Sounds great. Good morning. Thank you for coming to the 2025 Citi Biopharma Conference in Boston. I guess let's get started here. Next up we have Cogent. Cogent's had some news recently. If you could just kind of introduce yourselves, perhaps talk about the company, the mission, and your overall path to this point. Yeah, great. David, thanks so much for inviting us to your conference. My name's Andrew Robbins. I'm the CEO of Cogent Biosciences. Cogent is a company that's focused on the discovery, development, and hopefully very soon commercialization of targeted therapies for patients with rare genetically driven diseases. Our lead asset is a drug called bezuclastinib, which we believe is the best-in-class selective potent KIT inhibitor for patients whose diseases are driven by mutations in the KIT gene. Those groups are typically divided into patients with mastocytosis. That disease is further divided into several subgroups, grouped mainly into the advanced form of the disease and the non-advanced form of the disease, as well as a completely different disease driven by KIT mutations known as gastrointestinal stromal tumors, which is a malignancy, a rare sarcoma. Several years ago, we kicked off pivotal studies across all three of those patient populations. As you mentioned, very recently, just this summer in July, we read out the first of those three pivotal trials known as the SUMMIT study in the non-advanced systemic mastocytosis population with what we believe are very positive data, speaking to the potency, the favorable safety profile of our drug, and we believe will lead us to our first FDA submission and ultimately, approval in 2026. In addition, the other two pivotal trials known as the PEAK study in gastrointestinal stromal tumor patients and the APEX study in the advanced form of mastocytosis are slated to read out later this year. Certainly a very busy 2025 looking at those products. In addition to bezuclastinib, which I believe we'll spend most of the time talking about today, Cogent is also building a portfolio of early stage, early clinical and predominantly non-clinical at this point, best-in-class programs for other targets, including FGFR, ERB2, and PI3K, as well as KRAS or PAN-KRAS. While we won't talk about those programs today, we're certainly very excited about the future of the company, building what we believe to be a broad portfolio of many, many best-in-class therapies for these patients with high unmet medical need. I guess to start, could we just talk about the mechanism itself? Targeting even KIT has a long history, a lot of trials through multiple indications. What about the mechanism itself is attractive for each of these diseases? What have been the challenges that the various competitors have had? Use that to kind of move into bezuclastinib and how that molecule is designed and how it might be different to actually achieve something that some of these other molecules have not been able to achieve. Yeah, I think as with many other targets and many other genetic mutations, one of the keys to finding a best-in-class drug for these patients is really focused on potency, how well your drug can engage the target and the cells that have the mutation, as well as selectivity, how well your drug does at avoiding off-target effects. With these patients that have very specific genetically driven diseases, I think we can all get behind the science of trying to find a program, a molecule, a drug that can hit that target and not do a lot of other things in that patient. There are other sort of drug properties that we at Cogent Biosciences think prospectively around either designing in or out depending on the specific disease. In the case of mastocytosis, this is a disease of mast cells or the immune system where mast cells have a specific mutation in the KIT gene known as D816V. Mast cells typically don't aggregate in the central nervous system tissue. When you're designing a therapeutic, you want to design out the penetration into the central nervous system tissue. Some of the elements of differentiation for bezuclastinib in mastocytosis are not being central nervous system penetrant, unlike a very well-known predecessor compound that's already approved known as avapritinib, which is significantly central nervous system penetrant as a liability of that compound, and also being very selective. If you look at the track record of KIT inhibitors past and present, almost every other KIT inhibitor that has been characterized clinically is essentially a Pan-Class III receptor tyrosine kinase inhibitor. In addition to hitting the KIT gene, they also all hit PDGFR as well as many other kinases such as CSF1R, FLT3, VEGF, KDR. In diseases like mastocytosis and then GIST, bringing along inhibition of those other kinases simply brings along off-target side effects. It doesn't bring any benefit to those patients. Having a drug like bezuclastinib, which is very specific and selective for only KIT and spares all of those other class III receptor tyrosine kinases, is exactly the type of profile you want in these patient populations. Got it. Let's start diving into systemic mastocytosis. I know that it's really broken down into multiple segments. I know that the street tends to look at it as two, advanced and non-advanced, or ISM, indolent. Could you tell us about the disease as a whole, the spectrum, frankly in more detail than we usually get in the street of what is the mild side of the disease and what is the severe side of the disease? What are the differences? Right. I think you got it right. Typically, folks think about mastocytosis in two large buckets, and then within those buckets, there's definitely subgroupings of