Cogent Biosciences, Inc. (COGT) Earnings Call Transcript & Summary

Good morning, and welcome to Cogent Biosciences' webcast. I will now turn the call over to Christi Waarich, Senior Director of Investor Relations.

Thank you, operator. Today's call will review the positive results from our Phase III PEAK trial in GIST. These results were shared in a press release earlier this morning. You can find the press release in the Investors and Media section of our website at cogentbio.com. Before we get started, please be reminded that remarks made during this webcast may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our planned regulatory submissions and timelines, future presentations of clinical data and financial projections. Please refer to our most recent filings with the Securities and Exchange Commission for a full discussion of risks and uncertainties associated with our business. With that, it's my pleasure to turn the call over to Andrew Robbins, President and Chief Executive Officer. Andy?

Thanks, Christi, and good morning, everyone. As I'm sure many of you have already read this morning in our press release, today is a historic day for Cogent Biosciences, and more importantly, for patients fighting GIST around the world. After analyzing the results from our PEAK Phase III trial of bezuclastinib in combination with sunitinib, I am very pleased to share that the results show a clear, dramatic, statistically significant advantage over sunitinib alone in patients fighting imatinib-resistant or intolerant GIST, as measured on our primary endpoint, progression-free survival. With a 16.5-month median PFS, a 46% objective response rate and a hazard ratio that shows a 50% reduction in the risk of progression or death for these patients, the profile generated by the bezuclastinib combination has positioned it to rapidly become the standard of care for second-line GIST patients. Taken together with the results previously reported from the SUMMIT trial of bezuclastinib in non-advanced systemic mastocytosis patients, bezuclastinib has emerged as the best-in-class selective KIT mutant inhibitor in a $7.5 billion global market with a path toward approval in both patient populations by the end of 2026. Now here on Slide 3, I'm very happy to introduce both Dr. Jessica Sachs, Cogent's Chief Medical Officer; and Dr. Neeta Somaiah, our special guest today, who is the Department Chair of Sarcoma Medical Oncology at the MD Anderson Cancer Center and a key investigator on the PEAK trial. Dr. Somaiah will take us through the results of the PEAK trial and join us for Q&A at the end of the call. Before we get to the peak results, here on Slide 4, I would like to remind us all of the current treatment landscape for patients with imatinib-resistant GIST. While imatinib demonstrates very impressive durable responses in the majority of first-line patients, the current treatment options for patients who develop resistance to imatinib have demonstrated much more modest clinical activity. There are currently 3 FDA-approved products for the treatment of refractory GIST, including sunitinib, regorafenib and ripretinib. Each of these products garnered an approval based on a pivotal trial, which demonstrated median progression-free survival of 5 to 6 months and drove responses in less than 10% of patients on those trials. Sunitinib was originally approved for second-line GIST in January of 2006 and has remained the standard of care around the world in this patient population for the past 20 years. With advances in quality of care, it is now generally associated with an 8-month median progression-free survival and an expectation of approximately 20% of patients demonstrating evidence of response. Keeping this current treatment landscape in mind, I'd now like to invite Dr. Somaiah to provide us with some background on this disease as well as describe the PEAK trial and the exciting results we have to share today. Dr. Somaiah?

