Kura Oncology, Inc. (KURA) Earnings Call Transcript & Summary

Good day, everyone. My name is Stephen, and I will be your conference operator today. At this time, I'd like to welcome you to the Kura Oncology Investor Call to discuss updated results from the FIT 001 clinical trial evaluating darlifarnib in combination with cabozantinib in renal cell carcinoma. [Operator Instructions].. At this time, I'd like to turn the call over to Troy Wilson, President and Chief Executive Officer of Kura Oncology. Please go ahead, Dr. Wilson.

Good morning, everyone, and welcome to Kura Oncology's update. This morning, we're going to talk about darlufarnib 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 Oncology website and the SEC's website for more information about risks, 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. Ayanambakkam. Dr. Ayanambakkam 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. Mollie Leoni, Kura's Chief Medical Officer. If we could please go to the next slide. So just before we get into the KCRS data, I just want to step back and recognize this is a really important time at Kura. We now have 2 major pillars in the company that are driving value for both patients and shareholders. On the left-hand side, with ziftomenib, it's really -- everything is going extremely well. The launch is going well. The enrollment in the Phase IIIs is going extremely well. We're looking toward a number of data updates that will help us to elaborate what we think ziftomenib can do both as monotherapy and in combination. Toward the goal of making it a broadly combinable AML backbone as a therapy for patients throughout the treatment continuum. So that's really a great story and 1 that just continues to move forward. Today, we're going to focus on the right-hand side on the Darlifarnib program. And the darlifarnib program is exciting because it's really a different way of addressing cancer. Using small molecule therapy. Darlifarnib 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, and with KRAS inhibitors. There's really -- the way we think about it is laid 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 Ia data for cabozantinib in RCC. But just to remind you, the Phase Ib is underway, in addition, we are preparing for the Phase Ia escalation with deroxonreceiv in second-line PDAC. We were excited to see that derox recips NDA was submitted and hopefully, we'll be looking toward an approval later this year or early 20 we'll be ready to add darlifarnib 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-alone basis. But darlifarnib offers a precision combination platform. And in that regard, Mollie 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 Ziftamenib side with things like venetoclax or gilteritinib, or whether it's now on the darlifarnib side with things like cabozantinib and deroxonrecib, 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 farnesyl transferase inhibitor can enhance the activity of targeted therapy. And here, you can see in the headline, we're 3 for 3, so starting on the left-hand side of the slide, previously, at the I KCS Symposium earlier this year, we showed you that darlifarnib could enhance the activity of cabozantinib in patients who were 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 KRASG12C mutated solid tumors where we combine darlifarnib and adagrasib. In each case, those blue bars, the activity of the combination the FTI combination is better than what 1 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 7, and this is just going to be an on-ramp to Dr. A's presentation. The way that we believe darlifarnib is working to enhance the activity of these targeted therapies is by blocking Reb. Reb is a farnesylated protein. One of REV's roles is to determine the localization of TORC1. So by blocking RevPAR installation, we prevent TORQ 1 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 darlifarnib, we're effectively putting 2 blocks on the pathway. In the case of cabo, you've got to block at the receptor level, and you've got a block at the TORC1 level. And we think that's -- that's a big part of the base is 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 ALK 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. AA and let him take you through the slides that were presented at the KCRS symposium. Dr. AA?

