Kura Oncology, Inc. (KURA) July 2026 Investor Update Transcript

My name is Stefan, and I will be your conference operator today. At this time, I'd like to welcome you to the...

Coming in the relatively near term from our partners at Q&A. If we could go to the next slide.

With that, that concludes the prepared remarks, and we're happy to turn it over now for a Q&A session.

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Good day, everyone. My name is Stefan, and I will be your conference operator today. At this time, I'd like to welcome you to the Cura Oncology Investor Call to discuss updated results from the FIT-001 clinical trial evaluating Dalifarnib in combination with Cabo's benefit rate was above 70% in that million.

If we could go to the next slide. With that, that concludes the prepared remarks, and we're happy to turn it over now for a Q&A session.

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sounds good loud and clear good day everyone my name is stefan and i will be your conference

operator today position with 580 million in cash as well as 180 million in anticipated collaboration payments coming in the relatively near term from our partners at keoacurin if we could go to the next slide with that that concludes the prepared remarks and we're happy to turn it over now for a Q&A session good day everyone my name is Stefan and I will be your

conference operator today at this time I'd like to welcome you to the cura oncology investicle to discuss updated results from the fit 001 clinical trial evaluating darlifarnib in combination with cabozantinib in renal cell carcinoma all lines have been placed on mute to prevent any background noise. After the speaker's remarks, there'll be a question and answer session. If you would like to ask a question during this time, and if you've joined via the webinar, please use the raised hand icon, which can be found at the bottom of your webinar application. To allow everyone the opportunity to participate, we ask that you please limit yourself to one question and one follow-up question. If time permits at the end of the Q&A session, we invite you to rejoin the queue for additional questions. At this time, I'd like to turn the call over to Troy Wilson, President and Chief Executive Officer of Cura Oncology. Please go ahead, Dr. Wilson.

Good morning, everyone, and welcome to Cura Oncology's update. This morning, we're going to talk about Darla Farnib in renal cell carcinoma, providing a clinical update from the KCRS symposium that was held in Boston. If we could please go to the next slide. In today's presentation, we will be making forward-looking statements, and we would refer you to both Kura Oncology website and the SEC's website for more information about the risks and uncertainties of an investment in Kura Oncology. If we could please go to the next slide. We're delighted today to be joined by Dr. Ayanam Bakam. Dr. Ayanna Bacom is an assistant professor of hematology oncology at the University of Oklahoma Health Sciences Center, and he is the presenter at KCRS, and so he's going to take the opportunity today to walk through the slides a little bit more slowly and a little bit more better detail. In addition, we're also joined, of course, by Dr. Molly Leone, Cura's chief medical officer. If I could please go to the next slide. So just before we get into the KCRS data, I just want to step back and recognize, you know, this is a really important time at Cura. We now have two major pillars in the company that are driving value for both patients and shareholders. On the left-hand side, with Siftomenib, it's really, you know, everything is going extremely well. The launch is going well. The enrollment in the phase threes is going extremely well. We're looking toward a number of data updates that will help us to elaborate what we think Ziftaminib can do, both as monotherapy and in combination, toward the goal of making it a broadly combinable AML backbone as the therapy for patients throughout the treatment continuum. So that's really a great story and one that just continues to move forward. Today, we're going to focus on the right-hand side on the Darla Farnab program. And the Darla Farnab program is exciting because it's really a different way of addressing cancer using small molecule therapy. Darla Farnab is a mechanism-driven, targeted therapy agnostic combination platform. We've shown you data with TKIs. We've shown you data with PI3 kinase inhibitors, with KRAS inhibitors. There's really, the way we think about it is darlafarnib is a drug that can enhance the clinical activity of other important targeted therapies, whether they be standards of care, such as cabozantinib, or they be investigational agents. Today, we're going to talk about the phase 1a data for cabozantinib in RCC. but just to remind you the phase 1b is underway in addition we are preparing for the phase 1a escalation with darox onrasib in second line pdac we were excited to see that darox onrasib's nda was submitted and hopefully we'll be looking toward an approval later this year or early 2027 we'll be ready to add darlafarnib to that regimen to see if we can build on the clinical data that we showed you that we were able to do with Adagrasib. So thinking more broadly, we're going to focus on what we can do on a go-it-alone basis, but Darla Farnab offers a precision combination platform. And in that regard, Molly showed you in our webinar at ASCO, we've started a combination platform study that gives us the ability to evaluate other potential combinations, combinations that we think can create value for patients and ultimately for current shareholders. If we can go to the next slide, please. So the way we think about this very simply is it's about precision combinations, whether it's on the ziftomenib side with things like venetoclax or giltaritinib, or whether it's now on the darlofarnib side with things like capozantinib and daroxonracib. We believe that by combining these targeted therapies and by enhancing their clinical activity, we can drive better outcomes for patients. We can go to the next slide, please. Just to remind you, we've now shown you multiple examples where a farnesol transferase inhibitor can enhance the activity of targeted therapy. And here you can see in the headline, we're three for three. So starting on the left-hand side of the slide, previously at the IKCS symposium earlier this year, we showed you that Darlafarnib could enhance the activity of cabozantinib in patients who were TKI exposed, and in particular, cabo-exposed. And we showed a 44% objective response rate versus what one might expect from the benchmarks, which is there shown in green, 17% to 22%. Today's presentation is going to be different. We're going to shift from the cabo-experienced to the cabo-naive. We got some questions after the last presentation, and I think you're going to see that the activity continues to be quite encouraging. As we work rightward across the slide, the Cabo example in renal cell carcinoma is just one. We've also shown whether it is in PIK3CA mutant head and neck with tipifarnib, or it is in the KRFG12C mutated solid tumors where we combine Darlafarnib and adagrassib. In each case, those blue bars, the activity of the combination, the FTI combination is better than what one sees with the monotherapy comparator. So that's quite encouraging. Now we have to ask ourselves the question of, let's start to put the blocks in place that will support paths toward eventual registration. If we could please go to the next slide. Another way of thinking about this is shown here on slide seven, and this is just going to be an on-ramp to Dr. A's presentation, the way that we believe Darla Farnab is working to enhance the activity of these targeted therapies is by blocking REB. REB is a farnestylated protein. One of REB's roles is to determine the localization of TORC1. So by blocking REB farnestylation, we prevent TORC1 from being where it needs to be. And that effectively provides a block on the signaling cascades that are downstream from the MAP kinase pathway on the left and the PI3 kinase pathway on the right. When we add a targeted therapy that inhibits a node higher up in the pathway, whether that be a RAS inhibitor, or in this case, a VEGF receptor TKI, in combination with Darlafarnib, we're effectively putting two blocks on the pathway. In the case of Cabo, you've got to block at the receptor level, and you've got to block at the TORQ1 level. And we think that's a big part of the basis why we're seeing enhanced activity relative to the monotherapy alone. What I'll say is what we were pleasantly surprised by is that that combination comes with acceptable safety and tolerability. And we've seen that now with FTIs, whether we combine them with TKIs, with RAS inhibitors, or with PI3 kinase alpha inhibitors, we can actually dose these FTIs and maintain the dose of the targeted therapy. And so we're able to provide a better block on the pathway, and hopefully that leads to better outcomes for our patients. We could go to the next slide. With that, I'm going to turn it over to Dr. A and let him take you through the slides that were presented at the KCRS symposium. Dr. A?

