Relay Therapeutics, Inc. ($RLAY)

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 updating with you today. You can access the press release for 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 expressed or implied statements regarding our strategy, business plans and objectives, the expected therapeutic and clinical benefits for our product candidates, potential of our platform and our product candidates and progress timing and execution of our clinical trials. Such forward-looking statements are not guarantees of 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 take -- undertake no obligation to update or revise at in these statements. I'm also joined here today by -- with Sanjiv Patel, our CEO; and Don Bergstrom, our President of R&D. And 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, our pan-mutant selective PI3K-alpha inhibitor, which has the potential to address 3 very large commercial opportunities. The first of these opportunities is second-line hormone receptor positive, HER2-negative metastatic breast cancer. Last month at ESMO [ Tech ] 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, capivasertib. And 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. And we've been pleased to announce today that we've selected atirmociclib, Pfizer's selective CDK 4, as the CDK combination partner for our first-line regimen with zovega. The data we'll share today will share why we're very excited about the choice, as in heavily pretreated patients, the early efficacy and tolerability of the zovega-atirmo 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. 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 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 [ ISPOR Conference ] in Philadelphia, will share data from [ the SERD ] 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 zovega 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 INAVO120 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 nonselective PI3K inhibitor with a nonselective CDK inhibitor leads to a profile that could be challenging for patients to tolerate for multiple years and has led to the 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 frontline by having a better tolerability profile that allows patients to maintain their dose intensity over multiple years. We hope to do that in 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 atirmo. We believe this selective, selective profile should drive greater tolerability, leading to greater efficacy. The data we report today from the triplet of zovega, atirmo and fulvestrant in median third-line patients gives us great confidence that we can hit this profile. And we're pushing to initiate the 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 atirmo triplet. And this long-term tolerability that we're seeing of the zovega-atirmo 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 zovega combined with atirmo and standard dose fulvestrant. We did observe an effect of atirmociclib on blood concentrations of zovegalisib. Atirmociclib increases the concentration of zovega by about 2.5 fold. So a 150-milligram dose of zovega combined with the atirmo [indiscernible] the blood concentrations of zovega that approximates the exposure we achieved at the 400-milligram dose of zovega combined with fulvestrant that we were testing in the ongoing ReDiscover 2 trial. Zovega does not appear to impact blood concentrations of atirmo. And we will prioritize moving forward with the 300-milligram dose of atirmo, which is the dose Pfizer investigated in the positive [ IV Light 1 ] trial and is currently investigating in the ongoing [ IV Light 3 ] frontline trial. We will disclose data from 62 patients treated with the triplet of zovega plus atirmo plus fulvestrant, with a median follow-up of 7.4 months. Patients were dosed with doses of zovega between 100 and 200 milligrams BID and doses of atirmo between 100 and 300 milligrams BID, all with standard dose fulvestrant. We are not reporting data on patients treated at the 200-milligram dose of zovega combined with the 300-milligram dose of atirmo 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 milligrams 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 1 prior CDK4/6 inhibitor therapy, and we're allowed to receive more than 1 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 [ SERD ] and more than 1/4 had been treated with chemotherapy or an ADC for advanced breast cancer. The patients also had notable features with nearly half of the patients being prediabetic 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 zovega. All 3 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 atirmociclib and fulvestrant approximated the zovega exposure, we achieved a 400-milligram BID in the double combination with fulvestrant, the dose we're testing in the ongoing ReDiscover 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 zovega plus atirmo 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 is ranged between 53% to 55% in registrational clinical trials. Importantly, the ORR was comparable in patients with both kinase and nonkinase domain mutations. And responses were observed in patients who had received a prior SERD and/or a prior PI3K pathway inhibitor. Of note, 1 patient, who initially was a confirmed CR, has now converted to an unconfirmed CR. With the acknowledgment that these are cross-trial comparisons, we can compare the 44% ORR observed for zovega plus atirmo plus fulvestrant with other PI3K triplets tested in later-line ABC patients. In December, Roche disclosed the triplet of inavolisib with 600 milligrams 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 zovega plus atirmo plus fulvestrant triplet. And 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. And 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. And with the tolerability profile we were observing for the zovega triplet, we expect this will translate into PFS benefit for frontline patients, and therefore, it gives us the confidence to take the zovega plus atirmo 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 2.5 to 3 years, and to be able to treat a broad spectrum of PIK3CA mutated patients in the front line, not just endocrine-resistant patients who are treated in the INAVO120 trial, inavolisib. We are very encouraged that the tolerability profile we are seeing with the triplet of zovega plus atirmo 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 prediabetic at study entry. Only -- or less than 10% of patients dose-reduced zovega and 16% dose-reduced to atirmo, with the combined rate of reduction either [indiscernible] drug being 23%. And there were very few discontinuations due to TRAEs, with 2 patients discontinuing zovega and 4 patients discontinuing atirmo. Of note, 2 of the patients who discontinued atirmo remained on study receiving the zovega 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% zovega reductions compared 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 ribo and abema, respectively and 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 zovega plus atirmo triplet. After 7.4 months of median follow-up, out 48 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 zovega plus atirmo plus an aromatase inhibitor versus a CDK4/6 of investigator's choice, ribociclib, abemaciclib or palbociclib plus an aromatase inhibitor. Given you're testing both zovega and atirmo 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 PIK3CA 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. And we can also explore other classes of combination partners, including oral SERDs. We've assembled an advisory board of leading global breast cancer investigators to guide us to 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 2 novel selective inhibitors could provide patients, and 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 atirmo 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 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 zovega to address 2 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 frontline patients. And we look forward to sharing initial vascular anomalies data next month at [ ISVA ] 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.

