Relay Therapeutics, Inc. (RLAY) April 2026 Conference Transcript

Good day, ladies and gentlemen, and welcome to the Relay Therapeutics Frontline Breast Cancer Update Call. As so in mind that this conference call is being recorded, I would now like to introduce your host for today's conference, Mr. Pete Wehmer, Chief Corporate Development Officer at Relay Therapeutics. So 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 in 1995, including expressed 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 guaranteed 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. I refer you to our SDC 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. We undertake no obligation to update or revise any of these statements. I'm also joined here today with Sanjeev Patel, our CEO, and Don Bergstrom, our president of R&D. And with that, I'll turn it over to Sanjeev.

Thank you, Pete, for the introduction, and thank you all for joining the call at late Today, we're going to share further data on our lead program, Zovega for short, a pan-mutant selective PI2K-alpha 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-TAC in Paris, we shared data with our pivotal trial dose in this indication, which increases our confidence that we will be successful in showing clear differentiation from the current standard of care, Capivacertib. And as a company, we're all laser-focused on executing our pivotal trial, Rediscover 2, True, 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, and we've been pleased to announce today that we've selected a termocyclic, Pfizer's selective CDK4, as the CDK combination partner for our first-line regimen with Zavega. The data we'll share today will share why we're very excited about this choice, as in heavily pre-treated patients, the early efficacy and tolerability of the Zovega termotriplet 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, so 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 PI3K-alpha 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. And we're also pleased to announce today that we have a supply agreement in place with Pfizer to supply a termocyclic for our Phase III trial and palbocyclic for part of the control arm. Finally, in what's a very busy time here at Relay, in a few weeks' time at the ISFA 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, and our hope is to show that Vega 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-alpha mutation, and they're served today by some very large billion-dollar brands. The recent Roche-Inavo 120 trial and its subsequent approval has shown that in PI3K-alpha mutated patients in the frontline, adding a PI3K-alpha 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. So the goal of a next-generation triplet is to maintain the increased efficacy that has been seen for a PI3K inhibitor in the front line 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 in Zovega and a CDK4 selective inhibitor in Atermo. We believe this selective-selective profile should drive greater tolerability, leading to greater efficacy. The data we report today from the triplet of Zovega, Atermo, 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 Atermo triplet. And this long-term tolerability that we're seeing of the Zovega Atermo 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, Sanjeev.

