Ladies and gentlemen, thank you for standing by. Welcome to the Arvinas SABCS Data presentation. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would like now to turn the conference over to Jeff Boyle, Vice President of Investor Relations. Please go ahead. Good morning, everyone, and thank you for joining us to discuss this program update for vepdegestrant, which includes a review of two posters that will be presented at San Antonio Breast Cancer Symposium, as well as an update on the development plan for vepdegestrant. Yesterday, we issued a press release highlighting this information, which can be accessed in the investor section of our website at arvinas.com. With me today are Arvinas President and Chief Executive Officer John Houston, Arvinas Chief Medical Officer Ron Peck, and Pfizer's Vice President, Development Head of the Breast Cancer Franchise, Adam Schayowitz. Ian Taylor, Arvinas's Chief Scientific Officer, will join for the Q&A portion of the call. Turning to slide 2, and before we begin the call, I want to remind you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined on page 2 of this presentation and in the company's recent filing with the Securities and Exchange Commission, which we urge you to read. Our actual results may differ materially from what is discussed on today's call. And now I'll turn the call over to John Houston, our CEO. John? Jeff, thank you, and welcome to everyone on the call today, where we'll discuss the very exciting data released yesterday morning from our phase I-B study of vepdegestrant in combination with palbociclib. I'm on slide four, and we believe this data show that vepdegestrant has the potential to become the best-in-class oral PROTAC estrogen receptor protein degrader, and endocrine therapy of choice for patients with ER+/HER2- breast cancer. As we have seen previously, vepdegestrant degrades both wild type and ESR1 mutant estrogen receptors. More than 350 patients and healthy volunteers have now been treated with vepdegestrant across 12 different clinical trials with a good tolerability profile. The generated data demonstrates compelling and consistent clinical activity in a heavily pretreated ER+/HER2- advanced breast cancer patient population. On slide five, you will see the vision we and Pfizer have for vepdegestrant and the expanded development program, which Adam will discuss later in the... We are currently evaluating vepdegestrant in multiple trials across settings in ER+/HER2- breast cancer. Along with our partner, Pfizer, we are confident in the potential of vepdegestrant to become the backbone ER-targeting therapy of choice in breast cancer, in monotherapy or in combination settings. This slide shows the ongoing trials we have across lines of treatment, including early breast cancer and lines of therapy in the metastatic space. In metastatic patients, we have our pivotal phase III VERITAC-2 monotherapy trial, our TACTIVE-E everolimus combination trial, and the phase I-B combo trial with Pfizer's investigational selective CDK4 inhibitor. Additionally, we are studying combinations with abemaciclib, ribociclib, and samuraciclib, the CDK7 inhibitor from Carrick. In the first-line advanced space, we have our ongoing VERITAC-3 study lead-in combination trial with palbociclib. In the early breast cancer space, we have an ongoing neoadjuvant study that will help inform any future adjuvant trial. Furthermore, pending additional data and regulatory agreement, we are planning additional studies with Pfizer in first- and second-line metastatic disease. We believe these trials will be critical to expanding our development program to position vepdegestrant as the backbone ER targeting therapy to potentially benefit patients with ER+/HER2- breast cancer. Adam will share more about these potential studies shortly. Turning to slide 6. But before we get into the details of the recently announced data for the phase I-B cohort of our phase I/II study, we want to provide a brief update to our ongoing phase II VERITAC monotherapy study of vepdegestrant in patients with metastatic breast cancer. We continue to see encouraging data on our San Antonio poster, PO30508, which describes continued durable activity and favorable tolerability in this heavily pretreated patient population. 40% of patients received vepdegestrant for equal to or greater than 24 weeks, and 11% received treatment equal to or greater than 48 weeks. At the time of the data cut-off, one patient remained on therapy for more than 79 weeks. From the phase II VERITAC study, there were eight patients who would meet the eligibility criteria for our ongoing phase III VERITAC-2 monotherapy study. These patients all had prior CDK4/6 in the advanced setting, but had no prior fulvestrant and had no prior chemotherapy for locally advanced metastatic disease. Now, although this is a small sample size, in a post-hoc analysis, when we look at the data from these 8 patients, we see a clinical benefit rate of 62.5%, a median progression-free survival of 19 months, and an objective response rate of 29%. Very encouraging indeed. Our phase III VERITAC-2 monotherapy study is on track to read out top-line data in the second half of 2024. On slide 7, before I turn the call over to Ron to provide a detailed review of the I-B combo data, I want to give you a preview of why