Good morning, everybody. It is my absolute pleasure to be walking through the next couple of slides about the GIST overview and the topline results. So moving on to Slide #6. So gastrointestinal stromal tumor is a rare disease, but it is a common sarcoma that I see a lot of, more than 6,000 new cases diagnosed annually in the United States. And over 80% of GIST tumors express KIT mutations, which is typically in exons 11 and 9. They can occur anywhere in the -- all along the GI tract from the base of esophagus all the way to the rectum, but majority of these tumors arise in the stomach and following that in the small intestine. While imatinib, as Andy has said, provides disease control in the frontline setting for majority of patients, at least 60% of patients with advanced GIST will develop resistance within 2 years. And this is primarily due to mutations in the ATP binding site of exon 13 and 14, or as we call it, the activation loop, which is exon 17, 18. And as you have seen, while there are additional FDA-approved sequential lines of therapy that includes sunitinib, regorafenib and ripretinib, they are effective only against the subset of -- effective only in a subset of patients, and this is because their activity is limited to a subset of the resistance mutations that we see and eventually disease progression results because of clonal heterogeneity. Next slide. So this is the key slide that talks to -- that excites us as investigators because there is a great rationale for combining bezuclastinib and sunitinib. So as you see here, no single TKI inhibits all the KIT mutations when we look at imatinib, regorafenib, IDRX-42, ripretinib and sunitinib. They have activity against the primary mutations, exon 9 and 11. But when you look at the slew of secondary mutations that can arise, we have regorafenib, ripretinib are skewed more towards the activation loop activity, including IDRX-42. And sunitinib is the only drug that we have that has strong activity against the ATP-binding pocket, especially exon 13. So when we combine bezuclastinib -- and bezuclastinib has more focused, targeted activity on the activation loop exon 17 and beyond mutations, so when we combine both of them, you do have a broad inhibition that covers the full spectrum of secondary mutations. Next slide. So moving on to the trial design of the Phase III portion of the PEAK study. Patients were randomized 1:1 to receive either bezuclastinib 600 milligrams once daily, along with sunitinib 37.5 milligrams once daily, and there were 204 patients on that arm. And sunitinib alone, 37.5 milligrams once daily, and there were 209 patients randomized to that arm. Crossover was allowed following blinded independent central review, confirming progression of disease. So it was a very -- actually, it was a great design. So it was a simple to accrue to study. Hence, the accrual did proceed fairly quick. The patient -- key patient eligibility included age greater than 18 years. Patients needed to have locally advanced unresectable or metastatic GIST with at least 1 measurable lesion per RECIST 1.1. And they had to have documented disease progression prior to entry or documented intolerance to imatinib, which is rare, but we do see that a couple of times. So the primary endpoint was progression-free survival per blinded, independent central review. The key secondary endpoints were objective response rates per BICR, overall survival. And other secondary endpoints included progression-free survival per the investigator assessment, disease control rate, time to response and duration of response. Moving on to the next slide, Slide 9. Here, we can see the Part 2, which is the Phase III portion of the PEAK study, the population that was represented in this part. When you look at patient demographics, when you're looking at the sex, male versus female, median age and the ECOG performance status across the 2 arms was fairly balanced, slight male predominance. The median age was around 63, 64, and majority of patients were between ECOG 0 and 1. When looking at the distribution because this study was open across multiple regions, there was a fair distribution among both the arms between -- of course, majority of enrollment was in North America and Europe, and the numbers were lower in Latin America and Asia Pacific. Other baseline characteristics, the KIT mutation profile, so the KIT mutation was per the molecular pathology report that was any time prior to enrollment in the study. When you look at exon 11 only, majority of the patients fell into that bucket because that is the most predominant GIST type. Then, following that was exon -- any exon 9 mutation. And then there were patients who had neither reported exon 9 or 11, and some had reported other mutations in KIT. And then, some had no mutations either detected or not reported because it was not a requirement prior to entry. Looking at the treatment -- prior treatment history, imatinib intolerance, as I had mentioned, is fairly rare, but was balanced across the 2 arms. Prior radiotherapy, now radiotherapy is not used often, but we use it sometimes for localized treatment for -- if they had focal progression on imatinib, they might have received this, but fairly low numbers. And then prior anticancer surgery. I think majority patients might have had this for their initial presentation or after response to imatinib, but they did have progression at the time of entry. Moving on to Slide 10, which is the most exciting slide. It shows that the combination of bezuclastinib and sunitinib extends PFS with a 50% reduction in the risk of progression or death. As you can see from these Kaplan-Meier curves, once the curves separate, which they separate early on, they seem to run parallel and remain separated. The median PFS was 16.5 months for the combination arm. And for sunitinib alone, it was 9.2 months with a hazard ratio of 0.5 and a p-value of less than 0.001. And this was the primary endpoint. Moving on to the next slide. This is also very exciting for us investigators. The response rate in the second-line setting for the combination was almost 46% for bezuclastinib and sunitinib and 26% for sunitinib alone. The difference in the overall response rate, the P value was less than 0.0001. And looking at complete response for the -- was higher in the combination arm with a 6.4% complete response rate for the combination and the 39.2% was a partial response rate. And the reason I say this is exciting and important, we have seen, and there is data for treatment with imatinib. When they have focal progression or some residual disease, we do normally take them to surgery