Good day, ladies and gentlemen, and welcome to the Relay Therapeutics frontline breast cancer update call. As a reminder, this conference call is being recorded. I would now like to introduce your host for today's conference, Mr. Pete Rahmer, Chief Corporate Development Officer at Relay Therapeutics. Sir, you may begin. Thank you, operator, and good morning, everyone. Thanks for joining us. We're excited to share our frontline breast cancer update with you today. You can access the press release from today, the slides we are reviewing, and a replay of this call by going to the investor relations section of our website. As a reminder, during this call, we will make certain statements that are considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including express or implied statements regarding our strategy, business plans and objectives, the expected therapeutic and clinical benefits of our product candidates, potential of our platform and our product candidates and progress timing, execution of our clinical trials. Such forward-looking statements are not guarantees for future performance, and therefore you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. We refer you to our SEC filings and on our website for a discussion of our risk factors. The forward-looking statements in this presentation speak only as of the original date of this presentation, and we undertake no obligation to update or revise any of these statements. I'm also joined here today by Sanjiv Patel, our CEO, and Don Bergstrom, our President of R&D. With that, I'll turn it over to Sanjiv. Thank you, Pete, for the introduction, and thank you all for joining the call at late notice. Today, we're going to share further data on our lead program, zovegalisib, zovega for short. A pan-mutant selective PI3Kα inhibitor, which has the potential to address three very large commercial opportunities. The first of these opportunities is second-line hormone receptor-positive, HER2-negative, metastatic breast cancer. Last month at ESMO TAT in Paris, we shared data from our pivotal trial dosed in this indication, which increases our confidence that we will be successful in showing clear differentiation from the current standard of care, capivasertib. As a company, we're all laser-focused on executing our pivotal trial, ReDiscover-2, which is recruiting patients globally as we speak. Today, we'll share data on the second of these large commercial opportunities in frontline hormone receptor-positive, HER2-negative metastatic breast cancer. We've been pleased to announce today that we've selected atirmociclib, Pfizer's selective CDK4, as the CDK combination partner for our first-line regimen with zovegalisib. The data we'll share today will show why we're very excited about this choice. As in heavily pretreated patients, the early efficacy and tolerability of the zovegalisib/atirmociclib triplet in median third-line patients is approaching being comparable to the standard of care in frontline patients. We know patients generally have worse outcomes as we move into later lines of therapy. This data gives us great confidence we'll be able to show clear differentiation when we move our triplet from these later- line patients into frontline patients and present the 40% of frontline patients who have a PI3Kα mutation with a much better treatment option. We plan to initiate our phase III frontline trial in endocrine-sensitive patients in early 2027, obviously subject to regulatory feedback. We're also pleased to announce today that we have a supply agreement in place with Pfizer to supply atirmociclib for our phase III trial and palbociclib for part of the control arm. Finally, in what's a very busy time here at Relay, in a few weeks' time at the ISSVA conference in Philadelphia, we'll share data from the third of these very large commercial opportunities, vascular anomalies, where we'll show approximately 20 patients' worth of efficacy data. Our hope is to show zovegalisib could offer a differentiated option for these patients. Right. Let's get into the detail of our disclosure today and focus on the frontline breast cancer space. This is a very large commercial opportunity, and there are approximately 35,000 frontline metastatic breast cancer patients across the major geographies that have a PI3K α mutation. They're served today by some very large billion-dollar brands. The recent Roche INAVO120 trial and its subsequent approval has shown that in PPI3Kα- mutated patients in the frontline, adding a PI3K α inhibitor to the standard of care CDK4/6 plus endocrine therapy doublet allows you to achieve greater efficacy manifested in both greater PFS and greater overall survival. However, the issue is that the tolerability profile of stacking a non-selective PI3K inhibitor with a non-selective CDK inhibitor leads to a profile that could be challenging for patients to tolerate for multiple years and has led to Dear Doctor letters being issued due to potentially life-threatening safety events. The goal of a next-generation triplet is to maintain the increased