we are so excited by the opportunity in front of us. In May, we disclosed an interim look at the data, which showed a 60% clinical benefit rate, which was very intriguing as we were expecting a CBR more in the range of what I'd previously seen by vepdegestrant in this very late-line setting of around 40%. But we are really thrilled to now show that this strong efficacy signal continued through the rest of the 1B trial with an objective response rate of 42%, a median progression-free survival of 11.1 months, a clinical benefit rate of 63%, and a median duration of response of 10.2 months. Overall, treatment-related adverse events in the trial were consistent with the known profiles of palbociclib and vepdegestrant. You'll see later in the presentation that the elevated neutropenia described, we described earlier in the year, was managed effectively per protocol, which was consistent with standard on-label dose reductions of palbociclib, resulting in a 72% decline in grade four neutropenia in subsequent cycles. Importantly, no febrile neutropenia was noted through the trial, and there were low rates of discontinuation. At the patient's final dose of palbociclib, only 11% of patients had grade four neutropenia. We believe this data set is compelling, and together with Pfizer, we are very excited about the potential expansion of the development plan with vepdegestrant to include new combinations, which Adam will discuss later in the presentation. But for now, I'll hand over to Ron, who will walk you through some of the detail, the data in more detail. Ron? Thanks, John. I'd like to start by reviewing the design of the vepdeg plus palbociclib phase I-B, shown on slide 9. The combination was investigated as the third cohort of the first-in-human study, running in parallel with the monotherapy phase I and phase II expansion. Palbo was administered in all patients at a starting dose of 125 mg once daily, three weeks on, one week off, regardless of dose reduction on prior CDK4/6 inhibitor therapy. Vepdeg was escalated from 180 mg up to 500 mg, and a majority of patients were treated at 200 mg and 500 mg. The 200 mg dose was the last cohort to be completed in this cohort study and was selected as the vepdeg dose in the two ongoing phase III studies. The patient population that was enrolled in this phase I-B was a very advanced group of patients with limited treatment options. Prior therapy included 87% of patients who had prior treatment with a CDK4/6 inhibitor, with 36 of 46 patients having progressed on prior palbociclib. 45% of patients received prior chemotherapy in the advanced setting. 80% were previously treated with fulvestrant. In addition, the percentage of patients with baseline visceral disease was high, including almost 50% with baseline liver metastases. Before walking through the efficacy endpoints, I will first summarize four recently completed phase II studies that evaluated CDK4/6 inhibitor therapy in patients who had previously progressed on a CDK4/6 inhibitor-based regimen. Although we cannot compare data across trials due to the fact that these are not head-to-head studies and there are differences in study populations, therapies, and other factors, you should not overinterpret these results. The trials shown on slide 12 can provide some useful context, since the great majority of patients who were treated with vepdeg plus palbociclib had progressed on prior CDK4/6 therapy, in most cases, palbociclib. Well, baseline characteristics for these trials vary between studies as well as within this data set. You will notice that the patients treated with vepdeg plus palbociclib were, on balance, more heavily pretreated. Of these four studies, PACE and row o ne and PALMIRA and row four, were randomized studies that were specifically designed to assess contribution of palbociclib when added to endocrine therapy after prior CDK4/6 inhibitor therapy, either as immediate prior therapy or with interceding treatment. Both trials concluded that palbociclib provided no added benefit to endocrine therapy in this setting. Efficacy measures results for these studies were otherwise similar in this post-CDK4/6 setting. We will bring these results back later in the presentation in order to provide context for the results I will review in the next couple of slides. Moving to the efficacy endpoints for the phase I-B of vepdeg and palbo, slide 13 shows the waterfall plot for RECIST response for the 31 patients who were evaluable for tumor response. One of the most exciting findings of this data set is the response data.... especially in light of the prior combination trials I just summarized, as well as results for non-CDK4/6 regimens recently reported. The overall objective response rate was 42%, and all responses were confirmed. The overall response rate was similar among those patients with both ESR1 mutant and ESR1 non-mutant tumors. This is particularly remarkable given the extensive prior therapy received by these patients. Excluding the 5 evaluable CDK4/6 naive patients also led to a similarly robust response rate of 38% in the 26 evaluable patients previously treated with the CDK4/6 inhibitor. What is also important is that the median duration of response was 12.2 months. We were equally as excited by the PFS results summarized on slide 14. Median PFS was 11 months, with