patients depending on severity of disease and prognosis. In the advanced form of the disease, that really is a disease of mortality. All patients with mastocytosis are fundamentally driven by the same point mutation in D816V. In the advanced patients that arise, it's sort of a more serious mortality disease where, in addition to mast cells having the mutations circulating in the body, they tend to aggregate in large numbers in places like the bone marrow, the spleen, the liver, and cause significant challenges for patients. Ultimately, left untreated, shortening lifespan significantly. In the non-advanced form of the disease, the mutant mast cells continue to proliferate, probably don't aggregate nearly as much in places like the bone marrow, the spleen, and the liver, but cause significant symptomology. The non-advanced form of the disease, you can think about it as a disease of morbidity where the patients that have this disease tend to live a normal lifespan, but their life is compromised significantly on a spectrum of symptomatic severity, with a host of different symptoms, probably most commonly symptoms of skin and the GI tract, but also leading to issues with pain, with fatigue, with CNS issues like anxiety, insomnolence, depression, cognitive symptoms, et cetera. While the sort of manifestation of the diseases is quite different—advanced form of the disease, mortality; non-advanced, morbidity—fundamentally all of these patients are driven by the same mutation. When you look across mastocytosis, there's a very good scientific basis for having a potent, selective KIT inhibitor that can turn off those cells that express this mutation in the body. When we drill into the non-advanced side themselves, there's a whole host of symptoms you start talking about relative to the disease. Which are the most problematic? Clearly, skin is the most prevalent. Which are the most problematic? Which are the symptoms that actually cause patients to go see doctors and actually begin them within the kind of diagnostic process to be identified as systemic mastocytosis? Yeah, it's an excellent question. Over the past few years, we've gotten to know many patients with the non-advanced form of the disease and, of course, interacted with many investigators. One of the probably the biggest issues and challenges right now is that there are thousands of patients with this disease, but only a handful or a fraction of those patients have an affirmative diagnosis of the disease. It is a challenging disease to diagnose. Many of these symptoms, when a patient presents to a primary care physician or a community gastroenterologist or immunologist or allergist, are not well known among tens of thousands of physicians. It's a patient struggle over probably years and multiple physician referrals before they finally find themselves in a physician's office like a hematologist or what we call a sophisticated allergist who really understands how to see those signs and how to affirmatively diagnose a patient with this disease. When you look at the patient populations that we've enrolled, and I think it's consistent across some of the other clinical trials that have looked at non-advanced systemic mastocytosis, probably the most severe symptoms tend to aggregate either in the skin, so things like skin redness, itching, wheals, rash. It's about 30%- 40% of patients who suggest that those are the most significant or bothersome, most severe symptoms. Another 30%- 40% is probably in the fatigue, so just debilitating tiredness as a result of their disease, inability to sort of interact with society, hold a job, interact with people outside of their world. Then there's a whole host of others that make up the last 20%- 30% of most severe symptoms at baseline, including some of those central nervous system symptoms, some of the pain associated with this disease. That's the symptom side of the disease. I think it's important to point out for these patients this constant fear and the potential of a severe anaphylactic reaction as a result of overactive and proliferating mast cells, which can be brought on by a host of different environmental triggers. You can sort of see how this constellation of symptoms, along with that underlying fear on a constant basis of a severe anaphylactic reaction, leads to significant morbidity for these patients. They are really looking for options to address how do I keep all of these things under control and not just stick Band-Aids onto the symptoms, but really searching for a therapeutic option that can get to the heart or the root of what their disease is caused by, that can lead them more towards really broad resolution of the symptoms. I think for the first time after we presented data this summer, there's starting to be talk of what does true disease remission look like from an agent like bezuclastinib that can potentially bring hope to this patient population. If we look historically before avapritinib came out on the market, these patients basically had to run through the antihistamines, some got up to XOLAIR, which would have been off-label. Of course, avapritinib came along. To this point now, how do you think the market has changed with AYVAKIT there versus these other medications, which are almost certainly, because they're cheap, probably still easily used? What has AYVAKIT done to change it? Yeah, so we acknowledge that avapritinib represented a very important step forward. For the first time, patients had an approved KIT inhibitor, albeit at a dose that's significantly below the target exposure that you would look to in a mutant-driven disease for resolution of symptoms and clearance of the objective measures of disease. As a