Kura Oncology, Inc. ($KURA)

Good day, everyone. My name is Megan, and I will be your conference operator today. At this time, I would like to welcome you to the Kura Oncology Investor Call to discuss recent clinical data and the company's updated development strategy for darlifarnib. [Operator Instructions] At this time, I would like to turn the call over to Troy Wilson, President and Chief Executive Officer of Kura Oncology. Please go ahead, Dr. Wilson.

Thank you, Megan. Welcome, everyone. It's a pleasure to come to you today and share the darlifarnib clinical results from ASCO as well as our strategy and next steps for the program. If we can go to the next slide. In today's presentation, we're going to be making forward-looking statements. We would refer you to the -- to our website and to the SEC's website for more information about Kura Oncology and risks and uncertainties relating to an investment in the company. Next slide, please. Today's participants include where Dr. David Hong, from MD Anderson Cancer Center. We're delighted to have him here today as well as my colleagues, Dr. Mollie Leoni, our Chief Medical Officer, and Dr. Francis Burrows, our Chief Scientific Officer. Next slide. This is an exciting time for Kura Oncology in addition to the substantial momentum that we're making in our -- with our ziftomenib program, both in the commercial marketplace as well as in the clinic. We're now in a position where darlifarnib is moving into a position that's quite exciting. And that's really the purpose of today's sessions to share with you the data some translational data and thoughts around strategies and next steps. Next slide, please. At Kura, 1 of our key focus for the company is on a concept we call precision combinations. And that is the idea that patients will do better, drive better outcomes through use in combinations. And if we can please go to Slide 6. Sorry, if we can go forward to the next slide, please. Thank you. So here, some of the challenges of developing an effective companion therapeutic to enhance clinical activity. This is really the opportunity and the challenge with darlifarnib. This is not a new concept. People have been trying to develop combination therapies, particularly against targets on the MAP kinase and PI3 kinase pathways for quite some time. Some of the requirements are, of course, that the targets have to be druggable. They have to be selective. Often, these combinations are limited by toxicity. We've seen this with various combinations. Sometimes those toxicities prohibit actually being able to reach doses where you can drive maximum activity. Similarly, there are pharmacokinetic or pharmodynamic interactions that can limit dosing. We go to the next slide, please. That's what we think we've addressed here with darlifarnib. We have a companion therapeutic. We've now demonstrated in multiple settings that we're going to walk through today the ability to combine and the ability to suppress this pathway signaling and enhance activity. With that, we think there's really a significant opportunity for patients and potentially for Kura's shareholders. Next slide. So darlifarnib is our next-generation farnesyl transferase inhibitor. As many of you know, we've been working on this program for a number of years. And this compound is really as optimized as 1 could be. Importantly, not to take anything away from others. We're not working on another tyrosine kinase inhibitor, another KRAS inhibitor, we're developing an approach with darlifarnib where we think we can enhance the clinical activity across multiple targeted therapies and multiple settings. And in that, we think FTIs represent a mechanism-driven targeted therapy agnostic combination platform approach. So it's quite different, we think, complementary and really positions us quite favorably relative to these rapidly evolving landscape. Next slide, please. So here, this pathway diagram, really several key points. First of all, we've shown you now 3 different examples where darlifarnib is able to enhance the activity of a targeted therapy. Working from left to right, we have that adagrasib, which the data we'll show you today. A few weeks ago, we showed you the combination data with cabosantinib, and last year, we showed you combination data of tipifarnib plus alpelisib. In each case, we've been able to see an enhancement of clinical activity. The common mechanism of action here is blocking RevPAR insulation. REV is responsible for the localization of TORC1. So by darlifarnib blocking the farnesyl transferase, that's able to attenuate pathway signaling MAP kinase pathway signaling and PI3 kinase signaling. This gives us opportunities within each of these classes. As you'll see, we think this approach can apply to adagrasib as well as other KRAS inhibitors. It gives us opportunities to go with alone, also gives us opportunities to collaborate with others. So it's quite an extensive menu and you'll -- this is why we wanted to give you the strategy update to help you understand our proposal for a platform study, which will really help us to evaluate these different combinations efficiently. Next slide, please. The opportunity for patients is really quite significant. Just working our way around to the circle here at the top, you have the indications that are relevant for the tyrosine kinase inhibitors, kidney cancer as well as neuroendocrine tumors. We have, of course, the PI3-kinase alpha mutant tumors in the lower right. And then really what will be the focus of today's presentation, the KRAS mutant tumors, pancreatic colorectal and non-small cell lung. These are significant numbers. And we have now, as you'll see a little later in the presentation, clinical proof-of-concept data in a number of these indications. We won't be able to prosecute all these on our own. We will, however, be able to advance some of them on our own, and we think to work with others to really be able to do what's best for patients. Next slide, please. With that, I'm going to turn it over to Dr. David Hong and let him walk you through the data that was presented this weekend at ASCO. Dr. Hong?