Good morning. Thank you for letting us present the data again. My name is Adama. I'm one of the GE medans and honored to present as part of the FITO1 study group and the results of the FITO1 study. Next slide, please. Here are my disclosures. Next slide, please. So we all are aware about the role of mTOR1 in renal cell carcinoma, especially in tumor growth and angiogenesis, and the limitations we've had with prior attempts at blocking the mTOR1 pathway. Dalifarnib is a potent next-generation Farnasell transferase inhibitor that blocks which directly results in selective mTORC1 inhibition without the mTORC2 inhibition and thus sparing some selective toxicity. At IKCS earlier this year, we had talked about data about the safety and efficacy of dalifarnib in combination with cabizantinib where it had demonstrated an objective response rate of 44% with an impressive disease control rate of 94%. Next slide, please. So the FIT-01 study is a phase one dose escalation, dose expansion study that's evaluating the combination of dalifarnib and cabozantinib in the locally advanced and metastatic RCC that has been refractory to prior lines of treatment, including immunotherapy. Multiple dose levels of dalifarnib and cabozantinib have been evaluated. And for the purpose of this discussion, we're talking about the safety data about all patients with RCC in this study, but also focusing on the efficacy data on cabozantinib-naive clear-cell RCC patients. Of note, the cabozantinib 60 mg and dalifanib 8 and 5 mg cohorts were limited to just cabozantinib-naive patients in comparison to others which had a mixed bag of both cabozantinib refractory and naive patients. Next slide, please. Baseline characteristics of our study. As of May of 2026, we had about 72 patients enrolled in the study, predominantly clear-cell in 80% of these patients. Important to note that these patients were heavily pre-treated with about 50% of these patients having had more than two prior lines of treatment. And of note, at least 67% of these patients had a prior IO plus TKI combination, 38% had prior cabozantinib at any line, and 17% had a prior HIF2-alpha inhibitor. Next slide, please. When we look at the safety and the tolerability data, it is an extension of what we had previously seen at the IKCS, where the combination seems to be safe, tolerable, with very acceptable side effect profiles. As we would expect, we did see some side effects that we all are aware of in terms of the TKI era, especially cabozantinib-induced diarrhea, nausea, stomatitis, and hand-foot syndrome. Important to note, they were predominantly less than grade 3, and significant grade 3 or higher events with TKIs were not significantly different from what we have seen previously. Of note, we did have treatment emergent adverse events of any grade in 90% related to talifarnib and 96% related to cabizantinib. Grade 3 or higher were 58% and 57%, with 76% in the overall group. Important to note that serious treatment emergent adverse events were minimal, less than 20% in both groups. Of note, the most significant difference in treatment emergent adverse event was neutropenia of any grade at 47% and grade three of 38%. Most of this neutropenia was initially during the initial DLT period where growth factor support was not allowed during this process. Next slide, please. Now, when we come to the anti-tumor activity, we want to limit our analysis to just the cabozatinib-naive patient population. And here, it's important to note that in this cabo-naive cohort, about 47% of these patients had a prior TKI, including lenbatinib oxidative. We had encouraging anti-tumor activity with objective responses ranging from 33% to 50% of northern darlifarnib 5 milligram cohort plus 60 milligrams of cabezatinib had an objective response rate of 50%. Disease control rate was acceptable with 83% to 100% among all groups and clinical benefit rate was above 70% in that target group of 5 milligram of darlifarnib plus 60 mg of cabozatinib, and 58% in the group that had darlifarnib at 8 mg and cabozatinib at 60 mg. Next slide, please. Here is our waterfall plot that's looking at the objective response rates at various dose levels of darlifarnib and cabozatinib. And what's important to highlight over here is that even at the lower dose levels of darlifarnib at 3 mg, 5 and 8 mg, we had some significant responses. and also in both the cabozantinib 40 milligram and 60 milligram cohort in this Cabo Naive population. Next slide, please. What is also important to understand was that the benefits that we had seen with these objective response rates were durable and they were evaluated across all the combination dose levels. Median progression-free survival was 13 months in these Cabo Naive clear cell RCC patients with 6-month PFS probability at 74% and 9-month PFS probability at 60%. Next slide, please. Here is a swimmer's plot that's telling us about the durability of these responses, but also important to note that more than half of these patients currently are on treatment at the time point of data cutoff, so hopefully our progression-free survival continues to increase. We also should note that most of these AEs that we had seen, the great three neutropenias, was manageable with dose modifications, including dose reductions and dose interruptions. and it tells us that despite these AE profiles, this is a safe, tolerable profile that we're able to manage without significant adverse events. Next slide, please. We'd like to highlight a couple of examples of patient scenarios and this is patient scenario number one, which includes a 66-year-old male with clear cell RCC diagnosed in 2023 who had double immune checkpoint inhibitors with nivolumab and epilumab as his frontline response, who started talifanib at 5 milligrams and 60 milligrams in January of 2025. As of data cutoff at May 2026, it continues to have a response in his ongoing treatment. And as you can see, pretty early on in the disease course at week 8, he had a partial response. And what is impressive is that this partial response continues to be maintained at week 48. And we see ongoing reduction in his tumor lesions even at week 24, which is impressive. Next slide, please. Now, not only is Dalifanib effective in the TKI-naive patient population, where we know cabozatinib is a good drug to use. Importantly, it is also effective in a patient cohort that has had TKI prior exposure as well. Here is an example of a patient who's had prior zanzalitinib plus nivolumab as his frontline treatment when he was diagnosed with RCC in 2022, had a partial response and then discontinued due to radiographic progression. He started dalifarnib at the lower dose at three milligrams and cabozatinib 60 milligrams in October of 2025 and again was able to see a partial response at week 8 through week 24, and ongoing disease response at week 24 as well, from a 33% tumor shrinkage to a 54% tumor shrinkage. Next slide, please. In conclusion, with long-term follow-up, this combination of Dalifarnib and Cabozatinib has demonstrated durable and encouraging antitumor activity in both the Cabozatinib-naive and the Cabozatinib-exposed patients. In this study, we've shown an objective response rate of 33% to 50% in the Cabozatinib-naive population with a median progression-free survival of 13 months. This combination was well-tolerated with a safety profile that was manageable with dose modifications, including interruptions and reductions in both the cabozantinib and darlifarnib. Neutropenia was successfully managed, and in the ongoing Phase 1b expansion phase, we do recognize this and allow GCSF support to avoid dose modifications for the darlifarnib if feasible. These data support the continued development of darlifarnib in this space, along with a combination cabozantinib and VEGF-TKI. Currently, the FIT-001 phase 1B portion of the study is enrolling. Next slide, please. In the expansion phase, we are testing two dose levels of dalifanib at 5 milligrams and 8 milligrams. The study is randomized in a 1 is to 1 is to 1 fashion to either dalifanib 5 plus cabo 60 versus dalifanib at 8 milligrams plus cabo 60 versus gabozantinib 60 milligrams monotherapy. Given the efficacy of darlifarnib combinations in a prior CABO-exposed population, we do allow those patients who enroll on the CABO-x post-population, we do allow those patients who enroll on the CABO-x post-population immunotherapy population or cohort to be enrolled in a subsequent cohort of combination darlifarnib and CABO-x post-population. Next slide, please. With this, I'll hand it over to Dr. Leone for further comment. Thank you.