step forward, what avapritinib can offer at the 25 mg or even the 50 mg off-label dose is some symptomatic improvement in an oral pill, right? That's a great option for patients to take, but we know that patients very rarely on lower dose avapritinib can achieve full resolution of their symptoms. They can get some improvement, which we again acknowledge is an important step for this patient population, but it leaves these patients still searching for something that can bring them all the way to resolution of their symptoms. The challenge with avapritinib, as I think folks know, is as you increase its exposure, you bring in some of the liabilities of that molecule, namely that it hits many other kinases in addition to KIT, as well as its potency in crossing the blood-brain barrier. Patients have a trade-off with that molecule of as they want to dose up to get the benefits of removing mutant mast cells, D816V KIT mutant mast cells from their body, they have to take the trade-off of nearly ubiquitous periorbital and peripheral edema, frequent cognitive symptoms, and then the risk of things like intracranial hemorrhage due to the off-target effects of avapritinib. SUMMIT Part II, you announced top-line data earlier this year. Could you talk about what you saw in that data versus what we know about avapritinib, and how much closer are we to full symptomatic resolution? Yeah, I mean, we're very excited to demonstrate a clear statistical win in the SUMMIT Part II data, bezuclastinib compared to placebo. We acknowledge that for basically a Blueprint Medicines-driven reason of wanting to trademark their patient-reported outcome scale, we at Cogent Biosciences created a new patient-reported outcome scale in concert with the FDA and working with investigators. When you look across trials, what we do to make it easy for folks is we score our data using their scale as well. Across essentially every measure, the speed, the depth, and the magnitude of symptomatic improvement is noticeably higher, deeper, better, faster with bezuclastinib compared to what you're used to seeing in the PIONEER study at low-dose avapritinib. That is really backed up in the data by what we showed with the objective measure of disease response, namely circulating serum tryptase, which is a protein marker of mast cell activity, where we showed close to 90% of patients getting what is considered a response, a greater than 50% reduction in serum tryptase at 24 weeks compared to low-dose avapritinib, which is closer to about half of patients getting to that measure. Backing up the potency, the exposure, the target engagement of a stronger KIT inhibitor, and then translating that into faster, deeper, more pronounced symptom resolution, all those things are tracking in the same direction to make sense for what we believe will become the standard of care in the non-advanced mastocytosis patient population. Got it. If you look back at the pioneer data, they eventually got to start releasing more details from the data, getting into the actual specific symptoms within the TSS itself, the total symptom score. What were the areas of strength that you saw? It was hard because you start spreading it out into symptoms, the powering goes way down naturally because of patient numbers. What did you see in there and where could we see differences once you ultimately get to the more detailed updates? Yeah, so we're speaking of the PIONEER data and this has been presented and published across many conferences and journal papers. If you look at individual items, which are things like fatigue or redness in the skin or any of the individual symptoms themselves, or you look at the aggregated sort of sets, which are called domains, on no individual symptom did avapritinib 25 mg show a statistically significant benefit compared to a sugar pill. Only when you look at the composite aggregate of all the symptoms together did avapritinib sort of squeak out a win statistically over placebo. To be fair to avapritinib, and just based on lots of conversations with investigators, with patients, low-dose avapritinib does seem to have some benefit in the skin symptomology. Patients that have rash or redness or wheals or itchiness, when they take low-dose avapritinib, some relief is gained with 25 mg of, but really people don't have a lot of anecdotal evidence or stories about patients whose fatigue or CNS symptoms or GI symptoms or pain is resolved with low-dose avapritinib. I think the standard practice that we've seen emerge is to try to titrate avapritinib up to higher doses and try to find that balance between driving to exposure in a mutant-driven disease against the target, where at 25 mg they're below IC20 on target engagement. I think science would tell you you want to push that dose up until you can engage those mast cells, the mutant cells, and get rid of them. Balancing that on the titration with bringing in the PDGFR inhibition, bringing in the central nervous system penetration, trying to avoid replacing symptoms with side effects. That is where Cogent and bezuclastinib come in. If you look at the profile that we've delivered and you think about the side effects that are symptomology for patients, patients feel we have very infrequent, especially compared to placebo, side effects that patients experience as replacement to symptoms. That allows us to dose bezuclastinib in the SUMMIT trial up to 100 mg, which is just around IC90 target inhibition of the KIT gene, and really show that through the objective measures of disease like the serum tryptase, where 100 mg of bezuclastinib is dramatically different than 25 mg of avapritinib at removing the bad actor mutant mast cells from the patient. Got