Good morning. Thank you for letting us present the data again. My name is Adanma. I'm one of the Meagan Honor to present as part of the FitOn study group and the results of the PDO-1 study. Next slide, please. are my disclosures. Next slide, please. So we all are aware about the role of M1 in renal cell carcinoma, especially in tumor growth angiogenesis and the limitations we've had with prior attempts at blocking the MTR 1 pathway. Dalifarnib is a potent next-generation farnesyl transferase inhibitor that blocks the farnesylation, which directly results in selective mTOR1 inhibition without the MK2 inhibition and thus adding some selective toxicity. At IKCS, earlier this year, we had talked about data about the safety and efficacy of dalifarnnib in combination with cabozantinib where it had demonstrated an injective response rate of 44% with an impressive disease control rate of 94%. Next slide, please. So the FIT 01 study is a Phase I dose escalation, dose expansion study that's evaluating the combination of talifaniband can in the locally advanced and metastatic RCC that has been refractory to prior lines of treatment, including immunotherapy multiple dose levels of dalifanib and cabozatinib have been evaluated. And for the purpose of this discussion, we are talking about the safety data of what all patients with RCC in this study but also focusing on the efficacy data on cabozantinib naive clear cell RCC patients. Of note, the cabozantib 60-milligram and dalafanib 8 and 5-milligram cohorts were limited to just cabozantinib naive patients in comparison to others, which had a mixed bag of both cabozatinib 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 pretreated with about 50% of these patients having had more than 2 prior lines of treatment. And of note, at least 67% of these patients had a prior I-O plus TKI combination. 38% had prior cabozantinib in any line and 17% had a prior HIF2-alpinhibitor. Next slide, please. When we look at the safety and the totality 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 cabozatinib induced diarrhea nausea, stomatitis and Hanford syndrome. Important to note, they were predominantly less than Grade 3 and significant greatly 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 Darlifarnib and 96% related to cabozantinib. 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 integrated at 47% and Grade 3 of 38%. And -- 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 antitumor 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 [ lenvatinib ]. We had encouraging antitumor activity with objective responses ranging from 33% to 50%. Of note, the Darlifarnib 5-milligram cohort plus 60 milligrams of cabozatinib had an injectable response rate of 50%. And disease control rate was acceptable with 83% to 100% among all groups. -- and clinical benefit rate was about 70% in that target group of 5-milligram dilaps60-milligrams cabozatinib and 58% in the group that had darlifarnib about 8 milligrams and cabozatinib at 60 mg. Next slide, please. SP999 Here is our waterfall plot that's looking at the objective response rates at various dose levels of dalafanib and cabozatinib. And what's important to highlight over here is that even at the lower dose levels of darlifanibb 3 milligrams, of 5 and 8 milligrams, we had some significant responses and also in both the cabozatinib 40-milligram and 6-milligram cohort in this carbonate population. Next slide, please. What is also important to understand was that these -- 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 Capa-naive PSL RCC patients with 6-month PFS probably at 74% and 9-month PF is probably at 60%. Bext slide, please. Here is a swimmers 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 and put a 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 latanatropenas 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 #1, which includes a 66-year-old meal with SRCC diagnosed in 2023. -- who had double immune checkpoint inhibitors with nivolumab and ipilimumab is is frontline response who started darlifarnib at 5 milligrams and 60 milligrams in January as of data cutoff at May 2026, it continues to have a response and is ongoing on treatment. And as you can see, pretty earlier on in the disease course that week at 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 tumor lesions even at week 24, which is impressive. Next slide, please. Now not only is stalifinib 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. get is an example of a patient who's had prior zanzolitinib plus nivolumab is is frontline treatment when he was diagnosed with RCC in 2022, had a partial response and then discontinued due to radiographic progression. He started line the lower dose at 3 milligrams and cabozatinib at a 60 milligrams in October of 2025. And again, was able to see a partial response at week 8, through week 24 and an ongoing disease response at week 24 as well from a 33% you missing to a 54% tumor shrinkage. Next slide, please. In conclusion, with long-term follow-up, this combination of darlifarbnib and cabozantinib has a demonstrated durable and encouraging antitumor activity in both the cabozactin-naive and the cabozantinib post 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 those modifications, including interruptions and reductions in both the cabozantinib and darlifarnib. Neutropenia was successfully managed. And in the ongoing Phase Ib expansion phase, we do recognize this and allow GCS support to avoid dose modifications for the Darlifarnib feasible. These data support the continued development of dalifarnib in this space, along with a combination, cabozatinib and big-I Currently, the FIT 001 Phase Ib portion of the study is enrolling. Next slide, please. In the expansion phase, we are testing 2 dose levels of darlifarnib at 5 milligrams and 8 milligrams. The study is randomized in a 1:1 21 fashion to either dalafinib 5 plus cabo versus darlifarnib at 8 milligrams plus cabo 60 versus cabozatinib 60 milligrams monotherapy. Given the efficacy of darlifarnib combinations in a prior caboose population, we do allow those patients who enroll on the cabozatinib monotherapy population of cohort to be enrolled in a subsequent cohort of combination Dalian and cabozantin. Next slide, please. With this, I'll hand it over to Dr. Leoni for further comment. Thank you.

Thank you, Dr. AA. 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 tolerably enhance the clinical activity of cabozantinib. Because of the impressive results thus far, we are currently in dose optimization as described by Dr. A in our Phase Ib trial where we randomized to the 5- or 8-milligram daily dose and to a mono cabo 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 or of interest to bring this combination to patients even earlier in their treatment journey and provide 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 manner. 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? 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 unmet need that has a differentiated profile, including improved PFS and 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, Mollie. If we could please go to the next slide. So I think with today's presentation from CRS, 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 my KCS, you can see why we're so encouraged about the opportunity with daralifarnib . Darlifarnib 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 darlifarnib whether that be in the KRAS space on the left-hand side or potentially TKIs in the upper right or PI3 kinase inhibitors, really a very large number of potential patients we could benefit this -- we say this isn't another KRAS inhibitor. This isn't another TKI. It's a drug that cannot 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 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 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 Mollie indicated, we're looking toward full enrollment in the Phase Ib, and we'll continue to elaborate where we're going to take dalafarnib. But if we just focus initially in the addressable market for RCC, we think the future for darlofharnib is quite bright. If we go to the next slide, please. I just want to recap where we started, which is it's an exciting time at Kura. Ziftamenib continues to gain momentum as the market leader in relapsed/refractory NPM1 mutant AML patients. We really see a path to where we will be 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 darlafarnib side, it's -- this program continues now to pick up momentum. So the Phase Ib study is underway with cabozantinib. We'll be starting the Phase Ia with deroxonracib 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 Peloquin. 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.