We initiated dose finding of Zovega combined with Etermo and standard dose fulvestrins. We did observe an effect of Etermocyclob on blood concentrations of zovegalicin. Etermocyclob increases the concentration of Zovega by about two and a half fold. So, a 150 milligram dose of Zovega combined with Etermo leads to blood concentrations of Zovega that approximates the exposure we achieve at the 400 milligram dose of Zovega combined with fulvestrins that we were testing in the ongoing Rediscover 2 trial. Zovega does not appear to impact blood concentrations of Atermo. And we will prioritize moving forward with the 300 milligram dose of Atermo, which is the dose Pfizer investigated in the positive 4LITE1 trial and is currently investigating in the ongoing 4LITE3 frontline trial. We will disclose data from 62 patients treated with the triplet of Zovega plus Atermo plus flibestrant, with a medium follow-up of 7.4 months. Patients were dosed with doses of Zovega between 100 and 200 milligrams BID, and doses of Atermo between 100 and 300 milligrams BID, all with standard dose flibestrant. We are not reporting data on patients treated at the 200 milligram dose of Zovega combined with the 300 milligram dose of Atermo, as that dose had a safety profile that, while 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 Zovega dose forward as the Phase III dose, pending regulatory feedback. Dose escalation was performed in a heavily pretreated population. As with our prior disclosures on Zovega doublet therapy, all patients were required to receive at least one prior CDK4-6 inhibitor therapy, and we're allowed to receive more than one CDK4-6, multiple endocrine therapies for advanced disease, and prior chemotherapy or ADC for advanced disease. But 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 CERD, 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, a termocyclob increases the blood concentration of Zovega. All three Zovega doses, 100 milligrams, 150 milligrams, and 200 milligrams, exceeded our goal target coverage of 80% PI3K inhibition sustained for 24 hours a day. The 150-milligram dose of Zovega in combination with the termocyclob and fulvestrant approximated the Zovega exposure we achieve at 400-milligram BID and the doublet combination with fulvestrant, the dose we're testing in the ongoing Rediscover 2 Phase 3 trial. Even though this cohort was treated at unoptimized doses, with all patients being treated at or below our recommended Phase 3 dose, the triplet of Zovega plus a termo plus was highly active in this median third-line patient population with an overall response rate of 44% in patients with resist measurable disease, which begins to approach the ORR observed for CDK4-6 plus ET doublet therapy in first-line patients, which has ranged between 53 to 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 CERD 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 Zovega plus Atermo plus Fulvestrin with other PI3K triplets tested in later line ABC patients. In December, Roche disclosed the triplet of Inabolosib with 600 mg ribocyclob or abemocyclob with fulvestrin. And the ribocyclob triplet achieved a 33% ORR, and the abemocyclob triplet achieved a 28% ORR, both numerically inferior to the ORR achieved with the Zovega plus Atermo plus fulvestrin triplet. And we can also compare our triplet data to ORRs reported in frontline trials, where ribocyclob plus ET and abemocyclob plus ET doublets achieved 53 and 55 percent ORRs respectively in endocrine-sensitive patients across both VIC-3CA-mutated and wild-type patients. And the inovolosib plus palbocyclob plus flubestrin triplet showed a 58 percent ORR in endocrine-resistant patients. Given the historical meaningful increase in ORR, moving from later line to front-line patients, this gives us the confidence that our ORR will likely increase as we move into earlier line patients at optimized doses. And with the tolerability profile we were observing for the Zovega triplet, we expect this will translate into PFS benefit for front-line patients, and therefore gives us the confidence to take the Zovega plus a Termo plus ET regimen into a front-line 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 TIK3CA mutated patients in the frontline, not just endocrine-resistant patients who were treated in the ANAVA-120 trial of anabolicin. We are very encouraged that the tolerability profile we are seeing with a triplet of Zovega plus Atermo plus ET B 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. Only or less than 10% of patients dose-reduced Zovega and 16% dose-reduced Etermo, with the combined rate of reduction of either drug being 23%. And there were very few discontinuations due to TRAEs, with two patients discontinuing Zovega and four patients discontinuing Etermo. Of note, two of the patients who discontinued Etermo remained on study, receiving the Zovega plus filvestrin supplement. 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. or a 40% rate of grade 3 AEs with less than 10% Zovega reductions compared favorably to the recently reported data for inovolusib in the Morpheus trial in late-line patients, which showed a 68% rate of grade 3 or higher TRAEs with 47% inovolusib dose reductions in combination with ribocyclob and 92% rate of grade 3 or higher TRAEs and 33% anabolosin dose reductions in combination with abemacyclob. And in frontline regimens, CDK4-6 plus ET doublets on their own have shown 81% and 55% grade 3 or higher AEs for ribo and abemma, respectively. And in the anabolosin plus tabacyclob plus filvestrin triplet, tested in the ANAVO-120 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 Zovega plus a termo 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 HIC3CA-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 Zovega plus Atermo plus an aromatase inhibitor versus a CDK4-6 of investigators' choice, ribocyclic, abemocyclic, or palbocyclic plus an aromatase inhibitor. Given we are testing both Zovega and Atermo 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 amongst many that we can pursue in the coming years based on the differentiated profile of Zovega, which includes moving into early breast cancer in HR-positive HER2-negative PIC3CA-mutated patients, as well as exploring opportunities in other breast cancer segments. And as you've seen from today's data, we are moving Zovega 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 SIRDS. We've assembled an advisory board of leading global breast cancer investigators to guide us through the development of Zovega. 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 and are excited to announce today we are extending that relationship to a Phase 3 supply agreement. Under this agreement, Relay sponsors, fully operationalizes, and funds the frontline Phase 3 trial and retains full global rights for Zavega Listed. Pfizer supplies a terminal for the experimental arm and Palbo 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 3 design and dose and rapidly prepare to to start the phase three trial by early next year. We believe we have shown you over the last month the potential for Zovega to address two very large commercial opportunities in breast cancer, confirming the second line promise with the ESMOTAT data, and now initial data demonstrating the potential in frontline patients. And we look forward to sharing initial vascular anomalies data next month at ISFA for the third pillar of the large commercial opportunities that Zovega could potentially address. Thank you all for taking the time this morning to join us. And 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 1-1 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 1-1 again. Please stand by while we compile the Q&A roster. Now, first question coming from the line of Brad Canino with Guggenheim, Yolan is now open.