progression events seen in close to 50% of patients, also greatly exceeding our expectations. As with response rate, median PFS was similar in patients with ESR1 mutant and wild-type tumors. We also evaluated the median PFS, removing the 6 patients who were CDK naive, to see if they might be driving the observed benefit. The median PFS, excluding these patients, was similar at 11.0 months. Slide 15 brings the vepdegestrant and palbociclib combination results together on the same page as the efficacy measures from the CDK after CDK trial shown on the left. Again, noting that these are not head-to-head studies comparing these combinations, as well as other differences among the trials shown here. The vepdegestrant results are presented for all three key efficacy measures: objective response rate, PFS, and CBR on the right side of the page, and for the four benchmark trials on the left. The vepdegestrant plus palbociclib results were consistently robust across all three endpoints. Moving on to safety, neutropenia, a common AE associated with palbociclib, was more frequent in combination with vepdegestrant than for the two approved palbociclib indications. This was an expected finding since we first disclosed nearly a year ago that palbociclib exposures were approximately 1.5-fold higher than historical PK findings. While grade four neutropenia, the lab-related adverse event of greatest clinical relevance, was 40%, the combination was effectively managed per protocol, which aligned with the standard labeled palbociclib dose reduction algorithm, as reflected by two key important findings. 3 of 46 patients required discontinuation of palbociclib due to neutropenia, and no cases of febrile neutropenia were reported. The safety profile for the combination, otherwise, was consistent with the safety profile for the individual agents. The other important takeaway here is that the enrollment criteria permitted grade 1 QT prolongation, which was present in 9 patients. There was a single case of grade 3 QT prolongation, which occurred in a patient with a left bundle branch block at baseline. Finally, a retrospective review of all cases by an expert third-party cardiologist concluded no clear evidence of a drug-related QT effect. The swimmer’s plot for all 46 patients is shown on slide 17, with an overlay on when palbociclib was dose-reduced. Given that palbociclib-related neutropenia occurs early, dose reductions occurred early in the treatment course, and that treatment benefit extended well beyond the time of dose reduction. This is illustrated by the fact that the median time to resist response was 109 days, as compared to a median time to dose reduction of 40 days. With nearly 80% of patients requiring at least one palbociclib dose reduction, it was also not surprising that the trade-off for the higher palbo exposure was that patients in the study received only 63% of the intended full dose of palbociclib, as compared to 92% and 93% in palbociclib registrational studies, PALOMA-2 and PALOMA-3. Even when taking into account the 50% higher AUC with palbociclib, the exposure is not expected to be meaningfully different versus historical trials. These findings, together with the analysis on slide 18, supports the ongoing study lead in, in the VERITAC-3, phase III frontline study, that is randomizing 50 patients between a palbociclib starting dose of either 100 mg or 75 mg, in combination with 200 mg of vepdegestrant, in order to select the dose to take forward into the randomized portion of the phase III versus standard of care. Here we display in dark blue at top, the treatment duration in those patients who were able to receive and maintain treatment with the standard palbociclib dose of 125 mg. On the lower half of the page, in light blue, the majority of patients who were dose-reduced at least once. The takeaway here is that dose reductions had no impact on efficacy by virtue of the fact that treatment duration was longer in those who were dose-reduced. With that, I'll turn it over to Adam to provide more detail on the expanded development plan for palbociclib. Adam? Thanks, Ron. We're really encouraged by these results. On Slide 20, you can see that we recognize that 125 mg is not the optimal dose of palbo to move forward in combination with vepdegestrant, given the increased neutropenia seen in the phase I-B. However, as mentioned, the neutropenia was well managed through standard on-label dose reductions of palbo, as described in the approved label. Following the dose reduction, we observed 44% ORR and a 10.2-month median duration of response and a PFS of 11.1 months. 