Thank you, Dr. A. I would say the basis for our excitement is clear as we move through those patient outcomes. So thank you very much for presenting them. To the next slide, please. When looking at our renal cell carcinoma program, what you have seen is a new mechanism of action that can help reshape the RCC landscape. We have shown you that darlafarnib can safely and powerably enhance the clinical activity of carbozantinib. Because of the impressive results thus far, we are currently in dose optimization, as described by Dr. A, in our phase 1b trial, where we randomized to the 5 or 8 milligram Darley dose and to a monocabo dose that allows crossover upon progression. This will be the basis for future registrational trials. We plan to share these data with you in the second half of 2027. These data easily support initial registration into the second or third line advanced RCC space, but future combinations that could be explored in our platform trial design that is currently being developed are of interest to bring this combination to patients even earlier in their treatment journey and provided improved outcomes. If we go to the next slide. Important to remember, our combination data significantly outperformed what you would expect of CABO as a monotherapy in second line, as showed on this slide. And more importantly, the combination showed these improvements in a safe and tolerable This new mechanism not only holds the ability to enhance activity of the TKI, but also to overcome prior resistance. A new TKI partner that can enhance activity for these patients is a valuable addition to the treatment landscape.

Moving to the next slide.

So the next question is, of course, now what? You know, what is the registrational path? As we allow our data to mature and as the shifting landscape of RCC therapy evolves, there is a clear path to market in the third line plus RCC as is evidenced by our data versus the current third line benchmarks shown here. We could bring a new mechanism of action to the space of high-end met need that has a differentiated profile, including improved PFS. As our data mature and the landscape becomes clear, we will, of course, be looking to move into earlier lines through even broader combinations. This new mechanism of action that can broadly enhance TKI effectiveness is an important addition for patients and prescribers, and we look forward to sharing more data with you next year. And with that, I will hand it over to Troy.

Thank you, Molly. If we could please go to the next slide. So I think with today's presentation from KCRS in combination with the data that we showed you from ASCO and a little bit earlier this year, the data that we showed you from IKCS, you can see why we're so encouraged about the opportunity with Darlafarnib. Darlafarnib is a drug candidate that has the potential to improve the clinical activity of many other targeted therapies. And here we've shown you, we have both preclinical and in now many cases, clinical data, evidencing that we can drive better outcomes for patients potentially by doing rational combinations with Darlafarnib, whether that be in the KRAS space on the left-hand side, or potentially TKIs in the upper right, or PF3 kinase inhibitors. Really a very large number of potential patients we could benefit. This, you know, we say this isn't another KRAS inhibitor. This isn't another TKI. It's a drug that can not only make one member of the class better, could potentially make multiple members of these classes better. With that, if we could go to the next slide, slide 28. In the specific context of kidney cancer, what we've shown you today is we think there's a, you know, certainly a meaningful opportunity in third line plus. There may be an opportunity as well in second line plus. We haven't made the decision yet as to exactly what the design of the registration enabling trial will look like. But because of the improvements in therapy for these renal cell carcinoma patients, we're now seeing more patients in the third line plus setting. That's a quite significant opportunity at $2 billion a year. In the second line setting, potentially looking at a total market opportunity of up to $6 billion a year. And one of the reasons that we started with cabozantinib, of course, is as we look at the TKI landscape, cabozantinib remains the market leader. And what we're hearing from physicians is, you know, there's a desire to improve on those outcomes, whether it be in the cabo-naive or the cabo-experienced population. So we'll provide more information. As Molly indicated, you know, we're looking toward full enrollment in the phase 1b, and we'll continue to elaborate where we're going to take Darla Farnib. But if we just focus initially in the addressable market for RCC, we think the future for Darla Farnib is quite bright. We go to the next slide, please. I just want to recap where we started, which is it's an exciting time at Cura. Zift Amenib continues to gain momentum as the market leader in relapsed refractory NPM1 mutant AML patients. We really see a path to where we will have market leadership throughout the treatment continuum, not only in NPM1 mutant, but as well in other mutations. We're looking forward to providing additional data for you later this year. On the Darla Farnab side, this program continues now to pick up momentum. So the phase 1b study is underway with cabozantinib. We'll be starting the phase 1a with daroxonrasib early next year. And I think you're going to see us look to be selective and provide additional opportunities to provide value creation for patients, better outcomes, and potentially for our shareholders. And the company remains in a very strong cash position with $580 million in cash, as well as $180 million in anticipated collaboration payments coming in the relatively near term from our partners at Q&A Curran. If we could go to the next slide. With that, that concludes the prepared remarks, and we're happy to turn it over now for a Q&A session.