I don't know who's on the other line, but I'm sure as many of you talking about KRAS in general. I'm going to walk you through the combination that we've now started looking at with adagrasib. I'm very familiar with adagrasib, help lead a number of other combinations of that again. Next slide, please. This was a poster presentation that we presented this ASCO. Next slide, please. Yes. Okay. So really 3 dose levels from 3, 5 and 8. We really didn't feel like it was going to be able to be advanced further, but I think you'll see from the data on 3 and 5 that those doses also show some significant activity. Next slide, please. So this is the overall demographic profile of the patients, there are 15 patients at the 3 milligram darlifarnib and at 15, as you know, adagrasib was set up 100% standard of care. Dosing and then pretty much given distribution here. Most patients with good ECOG and really 3 tumor types that we're looking at non-small cell lung, PDAC and colorectal, you can see the distribution. Next slide, please. Typical of most Phase I trials. These patients had lots and lots of prior therapy. As you can see here, the majority of these patients had 2 or more -- many of them had prior your [indiscernible] or adagrasib, which is now the standard care in non-small lung and to some extent and also colorectal, and also had other investigational agents such as [indiscernible] smaller numbers. Next slide, please. And you can see here the distribution of tumor types, PDAC, non-small cell lung, and colorectal. Some of you may know [ Care SG12C-PDAC ] is a much harder subset of patients to identify. It's probably less than 5% of all PDAC. And you can see here that the majority of patients who had prior G12C were non-small and colorectal, which, as you know, there are 2 drugs approved in both areas. The majority of these patients got either [indiscernible] or adagrasib. Next slide, please. Yes, these are the adverse events. Pretty much it to compare that to like adagrasib especially the diarrhea, nausea, really no significant add-on toxicities. Clearly, there's no rash as we see with [indiscernible] and the overall neutropenia anemia that is probably associated with darlifarnib, we rarely see that with adagrasib, looks like pretty much no significant toxicities noted here. Next slide, please. But this is what is really, really, really interesting. And there's still small numbers. I'm going to be honest with you. But if you look at these numbers, look at the number of patients, particularly in the pancreatic subset. As you recall, both adagrasib and [indiscernible], the response rates are not [indiscernible] because I ran that trial is in the low 20s. And adagrasib maybe low 30s. This is like -- it's 60-some percent with darlifarnib here in the pancreatic setting. And every 1 of these patients are having some kind of tumor shrinkage. That is significant. I don't -- you don't know until you obviously add another maybe 10, 15 patients here. But that -- I don't think that's something that we can dismiss and that's what was really intriguing about this combination. Next slide, please. And again, you can see here, especially in the pancreatic subset. These are not just like 1 and done responses. They are ongoing. And so it tells me that this may definitely be something that plays out not only in responses but also PFS and possibly overall survival. Next slide, please. And you can see the spider plot, again, looks good. Next slide, please. And overall, again, 67% response in pancreatic. Non-small cell lung, the overall subset is 50%, but in the naive was also 67%. If you recall, adagrasib was probably in the high 30s to low -- sorry, mid-40s subsets. So there is something going on here. And especially with also colorectal cancer, you're seeing a 29% response rate. Remember, with daraxonrasib it's literally in the single digits that again may be a little bit higher, like 11%, 12%, but the fact that 29% is -- could tell you that there is something there. I really think that the colorectal subset I think you would see significant increase in response if we would add an EGFR inhibitor, which, as many of you know, is 1 of the reasons that single-agent RAS inhibitors don't seem to respond. But there's something about blocking red and row that definitely adds, if not, additivity maybe even synergy. Next slide, please. So this is an example of just a really nice, nice response. Fifth line treatment, somebody who's had a splendid went to -- sorry, went on to see second-line docetaxel and then got [indiscernible] progressed, got third-line [indiscernible] have then got vinorelbine and then went on darlifarnib and adagrasib it had this amazing response. Next slide, please. So against all with small numbers, but I do think that there is something a definite signal here in all 3 given. And particularly PDAC, I just -- I've not seen a combination where you're seeing things like that to date. Next slide, please. Okay. I mean, here's -- let me give you the reason I've been interested in this combination. In fact, I had approached -- I mean I was running this trial since my first trial, by the way, ever was tipifarnib many, many years ago. And I -- at that time, we didn't have NGS. And we -- I tried putting patients with KRAS hotspot, they were not responding. But many years afterwards, Kura picked this up and realized in patients with RAS, we could induce responses. But in addition to this, which I think is really important, there have been several really prominent investigators, including [indiscernible] , who's a good friend of mine, 1 of the godfathers of RAS, who would argue to you that the combination -- the next reiteration of RAS is really combinations. And what they've seen is that there are certain key molecules downstream that may significantly combine Axle, ERK, MYC and [indiscernible]. And right now, there's not a good real clean axle inhibitor. There are not really good MYC inhibitors and the ERK inhibitors have been tried in the past that they were just too toxic. And so the fact that this thing appears to have a strong signal really validates that preclinical data that [indiscernible] and others have generated. Next slide. I think that's my -- that's the end of my presentation.