Hey, good morning, and it's great to see these data and the progress towards the front-line A couple questions for me, if I may. First, you talk about the benefit of the novel selective-selective approach versus the combo with the CDK4-6 inhibitors, which you also tested. What were the safety data like for the PELBO 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. And obviously, as you know, these patients need to be on therapy for multiple years. And so tolerability really is critical. And so what we saw was a step change in difference with a termo, which is it's, you know, driven by its selective nature of it only targeting CDK4 and dialing out the CDK6 toxicities. And then obviously combining that with Ovega, another mutant selective inhibitor. And so 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 PI2K inhibitor or a non-selective CDK inhibitor just cannot lend itself to.

And second, you bill this approach as a competitive advantage for Relay with this Pfizer supply agreement. But I guess what's to stop Pfizer from supplying drug to other companies with mutant-selective PI3K alpha inhibitors to do the same thing for phase three trials? Pete, do you want to take that one?

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 three trial.

We believe that we will definitely be first to market with this selective-selective approach. Okay.

And then 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? And then that's it for me.

Yeah. You know, so what we've seen in rash has been primarily low-grade, well-managed antihistamines. You know, it is something that we've not seen at high rates before with Sovega, and I think we'll wait to see more robust disclosures from a termo, including that coming for like one disclosure to understand what the potential contribution of a termo 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 trend 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 lineup. Akash Talarin with Jeffrey. See, I'll be right back.

Awesome. Thanks so much for taking our questions. This is Amy on for Akash. So, 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, Mona Lisa has shown around 25-month PFS. I would love to kind of get your view on the confidence to beat that.

Thanks for your question, Amy. I'm going to hand that over to Dylan.

Yeah, so I think your point, Amy, with colorability is key here. And I think what we're seeing in our patients, and again, these are third line and later patients, is at seven and a half months, we have over three quarters of patients still on study. As you can see in the swimmer slot, patients in whom we're achieving responses are maintaining those responses with long durability. So 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 seven-and-a-half 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. So 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, Mona Lisa 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. So, these data would suggest that the PI3K mutant patients may not fare as well with frontline CDK4-6 doublet therapy. And 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.

And on your endocrine sensitive, why go into 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. And so what we've 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. And the ability to go prosecute this trial where there's no other pathway inhibitor approved is quite attractive from a probability success standpoint. So 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 Atermo and Palvo supplied for free, allow us to run a very manageable front-line trial from a cost-effectiveness standpoint.

Excellent. And then just another one. How much do you think Atermo is contributing to your ORR? I know Pfizer reported, I think the last cut was around 32% in a more refractory setting. So, would love to get any color here.

Yeah, so, 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 data set of the Atermo doublet in the later line patient population. So that 32%, I think, was based on 23 or 24 patients who had measurable disease. And specifically in PIK3CA mutated patients, they only attend what they call PIK3CA pathway-altered patients. So that was a patient population that included PIK3CA, P10, and AKT mutated patients. And those 10 patients were treated at both 300 and 400 milligrams of Atermo and treated with both Fulvestrin and Letrozole. So small data sets, very heterogeneous. You know, I think as we look at the data we're seeing, and given that we're exposures that we know are active exposures as a Vega, we think we're really seeing the activity of the triplets.

Perfect. Thanks so much. Thank you. Okay, our next question coming from the line-up, Jaron Weber with TD Kalani, Alanis Melvin.

Hi, this is Jaina on for Jaron, and thanks for taking our questions. I want to double click a little bit also on the contributions of Atumo versus Zovega. When we look at your prior doubler data, obviously this is at the pivotal dose and in a more refractory, in a less refractory population, but overall ORR seems pretty similar, what, 44% versus 43% for your FED data. Can you give us any more detail on how the ORR breaks down by the different doses for Zovega and how you might expect, what degree of improvement do you expect to see as you move to 1L, additionally, with an aromatase inhibitor instead of sylvestrin?