We will now move to our question and answer session. If you've joined via the webinar, please use the raise hand icon, which can be found at the bottom of your webinar application. When you're called upon, please unmute your line and ask your question. We ask that you please limit yourself to one question and one follow up question. You're welcome to reenter the queue for any additional questions. Our first question will come from Charles Zhu with LifeSci Capital. Please unmute your line and go ahead.

Excellent. Great. Good morning, everyone. And thank you for putting out your data and for hosting this event. Two questions from me. One, could you perhaps elaborate a bit more on the specific prior treatment history for your patients here? And where I'm getting at is that you talk about how many patients have had prior TKI, including CABO. Can you also talk about how many patients may have had prior lenvatinib, given some of the existing clinical data out there that strongly suggests that AVO has possibly wildly different outcomes depending on if patients have seen prior IOIO, axitinib, or lenvatinib sort of so forth? Thanks. And my second question, of course, is how would you, you know, position or contextualize your data relative to some of the TKI plus HIF2-alpha, as well as Lenvatinib plus Everolimus data out there?

Great, Charles. Thanks for the questions. Let me ask the first one. Your first question is on the prior treatment history. Dr. A or Molly, do one or both of you want to take Charles' first question?

Yes, sure, I can. So for the overall patient cohort, we have about 72 patients that were enrolled in this study. And in that group, about 67% of them had prior TKI. And that was TKI at any line, including frontline IO plus TKI. And if you factor in the patients who've had just tabazatinib, that's around 38% of these patients. So the analysis has been split into two parts. The first analysis that was presented at IKCS earlier this year were patients who had prior cabozantinib, and the efficacy that was presented recently, or just now, was efficacy in patients who were cabonaive. So in this cabonaive population, 47% of these patients had prior TKI, including lenbatinib, but obviously not all lenbatinib. I don't have the exact record on how many was lenbatinib, but there's a sizable portion here that was exposed to TKI, including linbatinib. We do not have a lot of patients on linbatinib plus belzutifan, if that's the direct question, because it is a regimen that's been recently approved. But interestingly, we do have patient snippets of those who have been on linbatinib plus belzutifan and also belzutifan monotherapy. About 18% of patients on this trial have had prior belzutifan exposure to and we've seen the response. Now, it's interesting to look at the recent CABOLEN trial that looked at cabozantinib versus lenvatinib evirolimus, where lenvatinib evirolimus seems to be doing better. But evirolimus is also a harder drug to tolerate, and that probably is coming from both mTOR1 and mTOR2 inhibition, whereas darlifarnib with a selective mTOR1 inhibition does not seem to have that same efficacy, sorry, same toxicity profile with the same efficacy being retained. We did not see the same side effects that we see with evirolimus as in worsening stomatitis or any of the significant pneumonitis or diarrhea or rash that we've seen with the problem is with Darlie. So it seems to be a better, more tolerable drug. But again, with limited data thus far, we'll need to see what the future data holds.

Mali, did you want to take Charles' second question, which is how do we think about positioning this relative to TKI HIF2-alpha or Charles, I think you called out specifically lenbatinib everolimus, as Dr. A was saying. Molly, you want to comment?

Sure. Well, first I want to remind that this isn't just a covozantinib combination. This particular darlofarnib activity can be seen in any TKI combination. So we think that, yes, we can enhance the activity of covo, but we can also enhance the activity of linvatinib, oxitinib, any of the others. So where do we see ourselves being positioned? We see a definite third-line play. However, I think as we watch the field settle down a little bit with all the HIP2 alpha data that's coming out and the kind of tinkering of different combinations being added together, we can see an earlier play as well. And I also foresee us going into, you know, more of these broader combinations. We are starting a platform trial, which will allow us to evaluate even broader combinations on earlier combinations in these patients. and so we look forward to sharing that data with you but ultimately this is a new mechanism of action we're introducing into this space so we really look forward to being able to bring it as early and as broadly as we possibly can excellent thank you very much for taking our questions

thank you our next question will come from we lee what sec with cantor fitzgerald Please unmute your line and go ahead.

Hey, good morning. Thanks for the update. I just wanted to follow up on the second line development strategy versus the HIF-2. You know, just given, you know, this combination now set a new benchmark in second line and we're seeing some of the next gen HIF-2 that seems to deliver even longer PFS benefit. And maybe Dr. A can comment on this as well. Just given the data you've seen so far, where do you think DALI plus couple can fit in the second and third on RCC? And then how are you thinking about, you know, potentially combining with or perhaps sequencing after the HIP2 class for initial target patient population?

Molly, you want to start? And then maybe you could turn it over to Dr. A?

Yeah, so as we said, you know, the field really is changing a lot, and HIF2-alphas will bring a lot of efficacy for these patients, and we're excited for that. We're introducing a brand new mechanism that can then help to even, you know, augment the activity that's being seen with these HIF2-alpha combinations. So really, anywhere you're seeing a TKI brought into a line of therapy, we can easily be the partner for that TKI, bringing in, you know, even more efficacy, preventing resistance, et cetera, in that combination. I foresee us starting, you know, the easy access into the third line and then obviously broadening out into the second line and ultimately going with an IO combination in the front line. Again, reminding you that we've started a platform trial that will enable us to really explore all of these things in parallel rather than in sequence. But Dr. A, I'd love to throw it over to you.