it. I guess, you know, fast forward, specifically with respect to the safety profile, what types of tolerability issues have been observed with bezuclastinib? I know that certainly the street had concerns about it after the first update, which was, I guess, a year and a half ago now. What were the expectations originally? What are they now? How have they evolved? Yeah, if you look at the safety profile that we presented in July, we're certainly very pleased, as I think are the investigator and the broad systemic mastocytosis community. If we rewind back to when we had our phase one results, we can sort of, with hindsight, understand from the investment community why there may have been concern with reporting a handful of patients with higher than grade two elevations in liver function tests. The concern in a small phase one study is that when you see those and you show up two years later into a larger pivotal trial, will those manifest into true liver toxicity? Putting ourselves a couple of years ago, maybe that's a rational concern, but now that we've read out the pivotal data and that did not occur, there are no patients that have any liver side effects other than lab abnormalities reported in the trial, treatment emergent completely across the board, nor are there any patients that have true liver consequences, no hospitalizations, no DILI reported as adverse event, no liver transplant, no liver toxicity. This is really truly confined to lab abnormalities in LFT numbers moving up and down. All of the patients, whether without dose mods, with dose mods, and in rare cases with discontinuation, have had their liver enzymes return to baseline very rapidly. We've even extended that a little bit further by saying across all of our clinical trials, including the PEAK study, which is dosed at six times the dose in patients that have fundamentally compromised livers, which is one of the main sites of metastasis of second-line GIST patients, we again have no significant liver toxicity findings, albeit in a blinded basis at this point. Where we are now, I think it's pretty clear that the profile of the drug, we will with bezuclastinib have patients with fluctuating liver enzymes. We have no evidence that that will lead to true liver toxicity or consequence. Beyond that, the safety profile looks very close to placebo. Probably the only other thing that you can point to is that patients, which is an on-target effect of KIT, have their hair grow in sometimes with white color. That is an easy-to-fix side effect. If you care about white hair, there are cosmetic ways to fix that. We think the profile of bezuclastinib at the appropriate target engagement in this mutant-driven disease, reaching that ICEC 90 type drug concentration is exactly what these patients are searching for. As a consequence of removing the bad actor mast cells from the body, we see a direct correlation to symptomatic improvement. While our predecessors, now Sanofi, but before Blueprint Medicines, had told a story of really no relationship between the objective measures of the disease and the symptoms of the patients, Cogent Biosciences was going to tell a different story, and I think a story that makes more sense scientifically. One more question on non-advanced, and that's regarding the actual process of treatment. Avapritinib, when they go in, patients essentially for the first few doses, they have to be, but they're monitored for a period of time. I would expect that you assume that practice would continue at least at the beginning of any prescription, and then eventually that would kind of dissipate once patients are beyond the initial few months. Yeah, so the question is about monitoring. In the practice of treating mastocytosis patients with KIT inhibitors, let's start with Avapritinib today. Number one, you want to monitor patients for signs of disease improvement. Not dissimilar than in a cancer treatment setting, the idea of never providing patients with a solid tumor a scan again after initiating treatment to see if their tumor is changing size or shrinking, that seems sort of strange, as it would be for us to never take blood from a mastocytosis patient to see if their tryptase or their variant allele fraction is changing. There's a positive reason why you want to monitor patients to see if the treatment you've chosen and that the patient has accepted is doing something beneficial to the patient. On a regular basis, physicians are going to monitor for things like tryptase and variant allele fraction. From a safety perspective, starting at 25 mg indefinitely in an off-label higher dose Avapritinib setting, it's a responsible thing to monitor those patients for their platelet counts because we know the history of Avapritinib. When a patient's platelets drop, it puts them in significant risk for bleeding events, including intracranial hemorrhage. On an ongoing and I think indefinite basis, patients with Avapritinib are going to be monitored for platelet counts. We have shown that on bezuclastinib with regards to liver function tests, it's probably a good idea to measure patients' LFTs for the first several cycles of treatment. There are going to be a small number of patients, based on the SUMMIT data, it's probably a small single-digit% number of patients for whom bezuclastinib might not be the long-term chronic treatment. For the other 95% plus of patients, they will not have issues. They will not have to dose mod. They will be able to get through the first several cycles without any LFT issues and continue on benefiting from the drug. We don't see any practice changing for bezuclastinib's hopeful approval next year to the frequency or sort of underlying