Okay, so maybe we'll break the question down. We'll just finish off the last question around the contribution of Atermo, I think the most kind of powerful thing is obviously the fact that Pfizer has entered into a supply agreement. So there's definitely a belief, you know, they have perfect information on the four light trials that there is going to be an additive component for Zovega. And so then if you come to your question around, you know, what is the comparison between our doublet data where we're sitting in the kind of high 40s with, you know, kind of close to second-line patients, and this triplet data in much more heavily pre-seated, median third-line patients, maybe I'll hand that over to Don.

Yeah, so I think we are, obviously, there's a difference in pretreatment, including we've got patients here who have seen prior PI3K pathway inhibitors, and we are seeing activity of the, 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 pool data every patient treated at or below the recommended Phase 3 dose of 150-300 because we've seen activity at every dose that we've studied, including starting at the 100 milligram, 100 milligram dose. So this is a regimen that's broadly active across the dose range that we've 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. And 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 in a bolusif moving from phase 1B and CDK4-6 or second line and later patients in the frontline, you're generally seeing a 20 to 30 percent increase in ORR as you move into the frontline.

Great. And if I could follow up to one more question. Your ORR data excludes kind of, as you mentioned, the 200-mig BID and the VEGA and 300-mig BID at TRMO, not due to the safety not being quite as optimal, even though it didn't quite reach level MPD. Can you give us any more details on what exactly you observed here to warrant those due prioritization?

Yeah, I mean, we just, you know, had a slightly higher rate of higher grade AEs that led to this reduction, right? And our goal here is really to have a regiment 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. So, 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. Colerability is going to be the critical part of this triplet.

Makes perfect sense. Thank you. Thank you. And our next question, coming from the lineup, Sean McCutcheon with Raymond James, Yolanda Snellman.

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 Zovega in combination with aromatase inhibitor ahead of starting that Phase III study? Yeah, thanks, Sean. We have ongoing expansions with both flivestrant and aromatase inhibitor. Our early experience with the aromatase inhibitor is that it should not – 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, and then we'll go have a regulatory interaction and then be able to move quickly towards initiating this frontline trial. So just some box-checking exercises to go through and a regulatory interaction are the main gating items before moving on.

Thank you. And our next question in queue coming from the line of Selvin Richter with Goldman Sachs. Yelena Selvin.

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 Selkuity and others in the marketplace. and, you know, how you think about the cadence of additional updates on this program over the year.

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 some very large billion-dollar brands. But they do come with these toxicity challenges, and the PI3K-alpha mutated patients do worse. And so we think that this approach allows us to solve both problems, which is having a PITK-alpha inhibitor should drive to greater efficacy, and then using a termo in combination with Zovega should allow us to get the tolerability. And obviously, it's an all-oral regimen. And so, as you know, these patients are on therapy for multiple years, and they're trying to live as normal as life as they can. And so 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, some of them will be using the traditional CDK4-6 backbones, and we think that they will have, you know, increased tolerability challenges. And obviously, we see that with the uptake of Inovolusib not being as robust as I think folks expected post the approval. And then obviously, you mentioned Getatolusib. As you know, Getatolusib is a weekly IV regimen. And so 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 multiple times a day, dexamethasone, mouthwash, and potentially then other concomitant medications for the AEs leads to quite a significant disruption in their lives. And so we don't think that is a viable regimen in the front line. And so that's why we're really excited about this oral-oral selective-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. Our next question coming from the lineup is our direct with Barclays, CLN is now open.

Hi, this is Luke. Thanks for taking our question. you know kind of similar to the previous ones just to see you know how your benchmarking is because you are in your phase three just doing versus a CDK4-6 and an aerobic case inhibitor as a comparator arm you know talking to KOLs is there anything like that they are looking for out of your triplet that we should that we should be paying attention to that may like you know kind of come out of that phase three trial yeah I think it's kind of more of what we talked about I mean, the Inalvo 120 trial showed you that by adding a PI2K alpha inhibitor, you clearly saw greater PFS and OS.