Yeah, I think it's definitely exciting. I think it's good to have all these options from an oncologist's standpoint and also a patient's standpoint. But I think there are a few caveats to remember here. We know that Belzutifan is now approved in the adjuvant setting. So that means that many patients are going to be getting Belzutifan and they're going to be Belzutifan exposed. We also know that there's a subgroup of patients who don't tolerate Belzutifan either due to significant immune hypoxia, and we as a community are trying to figure out how to manage that. But it is promising that in patients who are responding well to Belzutifan, there do seem to be durable responses. But when we come to the frontline setting, a significant portion of these patients are either going to have pembrolizumab, linvacinib combinations up front, and if they've had linvacinib combinations up front, they're not going to be eligible for linvacinib plus Belzutifan. And we also know that the frontline registrational trial, which has a preliminary result out that it's not positive when they've combined lindvacinib and balsurifan is interesting. So that combination of TKI plus tip to alpha is important, relevant, but it doesn't seem to have breached the frontline space as of yet. So maybe there's another combination that we need to look at for the holy grail of a triplet therapy in the frontline setting. And maybe, you know, FDI is one opportunity there that's definitely worth evaluating. but I think this space is wide open in terms of what we are going to do in the second line or the third line. So in patients who have not seen lenvatinib-belzutafan, we know that that's a good combination. It works. It has a good PFS and OS benefit, not OS, pending OS benefit. But in those patients, post lenvatinib-belzutafan, what we use in the third line setting is important. And tivozinib or axirinib in single agents have really not had great responses. So maybe the goal is to move from a synergistic combination approach in the front line to a combination approach in the second line and maybe third line. So Darlie Farniv, in combination with like Molly and Fry pointed out, any TKI is probably a good option post-belzudafen exposure, whether that's belzudafen monotherapy or belzudafen femoralizumab or lenvacinib belzudafen. And we do have some patient snippets who have responded to it despite being on lenvacinib belzudafen before. And I do personally have that experience as well on this trial. So we'll need to wait for more mature data to be confident that all patients post-Lindvac and Belzitofan will respond to this combination. But this is a new mechanism of action, so there's no reason to believe that they won't. And we have not seen any signals that tell us that they won't. So whether this is sequenced before or after that combination approach is yet to be decided by the company, but also will be informed by the data that we generated this expansion, please.

I might just, before we go to the next question, I might just add one more comment, Lee, to your question and for everyone on the line. We have here go-it-alone strategies with both cabozantinib and daroxonrasib and PDAC. One of the reasons we articulated the platform study is, just as Molly said, we're anticipating additional combinations. and we can't speak to specific discussions, but I would look forward to that in the months to come. That may provide us with even more options to be able to move Darla Farnham forward, whether that is as a doublet, as a triplet, I would say stay tuned. What is clear, as Molly said, is this combination we think really is compelling in the third line. We look at it relative to the competitors. So pretty clear that that would be a place we could go. We'd love to move it even earlier. Second line, we just want to make sure we do the right combination. And as Dr. Ace said, there's a number of things we can be looking at. So look for us to clarify that. Part of that will come from our own data. Part of that will come from the potential for additional combinations. I just wanted to add that thought. We can go on to the next question.

Thank you very much. Our next question will come from the line of Roger Song with Jeffries. Please unmute your line and go ahead.

Hey team, this is Nabil on for Roger. Congrats on the data and thanks for taking our question. Just maybe one quick one on the neutropenia management. So as mentioned, after the DLT period, the supportive care became permitted. I was just curious what percent of patients require any growth factor support, dose interruptions and reductions. And were there any cases of febrile neutropenia or infection or any discontinuation due to neutropenia? Thank you.

Dr. Ray, do you want to take that?

Yeah, I can take it. I think this is something that we are learning as we go, because we don't usually see neutropenia as a significant AE for RCC treatment. So in the initial phases of this trial during the DLD period, GCSF was not allowed. So these patients had to have those interruptions of their dalafarnib and cabozantinib, but as we have treated more patients, we know this is a dalafarnib-related effect. Most of our patients have been managed with just dose interruptions with three challenges at the same dose or at a lower dose, and they've tolerated it well. It seems to be an effect that happens early on, so patients either get neutropenia up front, and if they do, then they are modified, their dalafarnib dose is modified, or they never get neutropenia. So it's not a cumulative toxicity that we're seeing, but it's a signal that happens earlier on. And even despite these dose reductions, we've seen ongoing responses. For example, there is a patient of mine who had grade 4 neutropenia and neutropenic fever, was admitted with sepsis in the hospital, and hence had to hold Darlifarnib. But then he was re-challenged with Darlifarnib at a lower dose, and currently he's on that Darlifarnib combination for more than a year now. So dose reductions seem to be affected. But as we've moved on into the expansion phase, we realized that toxicity. So now patients are allowed to have GCSF support. So if we're seeing neutropenia pop in, we are supplementing them with GCSF, and we've been able to avoid dose modifications or dose reductions. So it does seem to be one of those easier to manage side effect. About 38% of patients have grade 3 or higher neutropenia, but neutropenia, fortunately, it's not very symptomatic. So yes, there have been cases of neutropenic fever. I think this is something that we are recognizing, but with GCSF support, it doesn't seem to be a major hindrance to treatment at this point.

Thank you. Our next question will come from Salim Syed with Mizuho. Please unmute your line and go ahead.

Great. Congrats on the data, guys. Just another one from us on the potential second line strategy here. Troy, you kind of spoke about maybe even doing some sort of doublet, I know kind of like the initial commentary was maybe going towards triplet. Just curious what the thoughts are from yourself or Molly or Dr. A here on CasDatafan plus Darlie, just given that Cas is already doing 15 months meeting PFS as a monotherapy in the ARC-20 study, and we'll get obviously some more data for that, you know, prior to ESMO, but what are your thoughts here on a doublet casdatafan plus Darlie-Farned for a second one? Is that an option?

I'm happy to take that and maybe ask Molly to comment. Salim, it's a good question. Because HIF2-alpha doesn't work through the MAP kinase pathway, you wouldn't necessarily expect additivity or synergy in a combination with Darlie. Were you to do the triplet with a TKI, HIF2-alpha, and DARLE, that could be quite interesting. But just mechanistically, we wouldn't necessarily expect DARLE to enhance the activity of HIF2-alpha the way that we're seeing it enhance the activity of both Cabo clinically and multiple TKIs preclinically. Molly, do you want to comment?