[Operator Instructions]. Our first question will come from Charles Zhu with a LifeSci Capital.

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 talked about how many pages have had prior TKI, including capital. Can you also talk about how many patients may have had far lenvatinib, given some of the existing clinical data out there that strongly suggests that Abo has possibly wildly different outcomes depending on if patients have seen prior IO-IO, axitinib or lenvatinib, so so forth. And my second question, of course, is how would you position or contextualize your data relative to some of the TKI plus HIF2 alpha as well as lenvatinib plus ever align this 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 Mollie, 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 grew about 67% of them had prior TKI, and that was PKI-lineincluding Santanol CKI. And if you factor in the patients who've had just cabozatinib that's around 38% of these patients -- so the analysis has been split into 2 parts. The first analysis that was presented at ICS earlier this year were patients who had prior cabozantinib and the efficacy that was presented recently is now was efficacy in patients who are cabo naive. So in this caba naive population, 47% of these patients had prior TKI, including lapatinib but obviously, not all in that net. I don't have the exact rate of how many was lenvatinib, but there's a sizable portion here that was exposed to TKI, including that patent. We do not have a lot of patients on lenvatinib plus the zurifam, if that's the direct question because it is a regimen that's been recently approved. But interestingly, we do have patients lipitothose who have been on lenvatinib plus burn and also the stipend monotherapy. About 88% of patients on this trial have had prior Bigiron exposure to, and we've seen the response. Now it's interesting to look at the recent Cabo length trial that look at cabozantinib which is lenvatinib polymetallic the problem seems to be doing better. But promos is also a harder drug to tolerate and that probably is coming from both mTOR1 and TROP2 inhibition, whereas darlifarnib with a selective MTR1inhibition does not seem to have that same efficacy so same toxicity profile with the same efficacy in retain. We do not see the same side effect that we see with aprons as inverse needs stomatitis or any of the significant pneumonitis or diarrhea or rash that we have seen with the products with Darlie. So it seems to be a better and more tolerable drug. But again, with limited data thus far, we will need to see what the future data holds.

Mollie, did you want to take Charles, the second question, which is how do we think about positioning this relative to TKI, HIF2 alpha or Charles, I think you called out specifically lenvatinib ever align us, as Dr. A was saying. Mollie you want to comment?

Well, first, I want to remind that this isn't just a cabozantinib combination. This particular darlafarnib activity can be seen in any TKI combination. So we think that, yes, we can enhance the activity of cabo, but we can also have an activity of lenvatinib, axitinib, 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 settled down a little bit with all the HIF2-alpha data that's coming out, and the kind of tinkering of different combinations being added together, we can see an earlier plan as well. And I also foresee us going into more of these broader combinations. We are starting a platform trial, which will rolls to evaluate even broader combinations on earlier combinations in these patients. 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.

Our next question will come from Li Watsek with Cantor Fitzgerald.

Thanks for the update. I just wanted to follow up on the second line development strategy versus the HIF2 just given this combination now set a new benchmark in second line, we're seeing on the next-gen HIF2 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 Darli plus cabo can fit in the second and third 1 RCC. And then how are you thinking about potentially combining with or perhaps decreasing after the HIP 2 class for initial target patient population?

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

Yes. So as we said, the field really is changing a lot. -- and HIF-2 alpha will bring a lot of efficacy for these patients, and we're excited for that. We're introducing a brand-new mechanism and then help to even augment the activity that's being seen with these 2 combinations. So really anywhere you're seeing a TKI brought into a line of therapy, we can easily be a partner for that TKI bringing even more efficacy preventing resistance, et cetera. in that combination. I foresee us starting the easy access into the third line and then obviously broadening out into the second line and ultimately going with an I-O combination in the front line. Again, reminding you that we have 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.