11% of the patients had grade 4 neutropenia at their final dose, which appears to be consistent with what we saw in the palbo plus standard of care endocrine therapies of PALOMA-2 and PALOMA-3. When looking at the patients who received a lower dose of palbo, which is nearly 80% in the study, the response rate is very strong. Importantly, the duration of response is equally as strong. Given the benefit seen at the lower dose of palbo, we remain enthusiastic about the phase III VERITAC-3 trial, the study lead-in portion of which is currently evaluating the optimal dose of palbo to combine with vepdeg. Slide 21. These data also give us the confidence to move forward in multiple combination strategies as part of Pfizer's and Arvinas' shared commitment to the development of vepdeg as a potential next-generation ER-targeted therapy in metastatic breast cancer. Pending additional data and feedback from regulatory authorities, we intend to expand the development strategy to include two new programs. First, we plan to initiate a new phase III trial in the second-line post-CDK4/6 setting with vepdeg plus palbo and potentially other CDK4/6 inhibitors. This is a space where combinations tend to be used for more aggressive disease, and we believe from the phase I-B trial data, that the use of vepdeg plus palbo in the post-CDK4/6 setting will add value. Our goal remains to establish vepdeg as a next-generation ER-targeted backbone therapy. Secondly, we plan to expand our frontline program by initiating a new phase III trial with vepdeg plus Pfizer's novel CDK4 inhibitor. Again, pending additional data and feedback from health authorities, expected in the second half of 2024. We believe planning for this study now will provide us the appropriate optionality in our development program to determine the best therapeutic combination for patients as we continue to progress the ongoing study lead-in of the phase III VERITAC trial. With that, I'll turn it back to John to start the Q&A. John? Thanks, Adam, and just before we open the call for Q&A, I want to reiterate how thrilled we are with the data from our vepdegestrant program, first as a monotherapy and now with this new data in a combination setting. As Adam stated, the totality of data gives us the confidence to move forward in multiple combination strategies as we work towards bringing this potentially best-in-class ER-targeted therapy to patients. Now let's open for Q&A. Thank you. As a reminder to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please limit to one question each, and if you need to ask an additional question, please return to the queue. Please stand by while we compile the Q&A roster. The first question comes from Ellie Merle with UBS. Your line is open. Hey, guys. Thanks so much for taking the question. Just in terms of the phase III run-in study, can you give us a little bit more color on when you expect to be able to make the dose selection and what updates we might get, if any, in terms of the safety as that's ongoing with the lower doses? Thanks. Thanks, Ellie. Ron, do you want to take that? Yeah, certainly. So, we can't—we haven't really actually guided on when those results will be available. It's a, it's a 50-patient study randomized between the two doses. You can be sure that, with our partner, Pfizer, that we're pulling out all the stops to make sure that enrollment is quick. And also, you can imagine that the follow-up does not need to be very long because it's just looking for safety and PK. But... And with regard to, what could be announced, I think it's probably safe to say that, we cannot really guide on that right now. This is a, it's a seamless trial, so ordinarily we would not be disclosing results in the middle of a trial. Okay. Understood. Thanks. Please stand by for the next question. The next question comes from Jon Miller with Evercore. Your line is open. Hey, guys, congrats on the results, and thanks so much for taking my question. Two for me. First, on the planned CDK combo in second-line phase III, the slide says palbo or potentially other CDK4/6, and I was wondering if you could give us a little more color on when you plan to make a choice there, what other CDKs you're considering, and maybe what you're hoping to see that will help guide that decision. And then secondly, maybe a little just broadly, the comps that you showed, while very illuminating, aren't for any of the other next-gen estrogen receptor drugs that are in development, maybe for obvious reasons, but we haven't seen CDK combos for those drugs mostly there. Should we be expecting similar PFS increments from CDK combo from other estrogen receptor drugs, or do you think there's something special about your degrader platform that's leading to PFS benefit beyond what we might expect from other estrogen receptor modulators? ... Thanks. Thanks, John. Certainly, we obviously think our compound's special, and a very targeted protein degrader, such as the vepdegestrant is, we believe, drives differential biology. But I'll let Ron illuminate more on that. But Ron, do you want to also talk about the planning around CDK4, and maybe Adam, kind of a view here as well? Ron? Yes. Yeah, certainly. For the question about the SERD class and what... We have a, let's put it this way. We use these CDK4/6 after CDK4/6 as what we thought were the most relevant benchmarks, but we have a, I'll tell you, a long list internally on other trials, so we can get our own handle on these data. And that also includes the SERD, a number of SERD trials in combination. All I'll say is that we're very thrilled with our results, even when we compare to the SERD trials that have been done in with CDK4/6, especially those in a late line setting. As for the second question about CDK4/6, I think I'll let Adam take that. Yeah. Thanks, Ron. So in terms of which specific CDK4/6 and when, you know, the short answer is it'll depend upon the data, right? I mean, we're comfortable with palbo now, given the data that you've seen in front of you, but as you know, we're