Yeah, absolutely.

So I agree with you, the castatophant data is impressive, but it's impressive as long as you're not the patient that is progressing after, you know, 13 to 15 months. So until there's a cure, we have to keep augmenting these combinations and getting patients into deeper remissions or, you know, overall remissions. So agree with Troy, this is a TKI combination, Darlafarnib is a TKI drug, but bringing that TKI new mechanism into other combinations is extremely important. And we are going to show through our platform trial that we are able to combine with these. So we will start to do something eventually where we show that we can be combined with the HIF2-alpha along with the TKI, can be combined with IO along with the TKI. So it's really a story where we want to continue to augment the efficacy of these various combination products.

Okay, got it. And just to, yeah, Salim, just to build on that one more thought, and Dr. A can comment on this as well. Interestingly, we've seen activity even at, you know, the starting dose of Darlafarnib and lower doses of Cabo. People may remember, if you look at the data, we initially dose escalated at 40 milligrams of Cabo. And that was on the recommendation at that time, you know, that that was the combination dose. As we advanced through that, you know, you saw the combination was well tolerated. So we then went to the 60 milligram dose. But you still see meaningful activity at those lower doses of both Darley and Cabo. So that could help to make a TKI regimen, you know, better tolerated and help to drive, you know, help to drive sustained activity. Dr. Wright, I don't know if you want to add anything to the thoughts or to Salim's question.

No, I think it's a very valid point of, you know, when we have successful drugs, we're always looking at, you know, how to improve their efficacy by being synergistic. And we've tried this in RCC for quite some time. And it's that elusive frontline triplet option that we still haven't established, like Iconic, Cosmic, all those trials looking at IO doublets and PKIs have not, you know, broken through. And we now have this upcoming result that will probably be reported by Dr. Chowdy, maybe at ESMO, where the combination of femoralizumab and vatinib plus a 52-alpha did not seem to make a difference in the front line compared to a very strong femoralizumab and vatinib. So whether our hypothesis that a triplet is better than a doublet is always going to be true is a question that remains to be answered. And it would be nice to test out all these newer mechanisms of actions like Darlef on it. But I think the toxicity profile is uniquely different. We do not see any overlapping toxicity with darlifarnib and hiptoalpha inhibition. Maybe anemia could be one example, but anemia is multifactorial, and I don't think that's an on-target side effect of darlifarnib. It's more than neutropenia with darlifarnib that we've seen. So theoretically, darlifarnib and any hiptoalpha could be combined with that synergistic toxicity, but we have to look at what the synergistic efficacy of both of them are. And I would be surprised if there is any synergy. Again, not knowing what the data is, just from a hypothesis standpoint, like Troy pointed out. But it is a tolerable drug. It does not seem to be super hard to tolerate, or we have not had to have dose reductions with cabozantin pretty up front. We've been able to treat these patients with cabozantin at 60 milligrams. Now, cabozantin is not an easy drug to tolerate, and many patients do have dose reductions. So when this trial first went from the CABO40 to the CABO60, I was one of those patient advocates who thought that this would be a harder regimen to tolerate. But I'm happy to announce that I've been wrong about it. And most patients who tolerate the CABO60 have not had significant toxicities from what we would normally see. So I do think that this is an easy drug to tolerate. But we have to be careful when we are adding them on without data. And that's where the Bayer platform trial is going to be important, where, you know, you have these small snippets of information and how you move this Dalifarnib drug combination in this wide open space of RCC, where there's no other drug that's inhibiting the final cell transfer mechanism is important. Okay, got it. Thank you so much.

Thank you. Our next question will come from Astika Gunawardeen with Learink Partners. Please unmute your line and ask your question.

Hey, guys. Thanks for taking my question. Maybe one for Dr. A here, please. So, Dr. A, among the 47% of the carbo-naive patients who had seen prior VEGF TKI, could you tell us a bit about what proportion had discontinued prior TKI either due to best response progressive disease or due to subsequent treatment resistance? I'm just wondering, how does that inform your view on how Darlie resensitizes patients versus if the patient had originally discontinued therapy due to toxicity. And then I have a quick follow-up.

Yeah, I don't have the exact numbers for you as to how many patients had stopped due to a side effect of a TKI versus progression, but the protocol doesn't include patients or specify that patients should have had progression of disease prior to enrollment. They don't allow patients who've just been on a break to go back on the table. Now, I personally have enrolled quite a bit to this trial, and I do have my own share of patients who've been on cabozantinib and progressed and then gone on this study and then have had a response. So, you know, there are specific patient examples that I can cite where patients have been on cabozantinib 40 milligrams a year or two into treatment with progression of disease that have gone on this trial combination and have responded. There are also patients who have gone from an IO doublet to go, but most of the patients, about 67%, if I remember right, had an IO TKI approach at some point during the course of the treatment. Not all of them, just immediately prior, but there is a good portion of patients who had a prior TKI as their immediate prior line before they came to the Kaposanthematary So there does seem to be some ongoing sensitivity despite Kapo. What I, from a physician standpoint, think is the more important or relevant data point here is not the efficacy signals that we're seeing in the cabozantinib-naive population, but the efficacy signals that we saw in the cabozantinib-exposed population that was presented at IKCS earlier this year in Paris. In that group of cabozantinib-exposed patients, objective response rates were above 40%. Disease control rates were about 90%. So this is a drug combination that works. And in that whole part, a majority of them, more than 50%, I don't know the exact numbers, we can look at it and get it back if it's not listed in the publication. A majority of those patients added TKI as the prior line of therapy before they came on the taboo and the dialed one. So there does seem to be some efficacy signal here telling us that there is some presensitization happening to the TKI. Now, whether that's all just presensitization to the TKI or whether there is a synergistic efficacy of the FDI inhibition is something that we don't know. But we also know that FDI monotherapy really hasn't moved the needle too much. So I do think it's the combination, and I'm assuming that there's some resensitization to the TKI regimen that's happening, but we don't have that answer yet.