So that is a given here. The fact that if you're going to run a triplet versus the doublet, we've seen that you're going to be successful. The issue is, do patients want to stay on therapy? And is this actually going to be commercially viable? And I think Inalvo is also starting to give us the answer there. And so 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 and 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 a termocyclips profile you see no grade 3 hyperglycemia here which is obviously being driven by the Vegas profile so that the things that could potentially disrupt these use patients in the front line on chronic treatment, you're seeing low rates of. So 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. And, 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. And 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. And we think that's really the profile we need to get both broad utilization and the position of superior medical.

Thank you.

Thank you. Our next question, coming from the line of Chief Bung with Bank of America, Yelena Smallfin.

Hey, guys. Thanks for the update, and thanks for taking my question. First one, maybe a follow-up. I believe you started exploring the palpable and ribotriplet earlier before a thermal came into the picture. I'm curious, can you talk about how the a thermal triplet data compared to palpable and right word triplet um what are you most impressed with the cdk4 combo data in comparison among efficacy safety and those inconsistency or target coverage ultimately wondering to what extent you can glean that cd4 uh cdk4 can add to so vega triplet more so than a cdk46 could as we think about the phase three 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 Palbo in the Inavo 120 trial. So I think coming back to, you know, what are we most impressed about we're impressed with the termo's ability to dial down the CDK6 related toxicities and you see it in you know all the data that Pfizer showed it's an impressive compact and so then you stack that you know with our data and you've seen plenty of data from our rediscover data that and you've seen it from our doublet data that we can dial down rash diarrhea, stomatitis, and also the most importantly is, you know, we have very low grade three hyperglycemia. So 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. And so I think what we're looking for is comparable tolerability, but superior efficacy with this profile. And we think the way to get there is a selective-selective approach.

Got it. And my second question is, I believe you have tested both the 150 milligram and 100 milligram dose of Zylvega. How did the response rate compare between the two dose drinks?

Yeah, we're still sitting at small ends, 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, especially at the 150. 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 pretreated patients, we'll continue to see that increase.

Got it. Just one last one from me. Does the first fine breast cancer development plan have any impact on your current cash guidance?

No, I mean, clearly we, over time, to fund the entirety of the study, we will need more cash. But 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 Porte 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 both context on the grade 4 events of neutropenia and hypokalemia seen in the study so far?

Yeah. I mean, I think the grade 4 events have been very rare and, you know, well-managed. So, in general, grade 4 AEs have not been an issue. Thank you.

Got it. Thank you. Our next question, coming from the line of Silvan Turkan with Citizens Bank, Kielan 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-kionist and kineist activity of this triplet? It seems like it's across both patient types. Is that true? And then maybe a Second question, just maybe big picture, Pfizer is developing this, you know, CDK4 and the 4-Live-3 trial in the front line. Did you think, would there be only one regimen in the front line, or would there be options between a doublet for Pfizer and a triplet, or how could we envision this coming to market at some point? Thank you so much.

So, I think to take your first question around kinase and non-kinase, we see basically the same response rate across the mutations. And so it's a real true pan mutant inhibitor that we have. And 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. So 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. But all we can say is in the PI3K-alpha mutated patients, 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. Our next question, coming from the line-up, for a speaker with John Strading, you're on a snobbin.

Great. Thanks for squeezing me in. Just a question on dosing. So you have a 2.5x exposure increase from a termociclib, and it looks like you took your 400-mig dose, and you divide it by 2.5 to get about to 150. 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 reduced a termociclib 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 the elements that you said. So that answers your first question. And your second one, it's not really that dependent on the etermocyclob dose. And so we would not need to dose reduce if the etermodose came down. So it should lead to a pretty simple dosing regimen for patients.

Got it. And maybe another question is on the medium follow-up that you've had so far as 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. And I am showing up for the questions at this time. I will now turn the call back over to Mr. Sanjeev Patel for any closing comments.

Thank you. Hopefully you can see today we're excited about using this selective-selective next generation combination to provide a much better solution for the 40% of patients that are mutated in the front line. And so we look forward to talking with you over the coming days and hopefully seeing you all in Philadelphia at the ISFA conference on May the 20th.

This concludes conference call. Thank you for your participation. You may now disconnect.