Yes. I think it's definitely exciting. I think it's good to have all these options from an oncology standpoint and also a patient standpoint. But I think there are a few caveats to remember here. We know that bazitupan is now approved in the adjuvant setting. So that means that many patients are going to be getting to defense and they're going to be built with the FX post. We also know that there's a subgroup of patients who don't tolerate residifa neither due to significant immunotoxin 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 belie seem to be durable responses. But when we talk to the frontline setting, a significant portion of these patients are either going to have pembrolizumab lenvatinib combinations upfront. And if they had lenvatinib combination front, they are not going to be eligible for lampanib plus and we also know that the front line registrational trial, which has a preliminary result out that it's not positive when they combine lenvatinib and [indiscernible] is interesting. So that combination of PKI plus 2 alpha is important relevant, but it doesn't seem to have reached the frontline space as of yet. So maybe there is another combination that we need to look at for the holy grill of triplet therapy in the frontline setting. And maybe 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 them backend. We know that that's a good combination. It works. It has a good PFS and OS benefit, not only spending a benefit. But in those patients, post-lenvatinib belated what we use in the third-line setting that is important and tivozanib or axitinib and 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 Darlifarnib in combination with like Mali and Tai pointed out, NATI is probably a good option post billion exposure, whether that's Belafonotherapy or bioemrolizumab or lenvatinib. We do have some patients in pet who have responded to it despite being on impactable with 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 invitation will respond to this combination. But this is a new mechanical of action. So there's no reason to believe that they won't and we have not seen any signals that sales that they want. So whether this is a sequence 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 phase.

I might just -- before we go to the next question, I might just add one more comment, Li to your question and for everyone on the line. We have here go-it-alone strategies with both cabozantinib and Deacon recip and PDAC. One of the reasons we articulated the platform study is just as Mollie 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 darlafarnib forward, whether that is as a doublet as a triplet, I would say stay tuned. What is clear, as Mollie said, is this combination, we think, really is compelling in the third line. We look at it relative to the competitors 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. A 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 want to add -- I just wanted to add that thought. We can go on to the next question.

Our next question will come from the line of Roger Song with Jefferies.

This is Nabeel on for Roger. Congrats on the data. Just maybe 1 quick 1 on the neutropenia management. So as mentioned at the DLT period, the support of care being permitted. I was just curious what percent of patients require any growth factor support, dose interruptions and reductions. And were there any cases of fibril neutropenia or infection or any discontinuation due to neutropenia ?

Dr. A, do you want to take that?

Yes. 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 DLT period, was not allowed. So these patients had to have dose interruptions of the darlafarnib and cabozantinib. But as we have treated more patients, we know this is a Darlafarnib-related effect. Most of our patients have been managed with just dose interruptions with challenges, the same dose or at a lower dose, and they have tolerated it well. It seems to be an effect that happens early on. So patients either get neutropenia upfront. And if they do, then they modified the Darlifarnib doses modified or they never get neutropenia. So it's not a cumulative proxy 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 a [indiscernible], but that he was rechallenged with dalafanam at a lower dose and currently tees on that dalafharmib 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 that are allowed to have DCF support, we're in neutropenia popping, we are supplementing them with GCS and we've been able to avoid dose modifications or dose reductions. So it does seem to be one of the easier to manage side effect. About 38% of patients had great or higher neutropenia, but neutropenia fortunately is not very symptomatic. So yes, there have been cases of neutropenic fever. I think this is something that we are recognizing. But with this excess support, it doesn't seem to be a median hindrance to treatment at this point.

Our next question will come from Salim Syed with Mizuho.

Great. Congrats on the data, guys. Just one -- another one from us on the potential second line strategy here. Troy, you kind of spoke about maybe you've been doing some sort of doublet. I know kind of like the initial commentary was maybe going towards triple. Just curious what the thoughts are from yourself or molar Dr. A here on on casodatifan plus Darli, just given that CAS is already doing 15 months median PFS as a monotherapy in the ARC 20 study, and we'll get obviously some more data for that. prior to ESMO. But what are your thoughts here on the doublet has data fan plus Charlie Farnbfor second line? Is that an option?

I'm happy to take that and maybe ask Mollie 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 DarlI. Were you to do the triplet with a TKI, HIF2 alpha and Darla, that could be quite interesting. But just mechanistically, we wouldn't necessarily expect early to enhance the activity of HIF2 alpha, the way that we're seeing it enhanced the activity of both cabo clinically and multiple TKIs preclinically. Molly, do you want to comment?

Yes, absolutely. So I agree with you. The Casa data is impressive, but it's impressive as long as you're not the patient that is progressing after 13 to 15 months. So until there's a cure, we have to keep augmenting these combinations and getting patients into deeper remissions or overall remissions. So agree with Troy, this is a TKI combination, darlifartibs 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 a HIF-2alpha along with the TKI can be combined with I/O 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 -- yes, Salim, just to build on that 1 more thought, and Dr. A can comment on this as well. Interestingly, we've seen activity even at the starting dose of darlofarnib in 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, that, that was the combination dose. As we advance through that, 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 better tolerated. -- and help to drive sustained activity. Dr. A, I don't know if you want to add anything to the thoughts or just Salim's question?