Got it. Thanks. That's encouraging. And then it's good to hear that you're able to manage neutropenia now in patients by giving GCSF. I'm just wondering, you know, if you can talk to us a little bit about the number of patients who you manage this way following the dose escalation work, what proportion of them did you avoid dosing down Darley? Or were you able to even avoid dosing down Darley completely by giving GCSF?

So it's important to understand that the dose expansion phase is in its initial enrollment It hasn't been a year or two since the dose expansion started, right, compared to the dose escalation, which has been a while. So I don't know the exact numbers again, but most patients, like my patients on the trial, we have not had to dose reduce on the Dalifarnib due to neutropenia. There have been other scenarios where Cabozacnib has been dose reduced, but so far on the expansion phase, I have not gone down on the dose of the Darlifanib. I've just been able to use GCSF. So for example, I had previously talked about a patient who had this great four neutropenias hospitalization and then went on a re-challenge with the dose reduction of the Darlifanib. In that patient, we did empirically add GCSF along with the dose reduction, and he's been tolerating it well now for about nine or 10 months since he re-challenged, and we've not had to dose reduced further. So it does seem to be an all or none phenomenon where some patients get it, some patients don't. And in those patients who get it, we've been able to get away without those modifications as of yet, but it's pretty early. And I don't know how, you know, these are going to change because if you look at the cabozampin naive population, median PFS is around 15 months. So I think that as patients stay on the Dalifarnib longer, we might encounter some of these neutropenias, but it's also encouraging to know that there's no cumulative toxicity, as in, as the longer they stay in the Darla Farnab, it's not like the neutropenia gets worse. Thanks for taking my question.

I just want to, I wanted to add a little bit to that, is that very rarely do we see a Darla Farnab dose reduction rather than a Darla Farnab dose interruption, and the Darla Farnab dose interruptions are really what is sufficient to, to, to allow the neutropenia to recover.

Got it. Thanks for taking my question, guys.

Thanks, Asika. Thank you. Our next question will come from Jason Szymanski with Bank of America. Please unmute your line and go ahead.

Good morning. Congrats on the great progress and thanks for taking our question. Maybe to connect some of the dots in recognizing this is somewhat speculative at this point, but based on what you've seen thus far from Darley's emerging profile, where do you think the ideal setting in RCC is for the FTI? And then given how entrenched and fragmented the first and second line markets are, is there potential to leapfrog some of the emerging novel regimens by simply adding on to one of the more established combinations? Thanks.

Dr. A, do you want to share some of the questions or comments you maybe got from your colleagues at the KCRS about their thoughts, you know, of how to use this? If, you know, if they could, setting aside, you know, Cura's designs, maybe speak to a little bit of the commentary you received in the feed.

Yeah, I think, you know, it's along the lines of what we expect and anticipate. So we're seeing data that tells us that this combination is doing better than what we would with just cabozantin monotherapy. Now, cabozantin was that gold standard second-line treatment, but then we've also had multiple trials needed, whether it was the LEN-Evodonomous trial or the LEN-Belsurifan trial, which had cabozantin as the comparator. Dr. Chowary, who chaired the KCLS meeting in Boston and who was the person who introduced cabozantinib and so on. His comment specifically was, well, this seems to be doing better than cabozantinib. Why are you not doing a frontline trial with that? So I personally, we as physicians do think that this is a regimen that's worth exploring in the frontline space, right? And adding it on to an existing regimen seems like the best strategy, whether that's pembrol and bapnib or nevocabo or pembroaxirinib. Now, obviously, we know the response rates are better for femoral and vatnib and knee vocabular, so maybe that's a scenario that we need to think about. So we've had discussions before internally in our meetings as to, you know, we're curious to see what CUDA is going to do with this drug too, and I do think it's going to be very easy to enroll patients in the frontline setting to this too. I, for example, I as a phase one physician will have no qualms against offering this to a patient in the naive setting. Now I do believe that it needs to be combined with a TKI because I think there's some synergy like we have seen, but I don't believe that it has to be cabozantinib. I do think it can be any TKI, whether it's Cabo, whether it's Lenvatinib, whether it's Sansa. We don't know what the efficacy signals of each of them are. So assuming that the basket trial that they're talking about shows that it's safe and effective with all these combination approaches, I think a drug like Darlefarnib could be one of those drugs that can combine with any upfront treatment strategy without marrying into a specific frontline treatment it doesn't need to be tied in with linvatinib or tied in with cabozantinib it can be iotki plus carlefarnib that's the way i would design a trial if i were given all the resources i wanted to but again easier said than done and i and like everyone else we're eager to see what cura will do to this combination great thanks for the color thank you and as a reminder if you have joined via the webinar please use the raised hand

icon which can be found at the bottom of your webinar application to ask a question. When called upon, please unmute your line and ask your question. Our next question will come from Phil Nadeau with TD Cowan. Please unmute your line and ask your question.

Good morning. Thanks for taking our questions. Two follow-ups from us. So first, in terms of the baseline characteristics of the patient in this study, any notable differences between these patients and the precedent cabozatinib second-line trials that you highlighted on the comparison slide. Anything that would bias the patient's either more likely or less likely to respond to Cabo. That's first. And then second, in terms of the pivotal study, the first pivotal, I guess, what exactly are you debating? Is it just the patient population that could be enrolled as well as the dose in third line, but you're committed to going forward with a Cabo combo? Or is there a scenario where you actually wait for the results from your platform study and perhaps move a different combo forward into the first pivotal? Thank you.

Yeah. Thanks, Phil, for the questions. Molly, do you want to speak to Phil's question about the baseline characteristics relative to the comparator trials that we highlighted?

So we attempted to show you the closest apples to apples comparisons that we could for what you'd expect Cabo to do in a second line setting. However, really, our patients were really in a third line plus. So that's your biggest difference between the groups is that, you know, we actually are showing you patients that are somewhat less pretreated. So really, our results then are even more outstanding, in my opinion, compared to what we would expect to see with these patients that are receiving CABO alone.