efficacy that has been seen for a PI3K inhibitor in the frontline by having a better tolerability profile that allows patients to maintain their dose intensity over multiple years. We hope to do that at Relay by combining multiple selective next-generation agents together that dial out the off-target toxicity. Our triplet will be anchored by a mutant-selective inhibitor of zovegalisib and a CDK4- selective inhibitor of atirmo. We believe this selective profile should drive greater tolerability, leading to greater efficacy. The data we report today from the triplet of zovegalisib, atirmociclib, and fulvestrant in median third-line patients gives us great confidence that we can hit this profile, and we're pushing to initiate a frontline trial in early 2027. We've deprioritized the other triplet cohorts we were testing given the step change nature we're seeing in the safety and tolerability profile of our atirmociclib triplet. This long-term tolerability that we're seeing of the zovegalisib- atirmociclib triplet will enable us to maximize efficacy in these patients. To cover the data and next steps in more detail, I'll hand it over to Don Bergstrom, President of R&D. Thank you, Sanjiv. We initiated dose finding of zovegalisib combined with atirmociclib and standard dose fulvestrant. We did observe an effect of atirmociclib on blood concentrations of zovegalisib. Atirmociclib increases the concentration of zovegalisib by about two and half-fold. A 150 mg dose of zovegalisib combined with atirmociclib leads to blood concentrations of zovegalisib that approximates the exposure we achieve at the 400- mg dose of zovegalisib combined with fulvestrant that we were testing in the ongoing ReDiscover-2 trial. Zovegalisib does not appear to impact blood concentrations of atirmociclib. We will prioritize moving forward with the 300 mg dose of atirmociclib, which is the dose Pfizer investigated in the positive FOURLIGHT-1 trial and is currently investigating in the ongoing FOURLIGHT-3 frontline trial. We will disclose data from 62 patients treated with the triplet of zovegalisib plus atirmociclib plus fulvestrant with a median follow-up of 7.4 months. Patients were dosed with doses of zovegalisib between 100 mg and 200 mg BID and doses of atirmociclib between 100 mg and 300 mg BID, all with standard dose fulvestrant. We are not reporting data on patients treated at the 200 mg dose of zovegalisib combined with the 300 mg dose of atirmociclib, as that dose had a safety profile that, while not a formal MTD, did not meet the safety profile we are targeting for chronic treatment of a frontline population. We intend to bring the 150 mg zovegalisib dose forward as the phase III dose, pending regulatory feedback. Dose escalation was performed in a heavily pre-treated population. As with our prior disclosures on zovegalisib doublet therapy, all patients were required to receive at least one prior CDK4/6 inhibitor therapy and were allowed to receive more than one CDK4/6, multiple endocrine therapies for advanced disease, and prior chemotherapy or ADC for advanced disease. Unlike prior disclosures that we've made, this cohort was also allowed to have received prior PI3K pathway-directed therapy, and 10 of the 62 patients had received a prior PI3K pathway inhibitor. Consequently, these 62 patients were third-line or later patients on average. More than half had already been treated with a SERD, and more than a quarter had been treated with chemotherapy or an ADC for advanced breast cancer. The patients also had notable features, with nearly half of patients being pre-diabetic at baseline, over 60% of patients having visceral disease, and over 40% having a co-occurring ESR1 mutation at baseline. As I described earlier, atirmociclib increases the blood concentration of zovegalisib. All three zovegalisib doses, 100 mg, 150 mg, and 200 mg, exceeded our goal target coverage of 80% PI3K inhibition sustained for 24 hours a day. The 150 mg dose of zovegalisib in combination with atirmociclib and fulvestrant approximated the zovegalisib exposure we achieve at 400 mg BID in the doublet combination with fulvestrant, the dose we're testing in the ongoing ReDiscover-2 phase III trial. Even though this cohort was treated at unoptimized doses, with all patients being treated at or below our recommended phase III dose, the triplet of zovegalisib plus atirmociclib plus fulvestrant was highly active in this median third-line patient population, with an overall response rate of 44% in patients with RECIST-measurable disease, which begins to approach the ORR observed for CDK4/6 plus ET doublet therapy in first-line patients, which ranges between 53%-55% in registrational clinical trials. Importantly, the ORR was comparable in patients with both kinase and non-kinase domain mutations, and responses were observed in patients who had received a prior SERD and/or a prior PI3K pathway inhibitor. Of note, one patient who initially was a confirmed PR has now converted to an unconfirmed CR. With the acknowledgement that these are cross-trial comparisons, we can