or have other means for focal-targeted control of focal progression. And those patients derive actually a much longer PFS or a time on imatinib that eventually extends their survival. So if we can extend that same high response rate to the second-line setting in patients who have developed resistance, I think it is quite possible that we will be offering them similar local control measures for focal progression that will allow them to stay on this combination for much longer. And this was not allowed as part of the study. However, in clinical practice, we might see that. And now moving on to the next slide, it is important -- again, you're using a combination, so I think everybody would be wanting to know whether it was well tolerated or not. What we see here is the combination is generally well tolerated and the safety profile not very different from sunitinib alone. The incidence of treatment-emergent adverse events and treatment-related adverse events was similar between the treatment arms. And you can see here, there was slightly numerically higher grade 3 treatment-related adverse events in the combination arm and also the serious adverse events. But when you look at -- there were no treatment-related deaths in the combination arm, 1 on the sunitinib-alone arm. And reductions of either drug due to the treatment-related adverse events were around 56% for the combination and 44% for sunitinib alone. And treatment-related drug reductions required for adverse events. It's not uncommon in our practice of treating patients with GIST. So that is acceptable. What is good is that the discontinuation of study treatment due to these adverse events was fairly low on both arms. And if you look at the adverse events that lead to discontinuation of either drug in more than 1 patient, this is mostly neutropenia in 2.9% patients; ALT/AST increased, 1.5%; and diarrhea in 1%. Moving on to the next slide. This is a table that lists all the grade treatment-emergent AEs that occurred in more than 20% of patients. And you can see it's fairly balanced between both the arms. The reported frequency was higher than 15% for the combination arm included ALT/AST increase, taste disorder and hair color changes. So that, of course, the ALT/AST increase are the only ones that had a higher grade. The others are usually low-grade events. What is very interesting is the treatment-emergent AEs reported less frequently in the combination arm. So there were ones that were less frequent in the combination arm, included plantar -- the PPE, plantar-palmar erythrodysesthesia, which is also known as hand-foot syndrome, stomatitis and thrombocytopenia. And these are frequently associated with sunitinib alone, and we can see lower rates in the combination. And hence, the safety profile of bezuclastinib combination is generally consistent with the known safety profile of sunitinib alone, and there were no new risk factors that were identified with the combination. Moving on to Slide 14. Here, we can go a little deeper into the grade 3 or higher TEAEs that occurred in more than 2% of patients. And as you can see, they're balanced across the arms. Majority of the Grade 3-plus TEAEs were reported at a similar rate in both the arms, except for ALT/AST increase and anemia that were reported. Those were the only 2 that were higher in the combination arm. And as you can see that, there are some that are higher in the sunitinib alone arm as discussed previously. There was no increase in the frequency of severe events observed in the combination arm for hypertension, neutropenia or diarrhea. And the ALT/AST elevations that led to bezuclastinib dose reductions in 12.7% of the patients, and only 1.5% of patients discontinued. So all Grade 3 ALT/AST events resolved, and no Grade 4 elevations were reported across the study. So again, discontinued -- I mean, most of the times, when you reduce the dose, we were able to get through the higher-grade LFT elevations. And then, I will move on to Slide 15. And the next 2 slides are going to be my patients of mine that are -- demonstrate nicely the efficacy of this combination, and then, I'll turn it over to Andy after. So this particular patient is a 66-year-old male with metastatic GIST. So he was diagnosed back in 2020. He had -- I mean, I call it, he had adjuvant imatinib. It was a little advanced at presentation, but imatinib worked, and he underwent debulking surgery in 2022 because there were some areas that were still residual. And thereafter surgery, imatinib was reinitiated. But unfortunately, he had disease progression around September-October 2023 with multiple peritoneal nodules. And this is the time, he was consented on to the PEAK study. He was, otherwise, well. He had some obesity, hypertension, anemia at baseline, some elevated ALT and creatinine at baseline, and he had noted some abdominal distension. He also had long-term leg swelling, some back pain and GERD, but all were well controlled. He enrolled on the study. And as you can see from this graph, right at the first restaging at Cycle 3, he was noted to have a partial response, which is very exciting. The images here, of course, are only showing the first -- the 2 nodules that you see there, but he did have multiple nodules in the abdominal cavity. And then, at Cycle 9, which is somewhere around April of 2024, he achieved a complete response, and that complete response continues until Cycle 26. He actually was on both full doses for quite some time, and sunitinib was reduced to 25 milligrams, I think, only recently. Moving on to the next slide. This is a 69-year-old gentleman who was diagnosed with GIST back in 2015. He did have some progression, had surgery in 2021. The imatinib dose was increased thereafter, but then he continued to progress and was enrolled in the PEAK study around end of 2022. This gentleman had a partial response achieved at Cycle 5, but the reduction in tumor was noted right at the first restaging. And that partial response has continued slowly to increase. And this gentleman is now on Cycle 36. He did have a dose reduction for sunitinib down to 25 milligrams as well, but has continued on the 600-milligram dose of bezuclastinib. He did have a dose interruption because of a Grade 3 anemia, neutropenia at one point. But after the dose reduction of sunitinib, he has continued. And as you can see, the treatment-related adverse events with the maximum grade reported are also on the slide. But again, nothing unusual that we don't encounter with sunitinib alone. And I think with that, I will pass it on back to Andy, and I will be available for questions thereafter. Thank you very much.

