Brian M. Wolpin, MD, MPH, and Eileen M. O’Reilly, MD, on Daraxonrasib in Previously Treated Metastatic Pancreatic Cancer

So maybe, Brian, do you want to walk us through just a little bit about the background of pancreatic cancer and the significance of these results? Sure. Thanks, Eileen. And it's great to be here to get to talk about this with you. So the RASolute 302 clinical trial is evaluating a new therapy, daraxonrasib, in patients who have metastatic pancreatic cancer and have had 1 prior line of chemotherapy previously. Currently, what we do in this situation is we use a second-line chemotherapy. However, that chemotherapy doesn't really work as well as we would like. Median progression-free survival is usually around 3 months for second-line chemotherapy and median overall survival about 6 to 7 months. The key thing, though, about pancreatic cancer is almost 95% of those cancers have a mutation in an oncogene, RAS, in particular KRAS. And most of those mutations are in KRAS G12D, G12V, or G12R. So daraxonrasib is an oral drug. It is a RAS multi-inhibitor, which means it inhibits multiple different mutant alleles of RAS. And it's now being tested to see whether it can be beneficial in patients with pancreatic cancer. Thanks so much, Brian. It's such an exciting time in pancreatic cancer to see these results. Do you want to summarize for us just the key outcomes from the RASolute 302 trial? Absolutely. So as we said, RASolute 302 is randomizing patients. It randomized about 500 patients to receive either daraxonrasib or standard-of-care chemotherapy, and that could actually be 1 of 4 different chemotherapy regimens, depending upon the patient and the doctor's choice. And so the main primary endpoint of the trial was overall survival, particularly in the RAS G12 population, which is a group of patients who have a RAS G12 mutation. And that primary endpoint demonstrated a statistically significant and substantial improvement in overall survival for patients who received daraxonrasib compared with chemotherapy. So the overall survival was between 13 to 14 months for daraxonrasib and 6 to 7 months for chemotherapy. These results are really pretty striking, right, when we see the outcomes for pancreatic cancer with current standard chemotherapy, to see a doubling of survival and then supported by progression-free survival and response rates. And you want to talk about the quality of life and the side effect profile? Absolutely. So I think, Eileen, as you said, really the trial met all of the primary and key secondary endpoints. So overall survival, like we just discussed, there also was a statistically significant improvement in progression-free survival and objective response rate. But critically, as you said, there was also an improvement in quality of life, that patients who are on daraxonrasib had a delay in the time to worsening either of pain or of global quality of life compared with chemotherapy. Now, obviously, that's really important to our patients, that they feel better in addition to having them live longer. Yeah. I think the internal consistency of the results is really compelling to me and that the control arm did as we expected the control arm would do, and I think provide a strong precedent for a change in the standard. So how do you see this moving forward? What's going to happen in practice? Yeah. I think, as you said, the results are quite striking and really quite consistent across all of the different endpoints that were evaluated. I think the data from RASolute 302 support daraxonrasib as a potential new standard of care for patients with previously treated metastatic pancreatic cancer. That obviously depends on some additional regulatory approvals, but that really would change how we think about treating pancreatic cancer, going from an era where chemotherapy really has mostly been what we have used to now the potential to use a RAS inhibitor. It's so exciting to see this at this moment in time. And I think, you know, big steps, right, for moving forward will be how we can integrate RAS therapies in other settings in this disease. Absolutely. But first, we need to see these hopefully results reviewed by the FDA and get their perspective, right, on the data. Right. And did you have other thoughts maybe about the data or what's coming next? Yeah, I think the other areas where I see it moving are in the adjuvant setting, looking at the outcomes for individuals who've completed all standard therapy, followed with or without a RAS inhibitor, and into frontline. That's where big impact is going to be. And I think we need to define what are the optimal combinations, whether with chemotherapy or maybe there's going to be a role for no chemotherapy and a single-agent targeted approach, which is a compelling consideration in pancreatic cancer. Yes. Oh, I totally agree. I think it really opens the door for some incredible studies to come, thinking about how we really