[Operator Instructions] And our first question coming from the line of Brad Canino with Guggenheim.

It's great to see these data and the progress towards the frontline trial. A couple of questions for me, if I may. First, you talk about the benefit of the novel selective, selective approach versus the combo with CDK4/6 inhibitors, which you also tested. What were the safety data like for the palbo combo? And how do you think competitors will fare if they are potentially going to go down the CDK4/6 triplet route?

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 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 atirmo, which is it's driven by its selective nature of it only targeting CDK4 and nulling out the CDK6 toxicities. And then obviously, combining that with zovega, another mutant selective inhibitor. And so for us, both agents together led to a tolerability profile that we think would lend itself to a multiyear frontline treatment that a nonselective PI3K inhibitor or nonselective CDK inhibitor just cannot lend itself to.

Okay. And second, you build this approach is 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 III trials?

Pete, do you want to take that one?

Yes. Thanks for the question, Brad. Yes, there are limitations for both us and Pfizer 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 selective approach.

Okay. And then last for me. It looks like the [indiscernible] 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.

Yes. So what we've seen in [ rash ] has been primarily low grade, well-managed with antihistamines. It is something that we've not seen at high rates before with zovega. And I think we'll wait to see more robust disclosures from a term including the upcoming [ IV Light 1 ] disclosure to understand what the potential contribution of atirmo 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 [indiscernible] patients who have seen those prior PI3K pathway inhibitors. But I think we need more experience to fully understand it.

Our next question coming from the line of Akash Tewari with Jefferies.

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 77% patients that are still continuing on trial, and safety to give you confidence that you could superiority in the setting? I believe [ Mona Lisa ] has shown around 25-month PFS. So 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 it over to Don.

Yes. So I think your point, Amy, with tolerability is key here. And 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 3/4 of patients still on study. As you can see in the swimmers plot, patients whom were achieving responses are maintaining those responses with long durability. So we haven't been able to really meaningfully calculate the ORR 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 [ sensored ] patients, those [ sensored ] 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 with 3/4 of patients still receiving the dose of drug that they started with when they started -- when they came on study. With regard to what we think we'll need to see in a frontline trial, as you point out, [ MonaLisa ] 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 this 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 the -- your endocrine-sensitive [indiscernible] sensitive, I think that it's the place where everyone would like to go if you had a regimen that afforded to 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 probably a success standpoint. So we will be running this trial, again, it's just a doublet standard of care without the involvement of a pathway inhibitor. That in combination with the supply agreement where we get atirmo and palbo supplied for free allow us to run a very manageable frontline trial from a cost effectiveness standpoint.