Excellent. Excellent. So thank you, Dr. Somaiah, for your great review of our data, including maybe most importantly, your own experience treating patients with the bezuclastinib combination. It's really just amazing to see patients responding so dramatically, and that with this combination, we may have to start measuring patient duration in years instead of months. So now turning to Slide 17. I'm going to pause here and emphasize a few points that Dr. Somaiah covered in her presentation. So first, the clinical activity of the bezuclastinib combination outperformed even our loftiest expectations for this trial: 16.5 months of progression-free survival, including a 50% reduction in the risk of progression or death compared to the current standard of care, a 46% objective response rate with 13 patients on the combination achieving a complete response with no evidence of original target lesions. A safety profile across 400-plus patients, which uncovered no unique safety risks of adding bezuclastinib to sunitinib. And for some known sunitinib-related adverse events, including, as Dr. Somaiah walked through, PPE, stomatitis and thrombocytopenia, evidence that the combination treatment may even show signs of reduced frequency and severity of these adverse events. Second, as we continue to review and analyze these amazing results, it's important to note that 73 of the original 204 patients originally randomized to the bezu combination arm remain on combination therapy as of the data cut. When we project their treatment course, we estimate that the mean treatment duration for patients on bezu combination is expected to exceed 19 months. The clinical benefit and durability of this novel combination continues to impress. Third, as we look forward, the Cogent team is already working diligently to put together a new drug application for bezuclastinib in GIST with plans to complete that submission in the first half of 2026. If granted priority review, bezuclastinib could be approved for GIST patients as early as the second half of 2026. But in the meantime, Cogent is committed to providing access for the bezuclastinib combination for GIST patients in urgent need as part of our already active no-cost bezuclastinib expanded access program. There are already several expert GIST physicians around the country, including Dr. Somaiah herself, who are participating in this program. Additional information about eligibility can be found on the bezuclastinib patient assistant website. Now on Slide 19, I'd like to remind everyone that we are still just crafting the beginning of the bezuclastinib story. We are weeks away from the results of our third pivotal study, the APEX trial in patients with advanced systemic mastocytosis. We plan to share those results in December and hope to demonstrate that potent inhibition of the KIT D816V driver mutation without off-target kinase inhibition and without CNS penetration can lead to robust clinical responses while sparing side effects that are associated with the current standard of care, including frequent edema, cognitive impairment, frequent high-grade hematologic toxicity and a demonstrated risk of intracranial bleeding. Separate from APEX, we are also on track to submit our first bezuclastinib new drug application in December based on results from the SUMMIT trial in non-advanced systemic mastocytosis patients. We're excited to have 2 oral presentations at ASH during which full results from the SUMMIT trial will be presented as well as the opportunity for Cogent to describe for the first time our novel, potent, selective JAK2 V617F inhibitor, which will also be shared at ASH. Certainly, a busy finish to 2025 for Cogent. And now finally, on Slide 20, I would like to take a look at the big picture as it relates to bezuclastinib. Five years ago, we acquired this product, informed Cogent around the idea that bezuclastinib's molecular profile, a potent and exceptionally selective KIT mutant inhibitor that did not cross the blood-brain barrier was ideal to develop and position as the best option for patients with both systemic mastocytosis and GIST. Now, with the results of the SUMMIT and PEAK trials, this vision is coming into focus. The global opportunity for these indications is north of $7.5 billion annually. And with very limited competition, Cogent is poised to transition into a rapid growth commercial stage company in 2026. With a strong patent protection plan through 2043, we are confident and excited at the opportunity in front of us, and we'll continue our focus on high-quality urgent execution against our goals. Before I open up the call for questions, I'd like to do a few things. I'd like to recognize the amazing team of Cogent professionals that we have assembled over the past 5 years who have worked so hard on behalf of patients to put us in this amazing position today. I'd also like to congratulate the PEAK investigators around the world, including Dr. Somaiah, who has graciously volunteered to join us today for their help conducting a PEAK Phase III trial that has delivered an exceptional result for GIST patients. And finally, and probably most importantly, to the GIST patients and their families who trusted in Cogent in the PEAK study, you did it. You are amazing, and we are forever grateful for your courage and bravery. So operator, we are now ready to open up the line for questions.