compare the 44% ORR observed for zovegalisib plus atirmociclib plus fulvestrant with other PI3K triplets tested in later-line ABC patients. In December, Roche disclosed the triplet of inavolisib with 600 mg ribociclib or abemaciclib with fulvestrant, and the ribociclib triplet achieved a 33% ORR, and the abemaciclib triplet achieved a 28% ORR, both numerically inferior to the ORR achieved with the zovegalisib plus atirmociclib plus fulvestrant triplet. We can also compare our triplet data to ORRs reported in frontline trials, where ribociclib plus ET and abemaciclib plus ET doublets achieved 53% and 55% ORRs respectively in endocrine-sensitive patients across both PIK3CA- mutated and wild type patients. The inavolisib plus palbociclib plus fulvestrant triplet showed a 58% ORR in endocrine-resistant patients. Given the historical meaningful increase in ORR moving from later-line to frontline patients, this gives us the confidence that our ORR will likely increase as we move into earlier-line patients at optimized doses. With the tolerability profile we're observing for the zovegalisib triplet, we expect this will translate into PFS benefit for frontline patients. Therefore, it gives us the confidence to take the zovegalisib plus the atirmociclib plus ET regimen into a frontline trial. For a triplet regimen that we will move into frontline development, tolerability is key, as the objective will be to be able to treat these patients for two and a half to three years and to be able to treat a broad spectrum of PIK3CA-mutated patients in the frontline, not just endocrine-resistant patients who were treated in the INAVO120 trial, inavolisib. We are very encouraged that the tolerability profile we are seeing with the triplet of zovegalisib plus atirmociclib plus ET is consistent with achieving these goals. Only 40% of patients experienced any Grade 3 or higher treatment-related adverse events, and most of the Grade 3 or higher events were neutropenia, with no cases of febrile neutropenia. Overall rates of hyperglycemia were low, with no Grade 3 or higher hyperglycemia, despite nearly half of patients being pre-diabetic at study entry. L ess than 10% of patients dose reduced zovegalisib and 16% dose reduced atirmociclib, with a combined rate of reduction of either drug being 23%. There were very few discontinuations due to TRAEs, with two patients discontinuing zovegalisib and four patients discontinuing atirmociclib. Of note, two of the patients who discontinued the triplet remained on study, receiving the zovegalisib plus fulvestrant doublet. We can contextualize the overall tolerability profile we are seeing relative to the other PI3K inhibitor triplets and standard of care CDK4/6 inhibitor plus ET doublets in frontline patients. Our 40% rate of Grade 3 AEs with less than 10% zovegalisib reductions compares favorably to the recently reported data for inavolisib in the MORPHEUS trial in late-line patients, which showed a 68% rate of Grade 3 or higher TRAEs, with 47% inavolisib dose reductions in combination with ribociclib, and 92% rate of Grade 3 or higher TRAEs, and 33% inavolisib dose reductions in combination with abemaciclib. In frontline regimens, CDK4/6 plus ET doublets on their own have shown 81% and 55% Grade 3 or higher AEs for ribociclib and abemaciclib respectively. In the inavolisib plus palbociclib plus fulvestrant triplet tested in the INAVO120 trial, a 91% rate of Grade 3 or higher AEs. The response rate and broader tumor reductions in combination with a quite favorable safety profile is leading to very encouraging durability in the zovegalisib plus the atirmociclib triplet. After 7.4 months of median follow-up, 48 out of 62 patients, or 77%, remain on therapy. The median PFS has not yet been reached. This slide shows the proposed phase III trial we plan to initiate in early 2027. We will focus on endocrine-sensitive, HR-positive, HER2-negative, PIK3CA-mutated patients who are 12 months or later from completing their adjuvant endocrine therapy or have been diagnosed with de novo metastatic disease. The trial will randomize patients to the triplet of zovegalisib plus atirmociclib plus an aromatase inhibitor versus a CDK4/6 inhibitor of investigator's choice, ribociclib, abemaciclib, or palbociclib plus an aromatase inhibitor. Given we are testing both zovegalisib and atirmociclib in the experimental arm, we anticipate we may need to account for the contribution of components. We are preparing to discuss the design of this trial with health authorities and anticipate being able to provide an update on final trial design and timing before we start the trial. This is just one opportunity among many that we can pursue in the coming years based on the differentiated profile of zovegalisib, which includes moving into early breast cancer in HR-positive, HER2-negative, PIK3CA-mutated patients, as well as exploring opportunities in other breast cancer segments. As you've seen from today's data, we are moving zovegalisib to where the field is moving by combining with an emerging selective CDK4 inhibitor