Excellent. And then just another one, how much do you think atirmo 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.

Yes. So I think what we're seeing really here is the triplet activity. First of all, we're coming in at 44%. We haven't really seen a large data set of the atirmo doublet in the later line patient population. So that 32%, I think, was based on 23 or 24 patients who were -- who had measurable disease, and specifically in PIK3CA mutant patients, they only had 10 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 atirmo and treated with both fulvestrant and [ latrizol ]. So small data sets, very heterogeneous I think as we look at the data we're seeing and given that we're exposures that we know are active exposures to zovega, we think we're really seeing the activity of the triplet.

Our next question coming from the line of Yaron Werber with TD Cowen.

This is Jaena on for Yaron. I wanted to double-click a little bit also on the contribution of atirmo versus zovega. When we look at your prior doublet data, obviously, this is at the pivotal dose and then a more refractory -- in a less refractory population. But overall ORR increased 44% versus 43% for your [indiscernible] data. Can you give us any kind of -- any more detail on how the ORR breaks down by [indiscernible] for zovega and how you might expect what degree of improvement do you expect to see as you move to [ 1.0 ] additionally with an aromatase inhibitor plus fulvestrant?

Okay. So maybe we'll break the question down. We'll just finish off the last question around the contribution of atirmo. I think the most kind of powerful thing, obviously, the fact that Pfizer has entered into a supply agreement, so there's definitely a belief. They have perfect information on the [ 4 Light ] trials that there is going to be an additive component for zovega. And so then if you come to your question around what is the comparison between our doublet data where we're sitting in the kind of high 40s with 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.

Yes. 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 stations, which to us suggests that we're seeing triplet benefit in those patients. In terms of the dose responsiveness that we've seen, we've reported out these data with pool data [indiscernible] patient treated at or below the recommended Phase III dose of 150, 200, 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 studied. I think as we get more data at our optimized doses, we expect we should be able to see 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, whether you're talking about the CDK4/6 inhibitors themselves with CDK4/6 retreatment, or the experience with inavolisib moving from Phase Ib in CDK4/6 or second-line and later patients in the front line, you're generally seen a 20% to 30% increase in ORR as you move into the front line.

Great. And I have a follow-up, then one more question. Your ORR data excludes kind of, as you mentioned, the 200 mg BID zovega and 200 mg BID atirmo, due to the [indiscernible] not being quite as optimal even though it didn't quite reach [indiscernible], can you give us any more details on what exactly you observed here to warrant this [indiscernible]?

Yes. I mean we just had a slightly higher rate of higher grade AEs that led to dose reduction, right? And our goal here is really to have a regimen that is giving us the target coverage you 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, we knew that we could move on from that highest dose that we tested. Tolerability is going to be the critical part of this triplet.

Our next question coming from the line of Sean McCutcheon with Raymond James.

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.

Thanks, Sean. We have ongoing expansions with both fulvestrant 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 the regulatory interactions, are the main gating items before moving on.

Our next question in queue coming from the line of Salveen Richter with Goldman Sachs.

Just a bigger picture question here about how you think of positioning versus competition such as Celcuity and others in the marketplace, and 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 -- 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 adding a PI3K-alpha inhibitor should drive to greater efficacy. And then using atirmo 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 a 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 you mentioned there are other agents in this field. Obviously, there's some of them will be using the traditional CDK4/6 backbones, and we think that they will have increased tolerability challenges. And obviously, we see that with the uptake of inavolisib not being as robust as I think folks expected post the approval. And then obviously, you mentioned gedatolisib. As you know, gedatolisib 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 [indiscernible] mouthwash and potentially then other concomitant medications for the AE, 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 frontline that should allow these patients to live as normal lives as possible.

Yes. On the updates from your question, 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.

Our next question coming from the line of Etzer Darout with Barclays.