[Operator Instructions] Our first question comes from Anupam Rama with JPMorgan.

Congrats on the data. Not really sure what to ask, even given this mic drop. But I'll ask one to the KOL here, which is, how do you think about incorporating this combination into your treatment paradigm given everything you know today? And would you consider using it in maybe even more refractory patients like third or fourth line, given the unmet need? And then one for the company, just you mentioned the EAP program, can you give us a sense of what demand has been like here in the early innings? And where do you think that could go?

Great, Anupam. Thanks for the question. And I'll take the second one first, and then, I will ask Dr. Somaiah to opine on how she thinks she's going to use the combination. So with regards to the EAP, we opened that, I think, this summer officially, and we have several, several patients who have already taken advantage of the opportunity to get the combination. But to be fair, until about 1.5 hours ago, those patients were signing up based on, I think, the advice of the investigators who already believed the trial would be successful. I think based on our announcement this morning, we expect many, many more patients might be interested in trying to figure out how to get access to this combination based on these results. So we've seen very good early demand for the combination. I would imagine we're in a different conversation now with the results of the PEAK trial that we've shown this morning. So Dr. Somaiah, do you want to opine on maybe how you think about using this combination? I'll expand on Anupam's question, certainly in the second line, but across the treatment landscape for GIST patients, both later lines and then even potentially, if you want to comment on, can you imagine using this in any first-line patients?

Well, okay. I'll take all those questions. So firstly, to follow up on your EAP, we have that open, and we were allowed from our institution initially only 10 patients, and we enrolled that so far. So we're going back to ask for increasing the enrollment to at least 30 at our sites. And we are enrolling not only second line, but later lines as well, bringing to the point that do I -- where do I foresee this? So firstly, once regulatory approval is obtained, I think this will become the preferred standard second-line treatment option for patients who are progressing on imatinib. There are still ongoing clinical trials in the phase -- in the second-line setting, and I think they will continue to enroll, as we learn more about the GIST mutation and treatment landscape. But I don't see any reason why this would not be adopted as the standard second-line option after approval. To the point of what beyond second line, I do think this combination is very effective even beyond second line. I mean, I know we will hopefully later see data on the crossover part of the study. I do think it works. And we have data from the initial Part 1 of the PEAK study that shows activity in patients, and those patients were not second line alone. A lot of my patients were on that part of the study as well who really benefited beyond second line. So I think it is really important to look at that population. And I hope with the expanded access program, you'll be able to generate more data in the later line setting so that patients will be allowed to get on this combination even after the second line because we have a lot of patients who are past second-line treatment right now who should get access to this combination.

Our next question comes from Michael Schmidt with Guggenheim.

It's Paul on for Michael. Congrats on the terrific results today. My first question is on safety. So could you provide any additional details on how the bezu-related adverse events versus SUTENT-related adverse events were adjudicated in a combo? And how that informed dose modifications for one versus the other on the study? And then my second question is, you mentioned the 19 months duration of treatment, which is longer than the median PFS that you're seeing. How are you projecting that number? And is there a particular subset of patients who are seeing more outsized benefits who are driving some of that duration? How confident are you that, that will translate to the real-world setting?

Great. Thanks, Paul. And I'll do my best to take these, and then, I'll ask Dr. Somaiah if she has anything to add. So with regards to during the conduct of the trial, how investigators determined dose modification for the combination drugs, the final answer is it was left up to the investigator locally with the patient to determine the right course of action and right care. Of course, Cogent did our best to educate -- Dr. Somaiah doesn't need our help, but across the world, physicians about what you might do if you see a specific adverse event or not. I think we are now in a very different position based on the results of the trial. So I'll give you an example. You can see in the slide that Dr. Somaiah walked through that one of the most frequent, albeit still at only 2% of patients, reasons for discontinuation of the combination bezuclastinib-sunitinib was for neutropenia. But then, if you move and look at the rates of neutropenia between the single-agent sunitinib arm and the combination arm, you'll see that the rate of all grades and Grade 3 is identical between sunitinib and sunitinib-bezuclastinib, which I think speaks to going forward in the future, maybe less likelihood of discontinuing bezuclastinib in a patient that presents with neutropenia. So, potentially, based on the results that we've shown in a very robust Phase III setting, maybe more likelihood to first reduce or discontinue sunitinib and maybe leave bezuclastinib in place to see if that's a possibility. So, hopefully, that's helpful. Number two, with regards to the mean duration of treatment of 19 months, I think, when you see oncology products that have long median progression of survival, you typically see a minority of patients getting very, very, very durable benefit. So 2 of the patients were described by Dr. Somaiah today with currently ongoing after 2 years and after 3 years. And so while they're not constrained to the responders, what we do see is that patients that have a response tend to be very durable. And so what we're doing here is projecting not the median duration of treatment, but the mean and that, that percentage of patients, call it, 25%, 30%, 35% of patients who get past 2 years and 3 years are really driving that utilization of the mean treatment duration, pulling the average, the mean much further than the median of progression-free survival. So I don't know if -- Dr. Somaiah, do you want to speak on anything else about how you determined dose modifications for the individual drugs on the trial and then maybe your thoughts about how that could change now that we have the results of the study?

