone on the face and triumsonalone on the back and on the chest. If the rash gets more severe even with prophylactic medicines, then sometimes you need to add other things. These can be other things like clindamycin. Topically, we've actually started to use retinate. So a retinoid like we do for acne that has worked well in some patients and even things like tachyrolymus ointments or things you can use are anti-inflammatories on the skin. I think what I would say is what has helped us and what I personally would recommend to your audience to is to try to identify a dermatologist who works in your area and picks one person ideally and really try to work with them on this because we need help sometimes as oncologists to manage the rash. And I have needed help from my dermatology colleagues. And I think what we need is our dermatology colleagues to get used to this and be able to work in partnership with us. And I think that will help us all as we try to keep patients on treatment as much as we can. A couple other points I would make about a third of patients had to have a dose reduction for a direction rassib. So it starts at 300 milligrams, but a third needed a reduction. I was almost always because of rash, right? So sometimes what we needed was a dose reduction or even a break, they needed a week off, they needed 10 days off, the rash quieted down and they could go back on. But I think your audience will get used to ultimately saying, oh yeah, this is the patient who needs the reduction or we need to take a break for a week. These are things that everyone will learn, I think, as we have more access to the drug. - I want to read right a couple of things because at the end of the day, quality of life matters and the only way we can manage and continue on this therapy is if we stay proactive with some of these measures here. With regards to rash, Brian, you mentioned oral antibiotics like doxycycline, minorcycline, topical steroids and sun protection and along with that, you mentioned dermatological partnership as well and also some role of tecrolymus, but again, dermatological colleagues will be able to help us out with that. With diarrhea, antidiereal therapy with low paramide amodium is going to be effective. Stomatitis, supportive oral care. We learned that from data DXD or Evalymus steroidal mouthwash is very helpful. So overall, the drug is not without side effects, but in general, what we saw was rather low grade and majority of the cases and low discontinuation rates as well, but at the end of the day, proactive is going to be the key. Brian, you mentioned 300 milligrams daily is what we start with, but the dose reduction is 200 milligrams. You mentioned rash is a bit dose dependent. How about diarrhea, stomatitis? - Yeah, so I think the points you made were great. One I should have mentioned is the sun exposure part that you mentioned, very important. Our dermatologists have really advised us that this is likely to flare with substantial sun exposure. So you're right on target with that. We should avoid that lots of sunscreen, hats trying to prevent full on sun exposure that I think is important. So I think in terms of dose reductions, yes, you're right. So 300 milligrams, then down to 200 milligrams, the new formulation will likely from what I hear be 150. We had used 140 in the trial, but it sounds like the way the pills are being formulated. That's like the where we will end up. That is the next dose reduction. I would say rash and stomatitis do seem responsive to dose reduction. So as you reduce the dose, the severity gets a little bit less. And sometimes also I think it's often paired with we get a bit more aggressive in the medicines we're using to treat it. So both of those things I think do help. I'm trying to think how often I really had to dose reduced because of the diarrhea or nausea. That was pretty uncommon actually that was needed. I think usually what we've been able to do is use sort of the standard nausea and banty diurel medicines that we're all used to giving with many of our regimens that that has usually been able to take care of things. And it's been uncommon that I've seen needing to dose reduce for those reasons. I also fully agree with you. Quality of life is very important. Part of the benefit of this is it's a pill once a day. There are no IV fusions. Infusions are not pumped to wear at home. But if they have terrible rashes in their quality of life is poor, then we're not really accomplishing our goal. So we need to be proactive and aggressive about managing these things. You know, the word proactive has come up a few times. The other thing is educating our patients on what to expect so that they can keep us informed on how things are so that we can make these adjustments. As we start to close, we've talked of rasp mutation being more than 90%. In our clinical practice, given we seem profound benefit for everyone, do I need to wait for that result to come back? Just in case if it was not checked upfront or can I broadly use this for all? - I've gotten that question quite a lot because we really are trying to think through what is a targeted therapy. It seems to work for everyone. So, you know, what I would say is one, I would still do testing in every way. We do sometimes find other drivers beyond rasp and it would be important to know what those are and there are other drivers for which there are combination