rather than existing standards of care. We can also explore other classes of combination partners, including oral SERDs. We have assembled an advisory board of leading global breast cancer investigators to guide us through the development of zovegalisib. I'll now pass it over to Pete to discuss the Pfizer supply agreement details and wrap up. Thanks, Don. We initially entered into a supply agreement with Pfizer to be able to explore what bringing together two novel selective inhibitors could provide patients. We are excited to announce today we are extending that relationship to a phase III supply agreement. Under this agreement, Relay sponsors, fully operationalizes, and funds the frontline phase III trial and retains full global rights for zovegalisib. Pfizer supplies the atirmociclib for the experimental arm and palbociclib for the part of the CDK4/6 of choice control arm. With these promising data in hand, we will now over the coming months conduct regulatory interactions to confirm the phase III design and dose and rapidly prepare to start the phase III trial by early next year. We believe we have shown you over the last month the potential for zovegalisib to address two very large commercial opportunities in breast cancer, confirming the second-line promise with the ESMO TAT data and now initial data demonstrating the potential in front-line patients. We look forward to sharing initial vascular anomalies data next month at ISSVA for the third pillar of the large commercial opportunities that zovegalisib could potentially address. Thank you all for taking the time this morning to join us. With that, I will open it up to Q&A and hand it back to the operator. Thank you. Ladies and gentlemen, if you'd like to ask a question at this time, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. Our first question coming from the line of Brad Canino with Guggenheim. Your line is now open. Hey, good morning, and it's great to see these data and the progress towards the frontline trial. A couple questions from me, if I may. First, you talk about the benefit of the novel selective approach versus the combo with the CDK4/6 inhibitors, which you also tested. I guess, what were the safety data like for the palbociclib combo, and how do you think competitors will fare if they are potentially going to go down the CDK4/6 triplet route? I mean, I think we know from the safety profile that we showed what a CDK4/6 plus endocrine therapy looks like in the front line. Obviously, as you know, these patients need to be on therapy for multiple years, and so tolerability really is critical. What we saw was a step change in difference with atirmociclib, which is, it's, you know, driven by its selective nature of it only targeting CDK4 and dialing out the CDK6 toxicities. Obviously combining that with zovegalisib, another mutant selective inhibitor. For us, both agents together led to a tolerability profile that we think would lend itself to a multi-year frontline treatment that a non-selective PI3K inhibitor or non-selective CDK inhibitor just cannot lend itself to. Okay. Second, you build this approach as a competitive advantage for Relay with this Pfizer supply agreement. I guess what's to stop Pfizer from supplying drug to other companies with mutant-selective PI3Kα inhibitors to do the same thing for phase III trials? Pete, do you want to take that one? Yes. Thanks for the question, Brad. Yeah, there are limitations for both us and Pfizer in moving forward in the near term with other PI3K or selective CDK4 molecules into a phase III trial. We believe that we will definitely be first to market with this selective approach. Okay. Last for me, it looks like the rash for the triplet is a new signal compared to the doublet data. Could you comment on the presentation and management of that AE? That's it for me. Thank you. Yeah. You know, so what we've seen in rash has been primarily low grade, well managed with antihistamines. You know, it is something that we've not seen at high rates before with zovegalisib, and I think we'll wait to see more robust disclosures from atirmociclib, including that coming for FOURLIGHT-1 disclosure to understand what the potential contribution of atirmociclib could be. We are in later line patients. We are in patients who have seen prior PI3K inhibitor pathway agents, many of which carry a rash AE. And there is some trends towards some of the rash being in patients who have seen those prior PI3K pathway inhibitors, but I think we need more experience to fully understand it. Thanks for your questions, Brad. Thank you. Now, next question coming from the line of Akash Tewari with Jefferies. The line is now open. Awesome. Thanks so much for taking our questions. This is Amy on for Akash. First of all, would love to get any color on your decision to go into ER-sensitive patients instead of ER-resistant like some of your peers, where the bar on PFS and OS is lower. What are you seeing on early durability in those, you know, 77% patients that are still continuing on trial, and safety to give you confidence