And Phil, maybe I can take your second question. You know, we're deliberately sort of not yet articulating that registration enabling design. And as in any case, right, what are we weighing off? We're weighing off the unmet need. We're weighing off the commercial opportunity, the competitive landscape, cost, and time. As Molly indicated, you know, we've gone in a relatively short period of time from FTIs being either, you know, I'll be harsh, irrelevant or an HRAS inhibitor to something that could broadly and, you know, broadly combined with TKIs in RCC and I think can really positively impact the evolving KRAS space. So we want to make sure that when we do this, we're doing it, you know, with all the available information. There are a number of combinations we can take forward. We want to make sure we think about and carefully consider the overall development plan. We won't be able to do everything, so we have to be selective. You do hear us wanting to move Darley as quickly as we can earlier in the treatment setting, but we also want to ensure that we give it the very best shot to get that first registration. So just look for us to provide more clarity either later this year or early next year. And to your question about dose, you know, the great thing is either five or eight, you know, both look to be pretty good. So I think we're in a good spot as far as that's concerned. For Project Optimus, we do need to make sure that we do the right experiment, right? The FDA is looking for the proper Project Optimus design, and that's what the Phase 1B does. then we'll be able to I think again later this year early next year articulate a registration enabling design I hope that helps yes thank you thank you our next question will come from Rennie Benjamin with Citizens please unmute your line and ask your question

great thanks for taking the questions and congrats on the data which is maybe just two for us are there any patterns that are starting to develop the patients you think are most likely to benefit from this combination?

Or in this study, are there any biomarker analyses that you guys are conducting that might help in identifying those patients? And just as a follow-up, you know, maybe for Dr. A, looking ahead, is there any additional data from the ongoing randomized phase 1B study that would be kind of most important for you as a practicing physician? Or is that really more for the company and you'd be more interested in really the registrational pivotal study path. Thanks.

Sure. Thanks, Ren, for the questions. Molly, do you want to take the question about biomarkers and potions, patients most likely to benefit?

Sure. I mean, it's a great question. It's early. Let us continue on with our phase 1B work. We'll have a good pool of more homogenous patients that will be able to help us potentially answer that question more. But again, you know, these are some questions that occasionally don't get answered for a very long time, but we hope to be able to gain more information from that to help guide, you know, maybe it's earlier line patients, maybe it's patients that haven't seen other TKIs, maybe it is patients that have. So let us continue to generate that data and then we'll share it with you.

And Dr. A, for you, anything in particular you're looking for from the phase 1B to Ren's second question, or are you really excited to, and Ren, I'm reframing your question, you know, excited to sort of move into that next combination or pivotal design?

I think we're all excited to see where this drug goes. We've had experience with it. It's been an easy drug to manage in clinic, and patients have stayed on it for a long time. And two things that we are all waiting to see is one, durability of response. So in the KCRS presentation where we had a PFS of 13 months, about 50% of these patients are still on treatment. So we know that we don't have long-term follow-up yet, and hopefully we can see a better PFS and a longer durability. Like six-month PFS was around 74%, nine-month was around 60% of that number, right? So it does seem to be durable when we're seeing these responses, and that's what the long follow-up will show. So the second thing that's going to be important is that this phase 1b expansion will be randomized. So it's randomizing to cabozampinib monotherapy at 60 milligrams, which we all know is a good drug. And that will tell us what the combination is doing in terms of incremental benefit. And the randomization is also stratified based on a prior TKI exposure. So instead of looking at it by saying, you know, this cohort of patients at this or that, I think we'll have prospective randomized data, which is always stronger. but we all hope and believe that this will be something that's promising and how you combine it or take it forward in the next line setting is going to be important. And I am not of a firm belief that it has to be CABO. I think it can be any TKI and probably a multikinase inhibitor is the one that CUDA should target. Now, whether that's CABO, CABO-like, LEN, LEN-like, or any of the other agents that are being investigated in this field is up for debate and it opens up the opportunities in the basket trial. So I'm optimistic that the trial will be relevant and significant and that the addition of the CABO to the DARI, whether it's at five or eight, will have some meaningful improvement in outcomes. And then hopefully by that time this data is out, the basket trial data is out, which tells us the safety of combining it with everything else. And then CUDA will have a good headache of trying to figure out which trial combination they need to take forward with. It'll be interesting times.

Great. Thanks for taking the questions.

Thank you. And our last question will come from David Dye with UBS. Please unmute your line and ask your question.

Great. Thanks for squeezing me in. Just a quick one. Thinking about the potential other combinations in addition to CABL and RAS inhibitors, maybe wondering if you can tease some of the potential combination strategies or interesting MOAs you're currently evaluating.

Yeah, David. Thanks. Thanks. Good question to end on, actually. This will be kind of my concluding comments. So we'd like to benefit as many patients as we can in RCC. As Dr. A mentioned, there's a rationale to combine with any of the TKI-containing regimens. you know, it would be great if we could do something akin to what we're doing in AML with Ziftamenib, where, you know, as you look toward the end of the year, you're going to see combinations with venetoclax and azacitidine, with FLT3 inhibitors, with other regimens like LDAC, would be great to do that in the RCC space. In the KRAS space, we've committed to moving forward with Deroxonrasib, because obviously that's the second line standard of care. Interestingly, a number of these companies are now pivoting and going to frontline. These are other RAS companies. You know, we're not doing that. We actually think we can build upon the strong data with Deroxon Resib and potentially make it even better. That puts us in an attractive place, I think, in this evolving KRAS landscape. But there again, we can combine with the mutant selective inhibitors, we can combine with the PAN inhibitors, and we can likely do it in each of the major tumor types. This is going to require a meaningful development spend, but I think the opportunity, there hasn't been a molecule like an FTI before, one that actually can work well in a solid tumor space like RCC, that as we indicated is $6 billion market opportunity in the second line, and then the RAS space, which is just on fire. So it's an exciting time. It's a high-class problem that we have to make these development decisions, but look for us to articulate that through the rest of the year. With that, I know we're a few minutes over. I want to thank everyone for your listening to us and participating. I particularly want to thank Dr. A for being so generous with his time, both at KCRS and in this webinar. We will be releasing earnings here in the next sort of within the next couple of weeks and look forward to talking to you all then. Until then, happy Monday and enjoy the rest of your day.

Thanks very much.