inhibit RAS with either other medicines or in other settings in combination. Really, I think incredible next steps. Yeah. And I think just to make 1 more point for our audience, just about the group of people that this applies to. And because RAS and the MAP kinase pathway are so activated in pancreatic cancer, this drug, right, looks like it has value across all subsets of individuals with this disease. That's right. And do you see kind of areas where we'll need further study? Yeah, I think that's a great point. I think, you know, for pancreatic cancer, it's mostly driven by KRAS mutations, and this is mostly in several different KRAS mutations that we see. But there are some rare mutations, such as Q61, and even tumors where we don't find a RAS mutation. I think it will be really critical to understand how a drug like daraxonrasib works in those patients. Also, it really would be exceptional to have a drug that could work across all of these different subsets, which at least the preliminary data suggest would be true for daraxonrasib. I think more data will help buttress that over time. Absolutely. Another important point that I think people will want to hear your thoughts on is the side effect profile and, in particular, the rash because that's gotten some visibility and attention, and how we manage that in practice. Yeah, I'm happy to give my thoughts. Love to hear yours too. So I think for daraxonrasib, there are 2 main side effects that we have seen that require some management. The first is rash and the second is mucositis. I think for rash, we've been learning as we've been treating more patients how to deal with that, both with prophylactic medicine. So using medicine before we even start the daraxonrasib to help blunt the severity of the rash and then some additional medicines we can use if the rash is more severe. I think for the mucositis, similarly, thinking about rinses for the mouth and anti-inflammatory approaches that can allow us again to blunt that or treat it if it occurs. I'm wondering what you're thinking about that. Yeah, I think it's a ripe area for study to understand how prophylaxis works and the magnitude of benefit from that, and then understand how to best treat this when it happens. We know that sometimes we need to introduce short dose holds and occasionally dose reductions. But I think overall, relative to a lot of things we do for the treatment of pancreatic cancer, this was, you know, fairly palatable, I think, for patients. Some GI toxicities, and like everything, as it integrates into practice in the future, I think we'll learn more how to optimally manage this. Yeah, I think you bring up a couple of good points for the comparison as we think about, well, what's the alternative? What we do now is chemotherapy. I think if you look at treatment-related adverse events that lead to dose reduction, there were substantially fewer of those for daraxonrasib than with chemotherapy, where we often need to use dose reductions. There also was a very small percentage of patients who had to hold or stop. And I'll say it again, there were very few patients who had to stop daraxonrasib because of toxicity. Only about 1% had to do that, whereas with chemotherapy, that was 11%. I hope over time, as you say, we'll get even better at managing the side effects for daraxonrasib. But when you compare the two, it does feel like this is a more tolerable approach than using multiagent chemotherapy. Yeah, it's attractive to patients, right? Oral, conceptually, that there's a target and a drug that matches that, that's an appealing strategy and something we haven't had the luxury of to any great extent in pancreatic cancer. Yes, yeah. I'm wondering, you've treated many patients over the years, sort of how you feel like this will affect the field and sort of what your thoughts were when you first sort of saw the results? Yeah, I found the results, you know, pretty stunning to be honest. And I think we all had a lot of hope. Ultimately, the magnitude, you know, hazard ratio of 0.4, that's a real number in this disease. And, you know, in several decades of seeing drug development in this disease, there's been nothing that's been close to that in terms of significance. And now the race is to try to make these types of approaches, right, available to as many patients as we can and understand what are the best ways to sequence these drugs, what combinations are most potent, and how we can build on this important first step. Yes, yeah, I fully agree. It does feel like a new time where we're now able to leverage so much science, so much biology. We've learned about pancreatic cancer and use drugs now that really step in and try to target that in a way we haven't been able to do before. We have had a lot of trials that have not panned out as we had hoped. It's nice to see this really pushing the frontier for us. Grateful. Congratulations, Brian. Congratulations. Still just delighted.