reasons for monitoring patients receiving KIT inhibitors for non-advanced mastocytosis. Let's move over to advanced. Tolerability also pops up there, but for different reasons, just like the non-advanced and overall there's a spectrum of disease. Could you talk a little bit about how bezuclastinib can differentiate from what avapritinib's been able to do? It seems like a lot of that is connected to that tolerability profile. Right. This is important from a history perspective. We just spent some time talking about avapritinib, which we acknowledge is a good step forward, a good first step for patients with non-advanced. The downside of 25 mg of avapritinib is that it doesn't actually have the potency to remove all the mast cells from the patient. In the advanced form of the disease, which was their first indication, they dose their drug at their ECIC 90 dose, which is 200 mg, almost 10x the dose of the non-advanced dose. We acknowledge that that dose is highly potent, highly effective at removing the bad actor D816V mast cells from advanced patients. The consequence, based on the profile of that drug, is that 1 in 20 patients died from a fatal adverse event. They have a greater than 5% fatal adverse event rate at that dose. In addition to that sort of headline, about 80% of patients experience periorbital and peripheral edema because that drug is a very potent inhibitor of PDGFR. About 40% of patients experience significant cognitive side effects because that drug is exceptional at crossing the blood-brain barrier and aggregating in the CNS tissue. In addition, they have about 25% incidence of Grade III-Grade IV thrombocytopenia, neutropenia, and anemia because that drug is a class III receptor tyrosine kinase pan-inhibitor. It hits many of the kinases required for formation of healthy blood cells. When you put that profile together of that CNS activity with the detriment to the platelets, what you saw as a consequence is in over 20 confirmed patients during their clinical program was evidence of intracranial bleeding. Bezuclastinib, in the profile that we've delivered, has very low rates of Heme Tox, has very infrequent, if ever, shown any cognitive side effects, has very low rates of edema, similar to a placebo, does not lead to fatal adverse events at our dose. We think that the profile, again, we have to wait to see the data out of the APEX study, but if we can simply match the activity and the potency of 200 mg of avapritinib without all of the drawbacks of that level of toxicity associated, I think we're going to have a very strong commercial profile for those patients. Does this open up the possibility of moving into the associated hematologic neoplasm patients where avapritinib's kind of not been able to get used as much? Yeah, it's a great question. Now we get into kind of the subgroups of the subgroup. Within the advanced population, you really divide it into three forms of the disease: mast cell leukemia, which is a pretty rare and very severe form of the disease; aggressive mastocytosis, which is patients that have just D816V mutation, just the mastocytosis; and then about three quarters of the patients have the advanced form of the disease with another unrelated or they call it an associated hematologic neoplasm. A disease like myelodysplastic syndrome or CMML or potentially myelofibrosis, something else that's happening in their body at the same time as mastocytosis. Now those diseases, many of those have therapeutic options to treat, but those options are typically associated with significant heme toxicity. Treating those patients concurrently with those therapies, like azacitidine or ruxolitinib or chemotherapy, concurrently with avapritinib that has its own high rates of grade III heme tox is really dangerous for patients. It is uncommon to try to treat avapritinib concurrently with those drugs. In that three quarters of the ASM population, if bezuclastinib has a profile with significantly lower risk of hematologic toxicity, then to your point, that potentially opens up that concurrent treatment of bezuclastinib with the AHN-directed therapy. Obviously, Cogent Biosciences is very interested in that patient population. We are running what's sort of seen as a side cohort or a protocol separate than the registration APEX study where we're allowing concurrent dosing. While that cohort won't be ready at the time of the APEX top-line results, we're hoping to have many of those patients dosed concurrently by the time we would be approved as part of a commercial strategy. How much larger would the market be, including those patients versus excluding? About three quarters of patients with ASM have SM AHN as that subgroup. That's 75%. There are patients with SM AHN where you make a tough choice and you say the SM is the most challenging part of my disease today, so I'm going to take avapritinib and not the AHN-directed therapy. It's probably not all 75%, but I think a pretty healthy chunk of that patient population would want to try to achieve therapeutic treatment for both of the diseases that they're fighting at the same time. Got it. The readout for that's coming up pretty soon. The readout for APEX, the sort of the pivotal study, is coming up by the end of this year. Got it. Jumping over to GIST, certainly there's been a handful of, I wouldn't call them outright failures. They've had minor successes in areas of GIST for these KIT inhibitors. You're doing it differently again because of differences in the tolerability profile. They kind of stuck to monotherapy later lines. You're actually stepping into combination therapy in the second line. Could you talk to us about the upcoming trial and what the differences are and