Yes. No, I do hope it does change. So yes, when you -- on study, I think when there is a side effect, it's difficult to -- when you're assigning and the patient is on both drugs, I can imagine why people had assigned the relationship to both drugs in most places. But when you look at the side effect profile, it is clear. So majority of the times, I have not had to actually discontinue drug. I was just able to reduce the sunitinib dose down to 12.5 in some of the patients that were -- that had cytopenias, which was one of the reasons of needing to hold drug. We were able to continue patients with that lower dose sunitinib and bezuclastinib. So as you saw, of course, I think the liver function increased. That's one, if its high, might need reduction of both drugs because you don't know which one is the major driver. But for majority of the other side effects, I believe now in clinical practice, people will make an attempt to lower sunitinib first before lowering bezuclastinib. Also, I think -- and the good news is we did not see a drop in efficacy and that, I think, points to perhaps sunitinib, even a lower dose, being effective against the exon 13 resistance mutations and not affecting the efficacy much. So again, we'll see more once more data in the secondary mutation space comes out, but I think we should not have as many both drug dose decreases or discontinuations in clinical practice moving forward.

Our next question comes from Andrew Berens with Leerink Partners.

This is Amanda on for Andy. Congrats on the data. We'd like to get more information on the breakdown of patients that have the KIT exon 13, 14 mutations versus the 17, 18. Or is there any color that you can provide on these segments of patients?

Yes, it's a great question. And the simple answer is there's just a ton of emerging data from this trial that we're going to continue analyzing and be able to bring forward at a medical meeting. And one of the things we're doing on purpose is trying to preserve a lot of those results so that Dr. Somaiah and her colleagues get a chance to stand at a -- in a big room with a lot of people at a medical meeting in the future. What I can tell you, though, is we have looked preliminarily at it. And maybe most importantly, when we look at the baseline characteristics in the secondary resistance mutation genotypes, the population of the PEAK trial looks highly analogous to the population of the INTRIGUE study. So I think from a frequency of 13, 14, 17, 18, the mix across those 2, we're going to be looking at a dataset that we can do a nice job comparing, and we will have robust sample sizes from each of those genotype subgroups. And then at a very, very high level, I think what's potentially most exciting about the future is the combination, as Dr. Somaiah nicely walked through on that, mutational coverage grid slide earlier in the presentation that the science of this combination is that when you give patients bezu and SUTENT combo, it should help all of the genotype subgroups. And I can tell you broadly, that's what the finding is going to look like. We're not constrained to an outsized effect in a small group of genotype. This combination is really going to provide benefit across all of the genotype subgroups.

Our next question comes from Sam Slutsky with LifeSci Capital.

Congrats on the great data. Just 2 for me. I guess, first, any thoughts on eventually going into a frontline study, just given how strong these data are in the second line? And then, on safety, obviously, adverse events like PPE, thrombocytopenia, stomatitis look better with the combo than with sunitinib alone. How much of that do you think is associated with the DDI where you do lower sunitinib exposure a little? And then for Dr. Somaiah, I guess, how appealing is it to lower these specific AEs with sunitinib such as PPE, thrombocytopenia and stomatitis?

Great. So, Sam, thanks for the questions. And again, I'll kind of dive into that first one. But Dr. Somaiah, I'm curious to hear your thoughts on essentially all these questions. So what I can tell you is, obviously, imatinib is a very, very effective first-line therapy for GIST patients. I think we all have heard the story of Gleevec. It's probably one of the most impressive drugs ever developed in the drug industry from 25 years ago. But we have already had conversations, not since this data, but even leading into this data with investigators on both sides of the ocean interested in exploring the utility of bezuclastinib as a potential combination drug in the first-line setting. I think what we can sign up for is generating data in potentially smaller exploratory groups of first-line patients, doing something like bezuclastinib combinations in a handful of first-line patients to see what the activity looks like. I think there's really interesting scientific questions around, would you use a bezuclastinib combination in exon 9 primary mutation patients, where maybe imatinib is not as effective as it could be in exon 11? But look, we're just digesting these data, and those are really going to be fun conversations to have with the GIST community moving forward. On your second question around the -- what's going on, and how does adding bezuclastinib make some of these side effects look improved, which is obviously exciting for patients? I do think that there is a nice scientific hypothesis about that CYP3A4 drug-drug interaction that we reported a couple of years ago, where in combination with bezuclastinib, sunitinib exposure gets, I'm going to call it, smoothed out a little bit. And I think Dr. Somaiah has already talked about this during her comments. We, of course, always love the idea of some of these tolerability challenges for patients like PPE and stomatitis specifically that patients obviously feel getting less frequent or maybe less severe. But maybe I'll turn it to Dr. Somaiah for her thoughts about what the dynamics might be there and whether that's clinically relevant in her practice.