that you could show superiority in the setting? I believe, you know, MONALEESA has shown around 25-month PFS. Would love to kinda get your view on the confidence to beat that. Thanks for your question, Amy. I'm gonna hand that over to Don. Yeah. I think your point, Amy, with tolerability is key here. I think what we're seeing in our patients, and again, these are third- line and later patients, is at 7.5 months, we have over three-quarters of patients still on study. As you can see in the swimmer's plot, patients in whom we're achieving responses are maintaining those responses with long durability. We haven't been able to, you know, really meaningfully calculate a DOR yet, since all of these responses for the most part are ongoing. With 7.5 months follow-up, we're still too early to calculate a PFS. When we look at the Kaplan-Meier curve, it's a relatively flat curve. As you can imagine with a lot of censored patients, those censored patients, again, representing our patients who are ongoing on study, who have not yet had a progression event. We're very encouraged in this late line patient population, both by the efficacy we're seeing, but really the durability of benefit and the durability of being able to maintain dose intensity, you know, with three-quarters of patients still receiving the dose of drug that they started with when they came on study. With regard to what we think we'll need to see in a frontline trial, as you point out, MONALEESA showed overall in both PIK3CA mutant and PIK3CA wild type patients, PFS in the mid-20s, but the subgroup analysis looking at PI3K mutant versus PI3K wild type showed a 19-month PFS in PI3K mutant patients versus 31 months in PI3K wild type. These data would suggest that the PI3K mutant patients may not fare as well with frontline CDK4/6 doublet therapy. In fact, we've been able to see from some recent protocols that have been published on the European CTIS website that there are assumptions that the PI3K mutant patient population in the setting would have about a 20-month PFS, which would be where our assumption would be for what we would need to be. On your endocrine-sensitive, why go to endocrine-sensitive? I think that it's the place where everyone would like to go if you had a regimen that afforded you the tolerability to get there, and just most can't. What we demonstrated today is that we clearly have a safety and tolerability profile to bring to these patients. It's the largest portion of the frontline patients, over 37,000 of them in major geographies throughout the world. The ability to go prosecute this trial where there's no other pathway inhibitor approved is quite attractive from a probably a success standpoint. We will be running this trial against just the doublet standard of care without the involvement of a pathway inhibitor. That in combination with the supply agreement where we get atirmociclib and palbociclib supplied for free allow us to run a very manageable frontline trial from a cost effectiveness standpoint. Excellent. Just another one. How much do you think atirmociclib is contributing to your ORR? I know Pfizer reported, I think the last cut was around 32% in a more refractory setting. Would love to get any color here. Yeah. You know, I think what we're seeing really here is the triplet activity. You know, first of all, we're coming in at 44%. You know, we haven't really seen a large dataset of the atirmociclib doublet in the later-line patient population. That 32% I think was based on 23 or 24 patients who had measurable disease. Specifically in PI3KCA-mutant patients, they only had 10, what they call PI3KCA pathway-altered patients. That was a patient population that included PI3KCA, PTEN, and AKT-mutated patients. Those 10 patients were treated at both 300 mg and 400 mg of atirmociclib and treated with both fulvestrant and letrozole. Small datasets, very heterogeneous. You know, I think as we look at the data we're seeing, and given that for exposures that we know are active exposures as zovegalisib, we think we're really seeing the activity of the triplet. Perfect. Thanks so much. Thank you. Our next question coming from the line of Yaron Werber with TD Cowen. Your line is now open. Hi, this is Jane on for Yaron. [Congrats], thanks for taking our questions. I wanted to look a little bit also on the contributions of atirmociclib versus zovegalisib. When we look at your prior doublet data, obviously this is at the pivotal dose and in a less refractory population, but overall ORR seems pretty similar at 44% versus 43% for your slide data. Can you give us any kind of any more detail on how the ORR breaks down by the different doses for zovegalisib and how you might expect what degree of improvement you expect to see as we move to 1L additionally with an aromatase inhibitor instead of fulvestrant? Okay. Maybe we'll break the question down. We'll just finish off the last question around the contribution of atirmociclib. I think the most kind of powerful thing is obviously the fact that, Pfizer's entered into a supply agreement. There's