also generating data in combination with Pfizer's novel CDK4, as well as other CDK4/6s, and it will depend on the totality of the data from each of those ongoing programs that will really influence what the ultimate combination is. It makes sense. Thanks so much. Please stand by for the next question. The next question comes from Brad Canino with Stifel. Your line is open. Thank you. Looking at slide 18, where you outlined how the dose reduction of palbos did not sacrifice the durability effect, but I'd like to ask the question the other way as well, to either Arvinas or Adam. And first is, if the 125 mg dose has a 50% AUC exposure increase, what is the effective palbo dose administered, stated in mg? And for palbo, is there any evidence of the exposure-response relationship for PFS? Thank you. Yeah, great, great question, Brad. And, well, people giving versions of the answer here. So let's start with Ron, and I'm sure, Adam, and maybe Ian Taylor could have a view on this. Brad, let me just ask you to repeat your first question. The 125 mg dose, if there's a 50% exposure increase, what is that dose stated in mg, in your estimation? In mgs. Oh, okay. This may or may not answer your question. Let me just start here, is to say that when we look at relative dose intensity, so the relative dose intensity is what we talked about in the bullet on the SABCS plot slide, which is to say that when you, based on the patient diaries and collection of data of how much palbo is administered, we saw that on average, 63% of the intended 125 mg daily dose was received by patients. That's because with a higher rate of neutropenia, there's a much more interruption and dose reduction, for instance, by standard criteria, a patient who crosses from grade 2 to grade 3 has to stop their palbo and then resume it when it goes to, you know, go back to grade 2 or better. And then for any grade 4, you get those reduced. So there's basically, it's kind of like a wash, is that while there's a higher exposure, they're not getting as much dose through and through. And even when we adjust for the higher exposure to those numbers, we come up with something quite, quite similar. And what I would say is with regard to exposure response, and of certainly, the Pfizer team has been, are the experts here. I will say that when you look at publications out there and, you know, even the original FDA review document for palbo's initial approval, you'll see exposure response analyses that don't show any meaningful correlation between exposure and PFS at the recommended dose range. So between that and, you know, the quick dose reductions and all that, we really feel quite confident that with the optimal dose that we don't expect to see much of any impact on efficacy here. Adam, would you add anything there? I think it was well said by Ron. I would not, John. Thank you. Thank you. Please stand by for the next question. The next question comes from Yigal Nochomovitz with Citi. Your line is open. Hi, guys. This is Ashiq Mubarack, not Yigal. Thanks for taking my questions, and congrats on all the progress. I just have one broad question: How are you thinking about the relative contribution of efficacy from the combo for each of the components? I guess the question is sort of based on the idea that, you know, maybe some of the benchmarks you showed suggested that CDK4/6 isn't necessarily adding much in a post-CDK4/6 population. And similarly, in your monotherapy experience, you showed, you know, that your monotherapy had the best efficacy in the ESR1 population. So I'm curious how you're thinking about the contribution of components, especially in this late line setting. Thanks. ... Yeah, thanks. A great question. As you rightly point out, this is in a post CDK 4/6 setting where patients have maybe previously progressed in that setting. So yeah, it's really intriguing to see the data set where we believe that there's some kind of synergistic interaction happening. But Ron, why don't you give a kind of more comprehensive answer there? Yeah. So yeah, this is a point of discussion internally. And as Ian Taylor, who's actually here, will say, and it's also, I think, quite consistent with this being a very potent degrader, is that what we know for sure is that there is a strong level of synergy here that we're achieving, that we've shown pre-clinically, and Ian can certainly comment more about that. And so, for us, this is just really, we do believe that there is some component of the two drugs working together, for sure, exactly as you point out. So maybe, Ian, I don't know if you wanna add anything more to this. Yeah. I think the synergy between the ER pathway and the CDK pathway has been well established in the PALOMA studies. Clinically, we've certainly shown synergy with vepdegestrant and palbo, and other CDK inhibitors. Pre-clinically, we published some of that data, and we'll publish more. So I think that's what we're seeing here, is when you hit both pathways hard in this late line setting, you get tremendous responses in both the ESR1 mutant and wild- type. It's almost like the synergy is equalizing across those different molecular phenotypes of the tumors. In monotherapy, you're not getting that synergy, so there, the ESR1 mutant is really a strong signature for ER dependence, and that's why we see better response