what we could expect to see? Right. Great question. This really again gets back to science. Fundamentally, what is driving disease progression or tumor growth in GIST patients who have progressed after trying imatinib, which is an amazing drug, probably one of the biggest successes of our industry? Patients whose disease progresses after imatinib typically show mutations in the KIT gene in either the activation loop and/or the ATP domain, so exon 13, 14 and/or exon 17, 18. If you look at the history of KIT inhibitors that have been developed across avapritinib, a drug known as ripretinib, which is now approved in the fourth line for GIST, sunitinib, regorafenib, maybe most recently bezuclastinib, there really is no individual molecule that can effectively cover all of those mutations. While we agree with you, there's been a couple of notable failures recently, probably the most notable are the Phase 3 Trial of avapritinib versus regorafenib in the third line, and then more recently the Phase 3 failure of ripretinib versus sunitinib in the second line. Essentially, what those trials showed is that when you take a drug that covers half of the mutations and you measure it against another drug that covers the other half of the mutations, they have a very similar median progression-free survival, and therefore the new drug, the tie goes to the incumbent. The new drug won't get approved. Our strategy is to acknowledge the science behind this disease and to acknowledge that bezuclastinib, if we ran it as a similar trial design, bezuclastinib versus sunitinib or versus regorafenib, we would probably meet the same fate, where our drug is highly effective at treating patients with mutations in exon 17 and 18, but really not effective at treating patients with exon 13, 14 mutation. Conversely, sunitinib, which is the current standard of care in the second line, it is now a generic drug. It's been on the market for over 20 years. That drug is very effective at treating patients with 13, 14 and not with 17, 18. Instead of going forward with a similar design that has failed in the past, we chose a different clinical strategy, and that's enabled by the selectivity of bezuclastinib because unlike avapritinib, unlike repretinib, we are a selective KIT inhibitor. We don't bring in activity against the other Class III RTKs. It enables us to combine with sunitinib. The safety profile of bezuclastinib in combination with sunitinib does not noticeably worsen the safety profile that sunitinib has as a single agent. The benefit you get from activity against the disease is that the combination of bezuclastinib and sunitinib can cover all of the known KIT secondary resistance mutations. The design of our trial is the combo of our drug with sunitinib in one arm, covering all of the mutations compared to sunitinib alone in the control arm, which is really only effective at covering patients with about half of the mutations. It would be reasonable that efficacy should be improved. The question is, is the tolerability burden acceptable? I think that's a fair question. We've presented data to date on 60 patients with GIST with full dose sunitinib and bezuclastinib, and across the safety profile, what you see is a very similar combination safety profile of bezuclastinib and sunitinib to the sunitinib monotherapy safety profile. As much as we would want, we don't solve the tolerability issues of sunitinib. Those are probably most notably high-grade hypertension, fatigue, some of the GI and skin toxicities associated with pan kinase inhibitors. That will continue as part of the sunitinib safety profile. What bezuclastinib adds on top is sort of similar to what we've already talked about in the mastocytosis population. Maybe some of these patients will grow additional white hair. It's possible some of these patients will see fluctuating LFTs. Now we bring it back to this patient population from a risk-benefit. These are metastatic cancer patients who are looking to extend their survival. Even more so than in the patient population of non-advanced mastocytosis, refractory metastatic GIST patients I think are definitely going to be okay with the cosmetic effects of white hair if it can translate into longer survival. The update for that's coming in before the end of this year as well. That's right. I know that I'm getting ahead of myself here because we have to see this data first. In theory, if it's covering all the mutations, depending on the efficacy data you see, is this something that could be moved into combination into a frontline trial against the current standard, or would that be a heavy lift? It's definitely a heavy lift. People have speculated about this. Here's what we don't know. Imatinib, as I mentioned before, is the current standard of care in frontline. That trial was run in the late 1990s, very early 2000s, and the quality of care has advanced significantly since then for all cancer patients, but of course for first-line GIST patients. What we don't know is how good and how long would the PFS look for imatinib in the control arm in 2027, which would be when you'd be running a Phase 3 trial. I think folks have speculated that might be 30 months. It could be longer. A first-line trial might look like more than 1,000 patients. It might look like five, six, seven years. A different strategy for a company like Cogent Biosciences and for a drug like bezuclastinib might be to generate some clinical data in a group of first-line patients as opposed to a formal registration trial, which would be, as you mentioned, a pretty heavy lift. Got it. Thank you very much for your time. Appreciate it. I look forward to chatting again soon. Awesome. Thanks, David.