Thank you, Dr. Hong. Francis?

Thanks, Troy. Hello, everybody. I'm here today to give you a little bit of the highlights of our transactional work with darlifarnib combination with RAS inhibitors. This work was recently published in cancer research. So I'm just going to touch on a few of the highlights here. Here's the pathway diagram again, as Troy showed you, the reason why we at is such a big dog in oncology is that it drives signaling down both from MAP kinase and the PI3K-AKT pathways, but its control of MAP kinase is much stronger than the other side. And the red and talk node is downstream of both of those. And what you can appreciate from these charts here is that in all 3 major rate-driven solid tumor types. RAS inhibitor monotherapy fails to either completely suppress and top 1 activity, as you see here with adagrasib in the non-small cell lung cancer model or if we move on to a better RAS inhibitor daraxonrasib in our CRC or PDAC. In this case, you do get a nice suppression, but it does not last under continuous closure conditions, we see a pretty robust bounce back of the mTOR1 activity. But in all 3 cases, this can be rescued by combining the RAS inhibitor with the darlifanib to express and talk activity over a longer period of time. Next slide. When we started this work is probably about 4 years ago now, there was only a few RAS inhibitors in the clinic, the first few G12C and other selective compounds now, clearly, there is a really growing field here. But we've looked at all 3 of these classes. Mutant selected G12C or G12D or pan-RAS or pan-KRAS. And with all bases, we're able to get robust enhancement through blockade of the rear vendor node. So we think that this is going to be a broadly applicable combination approach. Next slide. As I mentioned, the early work was all in non-small cell lung cancer G12C mutant and we modeled that in combination with our adagrasib or [indiscernible] and other similar RAS inhibitor. And what I hope you can appreciate from this is that irrespective of how active the RAS monotherapy was on its own, we were able to enhance it. So on the left-hand side of the chart, you see models that were pretty refractory, but you throw in darlifarnib on top of that, and we can at least slow tumor growth. On the right-hand side, you see models that -- where you get regressions on the monotherapy, but we can deepen those regressions. And extend their duration. Most excitingly, perhaps in the middle there, you see a number of moderately responsive models, which when we add in the darlifarnib, we can move from progressive disease to some pretty deep regression. So we think that we shouldn't need to do any kind of patient selection to to take these trials forward. On the right, there's some data with daraxonrasib in a CRCE panel. Again, this is a slightly more challenging tumor type for for RAS inhibitors and the daraxonrasib is only able to generate best tumor stasis on its own. But again, we see across the range of activities that by adding in the FTI, we can enhance the activity and get some pretty decent progressions in some models. And next slide. As we've been talking about and the reason we're all here is that RAS inhibitor clinical development, it's really taken off. And even when we started this work, we anticipated that we were going to be accruing a lot of patients to our trials. We had already seen as inhibitor before. So we thought we would model that and it worked out quite well. As you can see here, this is a non-small cell lung cancer model. which does respond for a while to either daraxonrasib with a stasis or daraxonrasib with regressions, but it only lasts for a few weeks and then they do start to progress. If we add darlifarnib at this moment, next, we can record tumor control and induce deep regressions in these relapsing tumors. And indeed, next one, it doesn't look back different from if we did the combination upfront. So that's giving us at that time, some optimism that we've got perhaps not going to see huge differences in the types of responses in patients who are KRAS inhibitor naive versus those who are experienced receiving that class of drugs. And I think our clinical data has confirmed that. We see a similar situation in the colorectal model on the next slide. In this case, we've compared it to the G12D mutants. So we look at the [indiscernible] G12D selective compound MRTX1133 and also daraxonrasib on the right. and both of these do very nicely. They induce good regressions for a solid month. But at that time, the tumor controlled anticipates and the tumor starts to grow again. If we add darlifarnib at that time, we can recover the regressions and more, please. You can see