trials coming that are gonna combine drugs with rasp inhibitors and another drug where we're gonna try to make directs on rasp inhibitors work better, even better than what we've seen. So, I think that is still important to do. So, I still would do that. Do I think this is for all comers? I do. I think you can. I think if for some reason you couldn't get the answer because the tumor tissue just wasn't enough to do the sequencing or they didn't shed enough into the blood to do CTDNA, I think you can comfortably use this. The one place I would say is that I may use something else instead of this. Would be a patient where we do the sequencing, we don't find a rasp mutation, but we find another driver for which there's an FDA approved therapy, right? So, an N-TREC fusion, a N-RG-1 fusion, a B-RFV-600 emutation, there are FDA approved therapies. They're not only for pancreas cancer, right? - No, I think that's the answer. - For cancer types. But those really do target them. What we think would be the main driver in that cancer, I probably would use those drugs first. I think some of them may still be responsive to directs-interests of them, as we said earlier. So, I would still consider using it in the future, but I probably would go with the one that I think directly addresses the driver if I find one. Again, that's probably just a couple percent, though, patients with pancreas cancer. - And with regards to the testing, their liquid NGS is going to be enough or you would be relying on solid tumor here. - Yeah, so I personally think that we need to do tumor testing still. There are things you identify, particularly copy number changes, some fusions that are just not as easy to detect by CTDNA. And some of those things for CTDNA really depend about how much DNA is shed by the tumor into the blood. If there's not much shed into the blood, it's very hard to make copy number calls or fusion calls. So, what I generally do, and this is something we've started now at Dana Farber University, is actually the first day we see the patient, we actually do CTDNA testing if they have metastatic pancreas cancer. We've been doing that because rass inhibitors are now in the first line therapy and clinical trials. And some of them are immunolale specific. So, we need to know, is it a G12D or a G12V mutation? And the fastest way for us to get that answer often is with CTDNA. But we also then, as we're getting started with first line therapy, make sure we're doing the tumor testing too, so that we identify some of these other important drugs. I think in just a recap, the rucks are on the last set here is for all comers, but this does not negate the importance of biomarker testing and NGS testing. Okay, I think we've covered the study while Brian, as a final thought, I would love to hear what you were feeling when you saw thousands of us erupt and celebrate this data when this was presented very well knowing that at the center of all this, it's our patients. Every one of us in that room has had a patient or a friend or a family member that we've lost to pancreatic cancer. What emotions were you feeling seeing us all celebrate this progress? Yeah, I think I was mostly thinking about all the patients I've taken care of, right? So many, so many patients with pancreatic cancer. And just thinking, well, I wish we had this before, right? I know it's progress and we want to see progress a little bit of regret also at the same time of all the people we've lost. But I really think this is the start of a new day in pancreatic cancer. This is the first drug in this class, but there are many others and there are many ways for us to now think about doing combinations of therapy to really get durable responses for our patients, really make a difference. So I think really it's also a bit of relief. Like, man, it's about time, right? After all these years of work by so many people that God were here, right? It's about time. Yes. And again, this is a huge step forward because of this, our patients are going to live longer and we need to do better in managing these side effects that come along. Brian, thank you so much for taking the time to join us today for those tuning in. Let's go over a quick recap from today's discussion. In today's discussion, we touched on Razzaloo 302 study with Dr. Brian Wolpen. Besides focusing on that overall survival data, which is doubled in second-line settings for metastatic pancreatic cancer from 6.7 months to 13.2 months, we also touched on side effects. Bravo. As our patients live longer, we have to shift gears to ensure that we prioritize that quality of life alongside the survival. With Derricks and RSS, what we are seeing is GI and dermatological toxicity. That is rash, diarrhea, nausea, mucositis are some of the common side effects that we need to educate our patients on. We are eagerly awaiting approval, but this is an active agent in all our pancreatic cancer patients rather than a small subset. I agree, Rohehead, more than 90% of pancreatic cancer has razz mutation, but the benefit here with Derricks and Rasset was seen in all comers. We eagerly look forward for this drug to being available for all our pancreatic cancer patients. Thank you for tuning in. Make sure to tune back in for other ASCO conference highlights, including more GI studies, long head and neck cancer, breast cancer, sarcoma, and G.U. malignancies. We are the oncology brothers.