there. We see, obviously, some good response in wild-type, but not as much as when you have the synergistic action of the two compounds coming together. And on top of that, we've always said, we really believe it, vepdegestrant is the best way to target ER. Degrading is better. We have the best degrader. It all adds up to having great efficacy and combination. Yeah, and I'll just cap off to just say that this gives us also a lot of excitement to combine with Pfizer's novel CDK4 inhibitor. Got it. Thanks very much. Please stand by for the next question. The next question comes from Michael Schmidt with Guggenheim. Your line is open. Hi, good morning. This is Yigal on for Michael. Thanks for taking our questions, and congrats on the progress. One question from us on the phase I-B combo data. Have you looked at patients with dose reduced to 100 mg versus 75? I just wondering if you get any preliminary evidence here to show whether 75 or 100 is a better combo dose given the early dose reduction you mentioned. And then a quick follow-up. The CDK4/6 combo phase III you just announced makes sense, and you know, given the dynamic landscape, it sounds very interesting. What is the level of commitment to continuing rolling VERITAC-3, and how would you balance your resource? Thank you very much. Yeah, thanks. It's a great question, and starting with that second question, both Arvinas and Pfizer are completely committed to continuing the palbo vepdegestrant study. We've got the study lead-in phase, and then we'll get that data next year, and we'll be in a position to then segue into a first-line study based on the data. So what we're trying to do right now is basically create a lot of data between now and next year related to vepdegestrant plus palbo and vepdegestrant plus CDK4, and it just gives us great optionality for both Pfizer and Arvinas to help choose. So there's lots of options here, but we are very committed to moving and as are Pfizer, to moving forward with the palbo study. Ron, do you want to take the other question there? Yeah, certainly. So the question was around... Question. Yeah, I think the question was around whether we can discern from this data set which palbociclib dose is likely to be better between 100 and 175. I will say that this is not the right data set to really do that. Retrospectively, I would say directionally, if you look at the breakdown of patients who were dose reduced versus not, well, there's also a further breakdown of patients who were dose reduced in 75 versus 100. There's some bias when you get into that because patients who stayed on longer are more likely to have been dose reduced to 75. So this is not the right data set. And then the other thing I'll just add is that there's a poster being presented here at San Antonio that came from the clinical pharmacology group from Pfizer that does modeling to predict what is likely to be the optimal dose of palbo in combination with bebtel, and from that poster in particular, which is basically based on modeling, it looks like more likely than not, it will be the 100 mg, but really the, the answer is gonna be coming from the study lead-in. Please stand by for the next question. The next question comes from Derek Archila with Wells Fargo. Your line is open. Good morning. It's Yvonne for Derek. Thanks for taking our question. A quick one from us. Can you provide a bit more color on the neutropenia cases and how were these managed? And specifically for the 11% of patients with grade 4 neutropenia patients' final doses, can you discuss what these doses were and how do they compare to the phase III? Thanks. Thank you. Ron, that sounds like a question straight for you. Yeah. Well, yeah, I think with the, I mean, I'll start with the conclusion, and I'll work backwards. I mean, I think with even the higher neutropenia rate, and as a medical oncologist, I can tell you that grade 4 is really what oncologists care about. It's an absolute neutrophil count below 500. While we had grade 4 neutropenia of 40%, which is actually quite manageable. I mean, investigators thought it was perfectly not an issue. And we expect that with the optimal dose, it'll be lower. However, even with this dose, we saw that the neutropenia was actually very responsive to dose reduction. This is actually already known quite well for palbociclib. We had actually more than 70% impact of dose reduction, dropping the rate of grade 4 neutropenia pre versus post-dose reduction. Very effective. Only 3 out of 46 patients had to discontinue due to neutropenia, so that's one measure. The other thing, as I mentioned in the presentation, is we had no cases of febrile neutropenia. That is the most important consequence of this, and the fact that we did not see any febrile neutropenia is really boding for the safety, even at a dose that we're not likely to go forward with. So and I think the question was about the other part of that question, I think you were asking, was the rate of neutropenia after dose reduction? Perhaps I think that was, that was in our presentation, and, and I guess the point was that while a neutropenia overall was grade 4, was about 41%, if you look, all told, only about 10% of patients had a persistent grade 4 after dose reduction across the denominator of 46 patients. So all told, we're really, you know, confident with the manageability, even at a dose we're not likely to go—that we would not be going forward with. Please stand by for the next question. The next question comes from Akash Tewari with Jefferies. Your line is open. Good morning. This is Irene from Akash. Thanks for taking our questions. We just have one quick question, is how long have patients enrolled in this combo study pre-treated by prior CDK? 