that the outcomes are not that different from upfront combo. So what we concluded from this work on the next slide. is that we could see enhancement of activity of all the classes of RAF inhibitors we've looked at. We've looked at a total of 7 or 8 now in various models. And we see that whether they work well or less well in a decent panel of preclinical CDX and PDX models. The combination is able to reduce regressions even in these preclinical models where there has been previous exposure and progression on either mutant selective or pan-RAS inhibitor monotherapy. So we feel that this preclinical data supports evaluating darlifarnib both pan-RAS and mutant-selective inhibitors. And as such, darli represents a mechanism-driven RAS inhibitor agnostic combination platform with potentially very broad applicability. Thank you.

What have we seen thus far? We have seen preclinical data that has translated to clinical data across a combination partners and indications. We have seen a mechanism-driven and targeted therapy agnostic combination platform. Next slide. Across 3 different combination partners and 5 different tumor types so far, we have shown you that the combination consistently outperforms what you would expect with backbone therapy. Let me emphasize, we would not expect darlifarnib have more than minimal to no monotherapy activity in a -- so what does that mean? It means that darlifarnib is able to augment the activity of these targeted agents. And based upon the preclinical data, we know that this mechanism can augment more than cabo and real cell carcinoma, more than [ palisib ], a PIK3CA mutant head and neck more than pancreatic, non-small cell and colorectal in combination with adagrasib. This truly is a mechanism-driven targeted therapy agnostic combination platform, and we can consistently make good therapies better for patients. Next slide. And the number of patients that could potentially benefit is extraordinary, likely with [indiscernible] 1 therapy that can improve outcomes across PDAC, CRC, non-small cell lung cancer, breast cancer, head and neck cancer, neuroendocrine tumors and renal consult carcinoma so far. Next slide. So how do we get this drug to patients? What are the next steps? So for renal cell carcinoma, we are currently enrolling our Phase Ib that is evaluating darlifarnib in combination with 1 of the commercially available VEGF-TKIs namely cabozantinib. We anticipate having these data that confirm the recommended Phase II dose as well as continue to support the overall hypothesis in 2027. We are also preparing for a registrational path with the same combination that would at least allow for a third line registration and likely second line plus that can be initiated in 2028. From there, we can expand to the frontline Stalofarnib is easily combinable making triplet regimens the likely and best next step for patients. Wherever the TKI can go, be it in combination with HIF-2 alpha or IO therapy, darlifarnib can follow and augment the activity. Next slide, with regards to KRAS-driven tumors, we are currently operationalizing our platform trial that will allow valuation of darlifarnib in combination with any pan-KRAS or KRAS mutant selective agents. Our first cohort in the trial will be a combination with daraxonrasib with pancreatic cancer anticipated to initiate in early 2027, from there, we will continue to build on this mechanism-driven targeted therapy agnostic combination platform and move towards a registrational path in second line plus KRAS-driven tumors, and ultimately to the front line as we look to improve patient outcomes. Next slide, explore combinations and indications through a platform study allows us to evaluate outcomes in parallel rather than sequentially. And overall demonstrates the broad applicability of this mTORC1 inhibition. The design is flexible and both approved investigational therapies could be evaluated, making way for the ability to collaborate with multiple partners. If new and interesting possibilities become available, they can be evaluated in the same trial. Each combination and indication can be individually evaluated for milestones that will result in a graduation to the next phase of development. As I said, daraxonrasib and PDAC will be among the first combinations evaluated. However, colorectal cancer, possibly in combination with EGFR inhibitors as well and other indications are subsequent opportunities that need to be explored. This trial will allow us to demonstrate the vast applicability of this mechanism to enhancing the targeted therapies already available. And I look forward to being able to share these data as we progress. With that, I'll turn it back to Troy.