This is Luke on Etzer. Kind of similar to the previous ones [indiscernible] to see how you're benchmarking this, because you are in your Phase III [indiscernible] versus CDK4/6 and an aromatase inhibitor as a comparator arm, talking to KOLs, is there anything like that they are looking for out of your triplet that we should be putting attention to that may like kind of come out of that Phase III trial?

Yes. I think it's kind of more of what we talked about. I mean, INAVO120 trial showed you that by adding a PI3K inhibitor, you clearly saw greater PFS and OS. So it's -- 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 inavo 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 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 this is a heavily pretreated patient population. We're seeing low rates of neutropenia, which is obviously being driven by atirmociclib's profile. You see no Grade 3 hypoglycemia here, which is obviously being driven by zovega's profile. So the things that could potentially disrupt these patients in the frontline on chronic treatment, are you're seeing lower rates on. So I think that's the thing that people are most focused on when we talk to KOLs. Don, if I missed anything.

No, I think you really hit. And the other part of that is not just keeping patients on the triplet by being able to choose to use the triplet in a broad range of patients, as opposed to your very narrowly selected [indiscernible] patients. And it comes back to the profile that we're looking to achieve, one where the overall toxicity burden on the patients and the physician for the triplet can be comparable to but not worse, potentially even better, than the existing doublet study we used in the front line. And we think that's really the profile and we -- to get both broad utilization and [indiscernible] superior benefit.

Our next question coming from the line of Chi Fong with Bank of America.

Thanks for the update. First one, maybe a follow-up. I believe you started exploring the palbo and ribo triplet earlier before atirmo came into the picture. I'm curious, can you talk about how the atirmo triplet data compared to palbo and ribo 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 clean the CD4 -- CDK4 can add to zovega triple more so than a CDK4/6 could as we think about the Phase III comparison.

I think it's kind of more of the kind of high level that we've discussed, which is we're very familiar, a lot of data in the public domain around the CDK4/6 plus endocrine therapy in the front line. They have high rates of neutropenia, some of them have diarrhea. And so we know what that profile looks like. And we know what adding a PI3K inhibitor to that profile looks like because we've seen it done with palbo in the INAVO120 trial. So I think coming back to what are we most impressed about, we're impressed with atirmo's ability to dial down the CDK6 related toxicities. And you see it in all the data that has Pfizer shown. It's an impressive compound. And so then you stack that 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 we have very low Grade 3 hypoglycemia. So you stack the 2 together and you get a profile that, for the first time, you could potentially put 3 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 efficacy -- or sorry, 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 the -- both the 150-milligram or 100-milligram dose of zovega. How do the results compare between the 2 dose ranges?

Yes. 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 then straight through to the higher doses, ultimately, even -- especially at the 150. So everything has been relatively consistent to date. And we imagine as we get more experience at the 150 specifically over time and likely more like pretreated patients, we'll continue to see that increase.

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, 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 the study.

Our next question coming from the line of Eva Fortea with Wells Fargo.

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?

Yes. I mean I think the Grade 4 events have been very rare and well managed. So in general, Grade 4 AEs have not been an issue.

Our next question coming from the line of Silvan Tuerkcan with Citizens Bank.

Maybe a quick first one, what can you tell us about, at this point, about the [non-kinase ] non-Case and [ kinase ] 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 CDK4 and in the [ 4 Light 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 the triplet? Or how could we envision this coming to market at some point?

So I think to take your first question around kinase and nonkinase, 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 nonkinase. 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.

Our next question coming from the line of -- for a speaker with [ Jones Trading ].

Just a question on dosing. So you have a 2.5x exposure increase from atirmociclib, and it looks like you took your 400 mg dose and you divided it by 2.5 to get about to 150. I'm just curious how consistent is this 2.5 [ ex PK ] interaction across different patient weight 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 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. 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 atirmo dose 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 is about 7.5 months. When will we see the mature PFS for the triplet combo?

At some point in the future.

And 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 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 ISPOR Conference on May 20. Thank you.

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