Perfect. Yes. And I'll take the BDI, the side effect question first, and then, I'll move on to the first-line setting. So with regards -- I think with sunitinib and just these TKIs that follow imatinib, the palmar-plantar erythrodysesthesia, the PPEs, is one of the most problematic quality of life affecting side effects. So -- hypertension is also a problem, but people don't feel it unless it goes really high. Liver function abnormalities, it's standard practice that we monitor these every 2 weeks initially because that's when we see it, but patients don't tend to feel anything. So reduction in the PPE actually is quite a good effect of the combination that allows patients to stay on it long term. And even with sunitinib, as I said, most often, we're able to control that side effect by dose reduction. But, of course, with the combination, it allows -- it reduces the growth of these tumors, so allows patients to stay on the combination for much longer even with the lower dose of sunitinib. So I think that is a definite advantage. And I think the DDI reported is probably what is driving that. With regards to the first-line setting, I do think so this combination in the frontline might be a bit challenging just because imatinib works very well and -- looking at sunitinib plus bezuclastinib frontline, would only be possible if the patient had really bulky disease and already known secondary mutations with -- that we detected maybe perhaps in a liquid biopsy. But, otherwise, I think imatinib will still be frontline. Now, bezuclastinib has the benefit of being similar to imatinib in the sense it does not affect wound healing and patients can still go to surgery even if they're on the bezuclastinib. So combining bezuclastinib in the frontline setting with imatinib is a thought. And I think probably it will take a little bit more of patient selection because there are patients who have primary exon 17 mutations or certain combinations of mutations upfront. But if we are able to do that without increasing toxicity too much, I think that is definitely reasonable.

Our next question comes from Chris Raymond with Raymond James.

Congrats from us as well on this really groundbreaking data. Maybe first for Dr. Somaiah. Just a question for those patients that you have that are maybe just starting SUTENT that haven't progressed yet, just with this benign and maybe even improved safety profile of the combo, would there be a scenario where you would add bezu for those patients already initiated with SUTENT monotherapy? And then maybe for the company and for Dr. Somaiah. So -- I'm hearing you guys talk a lot about a potential dose reduction regimen here with SUTENT. This sounds a little bit like maybe there would be a need here for -- to develop some kind of formal maintenance regimen. Any sort of plan there? And congrats again.

Thanks, Chris, for your question. So, again, to your second question, I guess, my quick answer is we are literally like a couple of days into analyzing this data. And there are -- based on the results, like 100 questions and hypotheses we have about how can we move this forward as a standard of care, what can we do to help the GIST community, how can we partner with folks like Dr. Somaiah to do additional studies to really dial in the exact way we want to use bezuclastinib combo in these patients going forward. So I think yes to all your thoughts. I'll ask Dr. Somaiah to opine specifically on your question. And then with regards to the addition of bezuclastinib to sunitinib, one thing that Dr. Somaiah has already referenced, and we don't have these data yet, but we will bring them to light is part of the trial included a crossover where you add bezuclastinib for patients who have formally progressed on sunitinib, and we're going to get those results to see the performance of those patients. But I think your question might be why would you wait until somebody progresses who's currently receiving SUTENT, why not just add the bezuclastinib right away, both today on EAP and then in the future in a commercial setting for sort of that installed base of patients? I personally think that's a really good idea, but maybe we'll turn it to Dr. Somaiah to see what she might do in her practice.

Yes. It's a good question. And I think we need -- as the data evolves, I think that answer will get clearer. So what I will do currently for my patients, it would be very patient-dependent because it is also dependent on the bulk of disease. We get a sense of how long these patients are going to potentially stay on this monotherapy. And as I said, I had a lot of patients that crossed over and derived benefit after crossover as well. So again, we have to look at the data to see. And, of course, I think the OS, because the patients did very well, will take a long time to read out. But we'll have to look at the overall benefit of that sequential. So -- I mean, if the patient is on SUTENT and is tolerating it well and responding and doesn't have very bulky disease, I might not, might just continue them on it. Whereas if it is easy and it's available and there is access and they have bulky disease, it might make sense to add the combination or add them back on bezuclastinib right away. Now, the point is when they're on sunitinib, they don't stay on it long enough. So eventually, we will have to add the bezuclastinib. What I'm getting at is I don't know if early addition has benefit -- has a significant benefit or not. And I think, as I said, looking at individual patients, if it's a patient that I want a better response, so I can take them to surgery, those are the patients I would want to add them -- add on the second drug right away. And as we see with no worsening of side effects, I think there might be a lot of investigators who would do that or a lot of treating physicians who would do that.