Thank you, Mollie. We can go to the next slide, please. As Mollie mentioned, our initial focus is going to be in third line plus kidney, the potential to go earlier as well as third line plus PDAC. These are significant opportunities. We talk about ziftamenib as being a multibillion-dollar opportunity in AML. These large solid tumors. There's just, unfortunately, so many patients who are in need. So we really see this as a meaningful opportunity for the company and for shareholders. We've also prioritized, as Mollie mentioned, combinations with agents that are either available in standard of care in the case of cabozantinib or that everyone anticipates will very shortly be the standard of care in the case of daraxonrasib and [indiscernible]. So we are open to additional combinations as the science and the development plans and the interest from potential collaborators guide us. Next slide, please. And just to summarize it again, a whole set of milestones for ziftomenib. We really are going to be the market leader in not only relapse-refractory NPM1 mutant AML, but we think we've got the opportunity to dominate the frontline setting. And now with darlifarnib, we have a completely separate wholly owned asset where there's going to be a lot going on. There's been a lot of inbound interest. Everyone wants to be involved. Everyone wants to do the best for patients. I think everybody recognizes the need for these precision company. And we think we're in a very good spot. So if we can go to the next slide, we're happy to at this point and end the prepared remarks and open it up for questions. Before we do, I will just say, Dr. Hong was very generous to share his time with us. He has a hard stop at the top of the hour. So we would ask you if you have questions for him to please prioritize those. We'll get to as many questions as we can. Again, we'd limit each of you to 1 question and 1 follow-up so that we can get as many analyst questions answered as possible. But with that, Megan, we're happy to open it up to Q&A.

[Operator Instructions] Our first question will come from Li Watsek with Cantor Fitzgerald.

I guess for pancreatic cancer, how should we think about the translatability of the G12C data that you've seen to the G12B and D and other [indiscernible].

Francis, do you want to give that a short answer?

Yes, Yes, yes. As I said, we see the same kind of patents with all of the different classes of RAS inhibitors. The pan-RAS are more active than the mutant selective in most models and that it will be in part because of resistance mediated by the wild-type RAS. But nonetheless, in -- even with daraxonrasib, which is an awesome compound, it takes a lot to get a standing ovation at ASCO and that's a truly great compound. Even with that compound, it is able to suppress the M-Tor pathway, but you need 10x as much drug to achieve that as you do to suppress the MAP kinase pathway. So our goal is to combined with the FTI and enable us to get at those more resistant cells. One thing we all know about PDAC is that it has the fibrotic TME, which retires drug access and really has made PDAC drug graveyard for decades now. So we feel that in order to get most efficient and as efficient as it needs to be suppression of the pathway throughout these pancreatic tumors, you are going to need a combination like this.

Thanks, Francis.

I can comment?

Yes. Dr. Hong, please.