definitely a belief, you know, they have perfect information on the fourth-line trials that there is gonna be an additive component for zovegalisib. If you come to your question around, you know, what is the, comparison between our doublet data, where we're sitting in the kinda high 40s with, you know, kind of close to second-line patients and this triplet data in much more heavily pre-treated median third-line patients, maybe I'll hand that over to Don. Yeah. I think we are obviously, there's the difference in pretreatment, including, we've got patients here who have seen prior PI3K pathway inhibitors. We are seeing activity of the triplet with responses of the triplet in those patients, which to us suggests that we're seeing triplet benefit in those patients. In terms of the dose responsiveness that we've seen, you know, we've reported out these data with pooled data of every patient treated at or below the recommended phase III dose of 150 mg, 300 mg, because we've seen activity at every dose that we've studied, including starting at the 100 mg, 100 mg dose. This is a regimen that's broadly active across the dose range that we studied. I think as we get more data at our optimized doses, we expect we should be able to see, you know, the data continue to remain where it is, if not improve, given that we would be at more optimized doses. Then as you've seen other agents go from later line settings to earlier line settings, into CDK4/6 naive patients, you know, whether you're talking about the CDK4/6 inhibitors themselves with CDK4/6 retreatment or the experience of inavolisib, moving from phase I-B in CDK4/6 or second- line in later patients in the front line, we've generally seen a 20%-30% increase in ORR as you move into the front line. Great. If I could follow up with one more question. Your ORR data excludes kind of, as you mentioned, the 200 mg BID and the zovegalisib and 300 mg BID at atirmociclib. Not due to the safety not being quite as optimal even though it didn't quite reach the level of MTD. Can you give us any more details on what exactly you observed here to warrant those deprioritizations? Yeah, I mean, we just had a slightly higher rate of higher- grade AEs that led to dose reduction, right? Our goal here is really to have a regimen that is giving us the target coverage we want with the optimized AE profile, low rates of dose reduction that allows patients to remain on therapy. Given that we were seeing activity at several lower doses, you know, we knew that we could move on from that highest dose that we tested. Tolerability is gonna be the critical part of this triplet. Makes perfect sense. Thank you. Thank you. Our next question coming from the line of Sean McCutcheon with Raymond James. Your line is now open. Hey, guys. Thanks for the questions. Maybe could you provide some detail on any additional work, if any, that may be required to determine the profile of zovegalisib in combination with aromatase inhibitor ahead of starting that phase III study? Thanks. Yeah. Thanks, Sean. We have ongoing expansions with both fulvestrant and aromatase inhibitor. Our early experience with the aromatase inhibitor is that it's an exercise of just getting a little bit of experience there to be able to move forward and take that to the regulators. We'll go have a regulatory interaction and then be able to move quickly towards initiating this frontline trial. Just some box- checking exercises to go through and a regulatory interaction are the main gating items before moving on. Thank you. Our next question in queue coming from the line of Salveen Richter with Goldman Sachs. Your line is now open. Good morning. Thanks for taking my question. Just, you know, a bigger picture question here about how you think of positioning versus competition such as Celcuity and others, in the marketplace and, you know, how you think about the cadence of additional updates on this program over the year. Thank you. Look, I think the bigger picture, thanks for the question, Salveen, is clear, which is, you know, this is a very large patient population, and as you can see, it's served by, you know, some very large billion-dollar brands. But they do come with these toxicity challenges, and the PI3Kα- mutated patients do worse. We think that this approach allows us to solve both problems, which is having a PI3Kα inhibitor should drive to greater efficacy, and then using atirmociclib in combination with zovegalisib should allow us to get the tolerability. Obviously it's an all-oral regimen. As you know, these patients are on therapy for multiple years, and they're trying to live as normal a life as they can. We think this is the best approach, and we've talked to a lot of patient advocacy groups, and they're very supportive of this approach. Now, as you mentioned, you know, there are other agents in this field. Obviously, there are some of them will be using the traditional CDK4/6 backbones, and we think that they will have, you know, increased tolerability challenges. Obviously we see that with the uptake of inavolisib not being