Okay. I think we're going to have time for one more question. And before we get to it, I just want to recognize Dr. Somaiah for her willingness to be with us very early to describe this very exciting data. It's incredibly helpful to have somebody who treats patients and is a deep expert to help us put this data in context. So thanks, Dr. Somaiah, and now, I think we'll take one more question and then wrap the call for this morning.

Our final question comes from Clara Dong with Jefferies.

Congrats on that really remarkable data. So one for Dr. Somaiah. How do you expect the mean treatment duration of over 19 months to translate into real-world practice from your perspective, maybe where factors like dose modifications and patient adherence also come into play? And then also a question for Andy. You referenced a $4 billion market opportunity globally for GIST. Maybe could you walk us through the key assumptions behind that figure, like patient population sizing and pricing, et cetera?

Sure, sure. So thanks for the question. I'll take the first one -- or the second question first, and then, maybe we can hand it to Dr. Somaiah to talk about her experience treating patients and durability. So when we talk about the global opportunity here, we're really kind of focused on the United States and Western Europe. I think outside of those territories, of course, there's also potential upside from a commercial potential over time. But if we look at just the epidemiology, and Dr. Somaiah already referenced this in her comments, each year, there's about 6,000 new patients diagnosed with GIST. I think there's about 85% of those with confirmed KIT mutations. And then, each year, about 60% of patients develop resistance or intolerance to imatinib from the first-line setting. So that gives you, on an annual basis, around 3,000 patients as sort of classic second-line patients on an annual basis. The current -- or the most recent drug approved in GIST is ripretinib, or QINLOCK, which is priced at about $43,000 a month WAC pricing. And based on the estimates from the PEAK trial of around a 19-month average treatment duration, you can multiply those up to get to that global number of about a $4 billion market with essentially no competition. As we know, SUTENT was approved now about 20 years ago. It's a generic drug. There's nobody promoting it. And quite honestly, we need sunitinib as part of our combination for the scientific and biologic reasons that Dr. Somaiah has gone through. Bezuclastinib is an excellent inhibitor of activation-loop domain mutations and some of the primary mutations, but it does need an ATP domain mutation partner, of which sunitinib is the best one available today. So looking to launch this drug in late '26. I think there is an excellent opportunity for Cogent partnering with investigators around the world to really rapidly penetrate this market with bezuclastinib combination as the emerging standard of care. Maybe I will hand it over to Dr. Somaiah for her opinions about durability of the combination. Again, I think we walked through how we've calculated this 19-month mean treatment duration for patients on the study. We do think that there is going to be a very large fraction of patients who have these very, very long durable responses like the patients that Dr. Somaiah used to exemplify her experience treating in the case studies. So maybe Dr. Somaiah, if you want to add anything to that.

Yes. No, so again, of course, there are some patients who eventually will progress and will need to go on. But those patients who are responding and continue to respond, the response seems quite durable. The other interesting thing in my -- there were some patients who came off due to focal progression. And as I said, the study did not allow us to do focal treatment or maybe liver-directed therapy or a resection of the progressing lesion and continue them on it because when those patients went on to the next lines of therapy, the progression was much faster and patients really wanted to get access and go back to the combination again for at least more -- a more sustained control. They were actually doing better on the combination. And I'm just saying that from my personal experience. So it will be great to have this option available, and I think patients will stay on it. And as I said before, when you have a great response and a deep response, we will -- all investigators will figure out how to keep patients on it longer. And if we see some focal progression, how to treat it and continue therapy? With regards to compliance, of course, patients on clinical trial are a motivated bunch, so their compliance is always higher. However, I will say that patients, once they have progressed on imatinib, I think they do come to a realization because if they have not been compliant with their imatinib and had progression, they are -- I have this talk with my patients all the time, it's like come to grips with what is reality. And when they're struggling with why we'll have to take this all the time, and this and when they're actually progressing and they're dealing with what comes next, their worldview and their ability to stay on drug changes. So compliance second line and beyond actually is better than in the front line. Of course, it will be very important to ensure access to medications so that patients can continue getting access without big cost burden, and all of that will also play into their ability to stay on the medication long term.

This concludes today's conference call. Thanks for participating. You may now disconnect.