History often does not repeat but it rhymes. I'm curious. So if you look at the BRAF story, right, BRAF plus cetuximab in colorectal that translated into what we -- as Scott presented, like the fifth time the breakwater set, right? It's going to -- it's translated into G12C with cetuximab. Likewise, I think what's going to happen is you're seeing in pancreatic, possibly and also colorectal and so long this combination, which in see it's less of a leap than even RAS to KRAS that you're going to likely have the same kind of mechanism in DEV, whatever, pan-RAS, whatever. I think that's just the reality of the situation. And I am a big fan of Mark Twain.

Our next question will come from Jason Zemansky with Bank of America.

Congrats on the data. Maybe a quick 1 for Dr. Hong. Obviously, the efficacy looks pretty potent. Just curious about the safety dynamics. Do you think the thrombocytopenia is going to be an issue at all? And are there ways to mitigate it especially as you explore some of those higher doses?

Yes. No, I'm not worried about thrombocytopine. We don't get worried about thrombocytopenia until patients platelets get below 10,000. But most of these patients and with darlifarnib, the vast majority the time we would just hold it for a couple of days and bring the patient back. I just -- thrombocytopenia is not an issue, neutropenia, as you know, we have ways to mitigate that. So -- and even now [ Nplate ] is actually approved in patients with low platelets. I don't -- it's not like -- it's not a quality of life issue, right? Like you get -- you have a platelet of 50,000 people aren't like worried about nausea, vomiting or anything like that. It's -- I'm not too worried. And there's no and the good thing is that there's really no overlap with daraxonrasib none of the -- I mean there are some small percentage of these patients who get cytopenias, but the vast majority don't. And I don't see where we're going to have [indiscernible] combining these drugs. The overlap in toxicity at all is very minimal, maybe some GI. But even then, it's -- I think it's going to be manageable.

Our next question will come from Charles Zhu with LifeScience Capital.

I know Charles.

Charles, please unmute your line and ask your question. The next question will be Jonathan Chang from Leerink Partners.

What settings in pancreatic cancer are you expecting to evaluate the darlifarnib plus daraxonrasib combination in?

Mollie, do you want to take that?

Sure. We're initially going to start in the second line plus area. Obviously, easiest to always see the signal in that relapsed recurrent setting. And then as our plan shows you with the potential for the platform trial, if we see what we expect to see, we can have a graduate to the next level towards a registrational program and then obviously start branching out further into into earlier line of therapy.

Next question, we will check on Charles Zhu with LifeSci Capital. [Operator Instructions] [Technical Difficulty]

Charles was having a problem with this mic.

Not a problem. We will move on to the next question. Erik Lavington with Mizuho.

I'm very curious about your thoughts on rationale and biology, if darlifarnib is kind of in your upfront, right, data, it kind of looks like you are getting breakout mutations. And I'm just curious if there's some underlying biology that might explain that if you have data on mutation landscape through time to explain that or to tease that out? And wouldn't that kind of point to bringing darlifarnib earlier as early as possible to prevent RAS mutations.

Yes. Erik, maybe I can take that question. There's a lot going on in these pathways into these tumor types. I think we have to be the biology that you're seeing with the ability to run the study. At the moment, we're talking about Phase I dose escalation and then potentially expansions. So we'll start there. our goal would be to move as quickly as the data supports to earlier lines. We really think of this as a potent means of attenuating pathway signaling, as Francis mentioned, through both MAP kinase and PIK13 kinase. The tumor is always going to be looking for other ways to get around it. But I think Dr. Hong said it nicely. This is a very potent way of adding to to inhibitors at the top of the pathway. And we do see patients their disease is failing therapy, but we'll move as quickly as we can.

Your next question will come from Phil Nadeau with TD Cowen.

Congrats on the data. Just to follow-up from us. So first, you said second line in pancreatic cancer, what do you define in second line? Is that post chemo? Or will you allow patients to have had the daraxonrasib monotherapy experience before, that's first. And then second, in terms of the adagrasib dosing, you mentioned 400 milligrams is what's moving forward. We're under the impression that in some indications, 600 milligrams BID is standard. What's the rationale for using 400?