as robust as I think folks expected post the approval. Then obviously you mentioned gedatolisib. As you know, gedatolisib is a weekly IV regimen. For frontline patients who are trying to live their lives as normally as possible to come in every week and have an IV infusion and then continually have daily or, you know, multiple times a day dexamethasone mouthwash and potentially then other concomitant medications for the AE leads to quite a significant disruption in their lives. We don't think that is a viable regimen in the front line. That's why we're really excited about this oral selective regimen in the front line that should allow these patients to live as normal lives as possible. Yeah. On the updates from here question, you know, the key one we can point to is coming back later this year on the other side of a regulatory interaction to confirm both trial design and dose before we set off to start the study in early next year. Thank you. Thank you. Our next question coming from the line of Etzer Darout with Barclays. Your line is now open. Hi, this is Luke on for Etzer. Thanks for taking our question. You know, kinda similar to the previous ones, just to see, you know, how you're benchmarking this because you are in your phase III just doing versus a CDK4/6 and an aromatase inhibitor as a comparator arm. You know, I'm talking to KOLs, is there anything like that they are looking for out of your triplet that we should be paying attention to that may like, you know, kinda come out of that phase III trial? Yeah, I think it's kinda more of what we talked about. I mean, INAVO120 trial showed you that by adding a PI3Kα inhibitor, you clearly saw greater PFS than OS. So it's that is a given here. The fact that if you're gonna run a triplet versus the doublet, we've seen that you're gonna be successful. The issue is, do patients wanna stay on therapy, and is this actually gonna be commercially viable? I think INAVO120 is also starting to give us the answer there. I think what the KOLs that we're dealing with, and we have a panel of, you know, some of the leading lights across the world advising us. The thing that they're most excited about is the tolerability profile. I think you see it in the data here. I mean, it's a heavily pre-treated patient population. We're seeing low rates of neutropenia, which is obviously being driven by atirmociclib's profile. You see no Grade 3 hyperglycemia here, which is obviously being driven by zovegalisib's profile. The things that could potentially disrupt the patients in the front line on chronic treatment are. You're seeing low rates of. I think that's the thing that people are most focused on when we talk to KOL. I don't know if I missed anything. No, I think, you know, you really hit it. You know, the other part of that is not just keeping patients on the triplet, but being able to choose to use the triplet in a broad range of patients as opposed to, you know, your very narrowly selected fittest patients. It comes back to the profile that we're looking to achieve, one where the overall toxicity burden on the patient and the physician for the triplet can be, you know, comparable to, but not worse, you know, potentially even better than the existing doublets that are used in the front line. We think that's really the profile we need to get both broad utilization and the potential superior benefit. Okay. Good. Thanks. Thank you. Thank you. Our next question coming from the line of [Shipeng] with Bank of America. Your line is now open. Hey, guys, thanks for the update, and thanks for taking my question. First one may be a follow-up. I believe you started exploring the palbociclib and ribociclib triplet earlier before atirmociclib came into the picture. I'm curious, can you talk about how the atirmociclib triplet data compared to palbociclib and ribociclib triplet? What are you most impressed with the CDK4 combo data in comparison among efficacy, safety, and dosing consistency or target coverage? Ultimately wondering to what extent you can glean that CDK4 can add to zovegalisib triplet more so than a CDK4/6 could, as we think about the phase III comparison. Okay. I think it's kind of more over the kind of high level that we've discussed, which is, you know, we're very familiar. You know, there's a lot of data in the public domain around the CDK4/6 plus endocrine therapy in the front line. You know, they have high rates of neutropenia. Some of them have diarrhea. And so we know what that profile looks like, and we know what, you know, adding a PI3K inhibitor to that profile looks like because we've seen it done with palbociclib in the INAVO120 trial. I think, coming back to, you know, what are we most impressed about? We're impressed with the atirmociclib's ability to dial down the CDK6- related toxicities, and you see it in, you know, all the data that Pfizer's shown. It's an impressive compound. You stack that, you know, with our data, and you've seen plenty of data from our ReDiscover data, and you've seen it from our doublet data, that we can dial down