Mollie, do you want to take those 2?

Sure. So as we get the trial started, we will be looking kind of at an all-comer patient population in that recurrent metastatic setting. So it will be a second line plus trial for the dose escalation where, yes, we would consider them having failed frontline chemo to define them as now being eligible for trial. In this initial those escalation cohorts, we would also allow prior to daraxonrasib exposure, just as we've done in pretty much all of our other trials. So we really do think it proves the point improves the mechanism to see to be able to save those responses. With regards to adagrasib, there's a lot of debate right now as to what the appropriate dose is, and BMS is actually performing studies in both 400 milligrams and 600 milligrams in order to satisfy some regulatory requirements. A great deal of their combinations right now are at the 400-milligram dose, and it does seem to still be very effective dose for these patients. But Dr. Hong, do you have any additional comments on that?

So yes, daraxonrasib is a very good drug. I mean I was -- I led the Phase I on that thing. But it's not pure. I don't know about you, but if you're a pancreatic cancer patient in the second line after chemo, which won't be approved for a while, if those get approved, which I think it will. But you want something better -- so if you -- if I was a pancreatic cancer patient to finish FOLFIRINOX, and somebody said, hey, I have daraxonrasib plus a new drug that's going to make this better I didn't role. I don't think that we'll have trouble finding patients, if that's your question.

Your next question will come from Charles Zhu with LifeSci Capital.

This is Peter on for Charles. Just wondering how do you feel that FTI plus daraxonrasib could be positioned against daraxonrasib plus KRAS-mutant selective inhibitors.

Mollie, do you want to take that? Dr. Hong, I don't know that they're mutually exclusive. I think we need to do everything we can.

Right now, like, for example, probably the 1 that's most ahead right now is sold on [indiscernible]. They're trying to, I think, Revolution Medicines trying to position Zoldon Plus dexon in the frontline setting, right? They've already announced that they're doing that trial. And we'll see how it goes. I think ultimately, like pancreatic cancer, 5 years from now is going to be a lot like treated like nonsmall cell lung. You're going to have KRAS, but you may have like KRAS bus Pentaploss. People are going to try to position themselves for that. We're going to try to position -- if you talk to any pancreatic doc, you saw that in the PRO daraxonrasib. They don't like chemotherapy and they don't want to give chemotherapy. And so if this darlifarnib plus whatever looks amazing in the second line, I mean, I definitely think it's going to have a likelihood that it could position us off in the front line. And then so you could have possibly [indiscernible], you could combine this with all done. Ideally, they can't obviously combine dax, I mean I'm not sure I'm not -- maybe they'll come out with some data that I haven't seen, but they can't combine the daraxonrasib with EGFR. So right now, at some point in colorectal, they're going to try to combine [indiscernible] plus EGFR. And then what if this thing that a, you can also combine it with that. I mean there's just so many different reiterations as to how it's going to pan out. But I think in the pancreatic space, everybody is going to try to push chemo out of the picture at some point. And this could be 1 of those situations where you either have a D inhibitor or the pandexon-RAS inhibitor, whatever in the frontline setting.

And Peter, just to add on to Dr. Hong's comments. This is part of the motivation for the platform study. We're getting approached, as you can imagine, by folks with all manner of targeted therapy looking to do combinations, we're not going to be able to do it all. We'd like to do the ones that make the most sense for patients and ideally not have regimens competing with each other. But there's a clear opportunity, we think, in pancreatic to test this combo. There are Dr. Hong's alluding to it, there are combinations in colorectal that we look to pursue stay tuned throughout this year and early next year. I think we'll have much more to say about that.

I have to go, guys. Thank you.

Thank you, Dr. Hong. We appreciate your time.

I'm just going to say, I'm excited. I'm very excited to [indiscernible]. So please support them is so I can do the [indiscernible]. Thank you. Bye.

We appreciate your time. Thanks, Dr. Hong.

Thanks, Dr. Hong.

Congrats on the progress. I guess since Dr. Hong has gone. Troy, maybe you can answer this. You talked about how darlifarnib is broadly applicable through a variety of these indications and combinations. How important is it to have additional combination agents on top of the KRAS inhibitors? And maybe just as a follow-up, I think Dr. Hong had mentioned EGFR on top of KRAS. I'd love to kind of get your thoughts as to how you're thinking about it. And as a follow-up, I probably missed it in the poster, but how many patients remain on treatment? And kind of what's the median duration of response? And any comments on resensitization of patients who are refractory to KRAS monotherapy?

Mollie, do you want to take that second question first, and then I can address Ren's sort of broader question.

Yes. So a good amount of the patients still remain on treatment as of the time of this data cut. Almost all of the pancreatic all but one are still on treatment and 37% of patients overall are on treatment. So they're doing very, very well. So not just deep responses, but actually durable responses. And we are seeing -- these are small numbers. So my statistician would kill me if I gave you true median duration of responses because they're so unstable to actually estimate. But for non-small cell, we have seen about an 8 months. PDAC is still evolving in 4 months. So these are still evolving numbers, but they're already starting to exceed what we would expect from the background therapy alone. So stay tuned. We'll discuss more as we get more data.

Yes, Ren, to your first question, I mean, there's no accident that, that second box in the platform study is darlifarnib plus compound A in colorectal. There is a clear need. I think we all recognize it's likely to be a triplet. One of the advantages you have with dali is it combines nicely with EGFR inhibitors. There was a trial run with tipifarnib and Tarceva, for example, was run in the wrong patient population, but there was good safety and tolerability part of this is we're juggling kind of what we can do internally with the folks who are approaching us. And -- but colorectal is of high interest, both for mutant selective inhibitors and for pan inhibitors. We'd like to find a way to move darlifarnib further along in that area for sure.

Your next question will come from Daniel Brims with Lake Street.

Just curious what you saw or didn't see in the 8 mg dose that you decided not to push that forward?

Sure. Mollie, do you want to take that?

Yes, sure. Obviously, every protocol has its defined toxicity limits. And while we didn't see any drug-drug interaction between the 2 molecules, as we got into the higher doses, we did start to see some overlap of the neutropenia. And that was simply -- we reached a level that we didn't think the benefit outweighed the risk enough to keep pushing it forward. But overall, it wasn't any different safety profile. It was just we felt that 3 and 5 were the more tolerable options and still efficacious.

And Dan, as a reminder to everyone, you don't mitigate toxicities in a Phase Ia dose escalation, you're -- the whole goal is actually to understand the tolerability profile. So as Dr. Hong indicated, I mean, many of these are clinical values, and they can be mitigated as we go forward. But for the dose escalation, that wasn't possible. And as Mollie said, it didn't -- the benefit risk didn't justify going forward at 8. But either 3 or 5, as you can see, are very active. It is going to be -- the only one tolerability or toxicity that I think we have to watch for is neutropenia. We've now been able to combine FTIs with cabozantinib, with alpelisib, previously, J&J combined with both chemo and a couple of targeted therapies. There's a very broad combinability. You do have to watch for neutropenia.

There are no more questions at this time. I'd now like to turn the call over to Troy Wilson for closing remarks.

Yes. Thank you, Megan, and thanks, everyone, for joining the call today. We're at a really exciting inflection point with this darlifarnib program. Apologies that we couldn't [indiscernible] Dr. Hong for longer. He had patient obligations, which obviously have to take priority. You can hear from his comments the enthusiasm around both the daraxonrasib combination and other combinations. He's been a tireless advocate for this program. So it sounds like a number of you have relations with them and would invite you to engage with them as you will. We will come back to you in about a week with another update back on our ziftomenib program and the frontline AML results out of EHA. That will be one to pay attention to. Those results, I think, are very encouraging for the potential for ziftomenib to drive clinical benefit in a frontline setting. And Molly will walk you through what that data means for the ongoing intensive chemotherapy arm in the COMET-017 study. So we look forward to talking to you again then. If anyone has additional questions, you can reach out to me or Greg, and we're happy to get back to you. We appreciate your time. We appreciate your interest. And with that, we'll conclude the call. Thanks, everyone.