rash, diarrhea, stomatitis. Also, most importantly, you know, we have very low Grade 3 hyperglycemia. You stack the two together and you get a profile that for the first time, you could potentially put three drugs together and be comparable and in the zone of what you see with the doublets of CDK4/6 plus AI. I think what we're looking for is comparable efficacy. Oh, sorry, comparable tolerability, but superior efficacy with this profile. We think the way to get there is a selective approach. Got it. My second question is, I believe you have tested both the 150- mg, a 100- mg dose of zovegalisib. How did the response rate compare between the two dose strengths? We, you know, we're still sitting at small n's, which is why we're pooling all the data together. As Don said, we saw responses starting at the lowest dose, and saw them straight through to the higher doses, ultimately, even at, especially at the 150 mg. So everything's been relatively consistent to date. And we imagine as we get more experience at the 150, specifically over time and more lightly pre-treated patients will continue to see that increase. Got it. Just one last one from me. Does the first-line breast cancer development plan have any impact on your current cash guidance? No. I mean, clearly, over time, to fund the entirety of the study, we will need more cash. As of now, our current cash guidance contemplates the starting of this study. Great. Thanks so much. Thank you. Our next question coming from the line of Eva Fortea with Wells Fargo. Your line is now open. Good morning. Thanks for taking our question, and congrats on the progress. A quick one from us. Can you provide more context on the Grade 4 events of neutropenia and hypokalemia seen in the study so far? Thanks. Yeah. I mean, I think the Grade 4 events have been very rare, and, you know, well managed. In general, Grade 4 AEs have not been an issue. Thank you. Got it. Thanks. Thank you. Our next question coming from the line of Silvan Tuerkcan with Citizens JMP. Your line is now open. Yeah, good morning, and thanks for taking my questions. Maybe a quick first one. What can you tell us about at this point about the non-kinase and kinase activity of this triplet? It seems like it's across both patient types. Is that true? Then maybe a second question, just maybe big picture. Pfizer is developing this CDK4 inhibitor for the frontline. Would there be only one regimen in the frontline, or would there be options between a doublet for Pfizer and the triplet, or how could we envision this coming to market at some point? Thank you so much. I think to take your first question, around kinase and non-kinase, we see basically the same response rate across the mutations. It's a real true pan mutant inhibitor that we have. Obviously that goes on the back of the data we showed at ESMO TAT, where we showed very similar PFS in the kinase and the non-kinase. Hopefully we are very clear that this is a pan mutant inhibitor. In terms of your question around the broader strategy of Pfizer's commercial, I'll leave that to Pfizer to comment on. All we can say is in the PI3K α- mutated patients, and if we can show the data that we hope to show here, and obviously both sides are excited about running the trial, it should become the standard of care for the mutated patients. Great. Thank you. Thank you. Now next question coming from the line of Boris Peaker with JonesTrading. You want to start, please. Great. Thanks for squeezing me in. Just a question on dosing. You have a 2.5x exposure increase from atirmociclib, and looks like you took your 400 mg dose and you divide it by 2.5 to get about 250 mg. I'm just curious how consistent is this 2.5x PK interaction across different patient weights or metabolic profile? And also thinking like if a patient dose reduce atirmociclib for some tox reasons or whatever, is there a protocol adjustment to increase the dosing of your drug to compensate for that? It's very consistent in all elements that you said. That answers your first question. On your second one, it's not really that dependent on the atirmociclib dose, and so we would not need to dose reduce if the atirmociclib dose came down. It should lead to a pretty simple dosing regimen for patients. Got it. Maybe another question is on the median follow-up that you've had so far is about seven and a half months. When will we see the mature PFS for the triplet combo? At some point in the future. Got it. Well, thanks for taking my questions. Thank you. Thank you. I'm showing no further questions at this time. I will now turn the call back over to Mr. Sanjiv Patel for any closing comments. Thank you. Hopefully, you can see today we're excited about using this selective next- generation combination to provide a much better solution for the 40% of patients that are mutated in the front line. Look forward to talking with you over the coming days and hopefully seeing you all in Philadelphia at the ISSVA conference on May the 20th. Thank you. This concludes today's conference call. Thank you for your participation. You may now disconnect.