'Cause if we look at the post-hoc analysis for EMERALD, it looks like longer prior CDK exposure seems to translate to better efficacy for the SERD. So what's your take on the role of prior CDK duration in relation to the efficacy within the current population? Thanks. Thanks for the question. Ron, prior CDK exposure? Yes. Yeah, certainly. I, for this data set, we don't actually have those data yet. That depends on collecting literally start and stop dates of prior therapy, and since this is an ongoing data set, we don't have that information. However, I would say that if we have looked at that question for the monotherapy phase II expansion, and when you compare the different buckets of exposure that are similar to the breakdown of Emerald in their presentation last year at San Antonio, we actually had more patients progressing earlier than the Emerald trial. So I suspect that it will be the same thing here because it's the same investigators, and even prior therapy breakdown was quite similar. So I don't... I, I think that there's not gonna be any surprises there. Thanks. Please stand by for the next question. The next question comes from Christopher Liu with Leerink. Your line is open. Hey, guys. Thanks for the question, and congrats on the data. Just two questions from me. So for the first one, based on the efficacy profile you guys have between ESR1 mutant and ESR1 wild type, it looks like you guys have efficacy in both kind of subgroups. Do you feel like this is something kind of unique to Arvinas or, you know, something that we could also see with the other ER modulators or degraders, and oral SERDs? And then for the second question, more of an enrollment one, I guess, for phase III, do you feel like having a lower dose of palbo is going to affect enrollment at all? Thanks. Thanks for the question, and couple of different ones there. Ron, do you want to tackle the efficacy one, and maybe Adam can talk about enrollment, the lower dose? Yeah, I might actually bring Ian in to answer the question, just from a biologic perspective. Yeah, I mean, it's similar to what I was saying before. So, you know, I can't speak to what other, what the SERDs might show in combo in the same late-line setting. But I will say again, that we believe vepdegestrant is a unique way to degrade ER. We've shown it many times that degrading is better, and having the best degrader is the best approach, which is what vepdegestrant is. So, the fact that, when you add in the synergy of the pathway, hitting both pathways with the best degrader- ... then I believe that's why we're seeing this equal efficacy across the wild type in ESR1 mutant pathways. It's, it's synergy plus best degradation equals great PFS. Enrollment at lower dose. Any answer there from Adam or Ron? Yeah, happy to, John. I mean, the short answer is no. We don't anticipate any enrollment challenges. I mean, the doses for palbociclib that we're talking about are all within the standard recommended doses for the label, and standard dose reductions. While we may be starting at a slightly lower dose, we're all within a very comfortable therapeutic range that we don't anticipate any activity. And to be clear, we're talking about the doses of the experimental arm, not necessarily the control arm, which will start at full dose palbociclib, assuming that is a control there. So no impact on enrollment from our perspective. Thank you. We're just waiting for the next question. Operator, are you still there? Yeah. Our next question comes from Li Watsek with Cantor. Your line is open. Good morning. This is Rosemary on for Li. Thanks for taking the question. Just a quick one from us. Can you maybe give more detail on why, like, the responses with the full palbo dose versus reduced, why this doesn't seem to translate into differential ORR? Or do you think maybe the ends are too small to draw this kind of conclusion? Thank you. Thank you for the question. So, related to differential ORR, Ron, do you want to take that? Yeah, I mean, I think what I would say is it kind of goes back to the question about exposure response analysis that we talked about, which is that at least with palbociclib, you see it and within the recommended dose range, there hasn't been any clear relationship or meaningful relationship between exposure and efficacy. So I think that really kinda addresses this. And then also I mentioned earlier or in the presentation, that there's kind of a wash element here because there's gonna be a you know a compensatory interruptions and dose reductions to account for the neutropenia. So it kind of it works out to be a wash here. So that's why we think that there's no added advantage for 125. Thank you. Please stand by for the next question. The next question comes from Peter Lawson with Barclays. Your line is open. Good morning. This is Shayon for Peter. Thanks for taking our question. In regards to the new trials that you're doing with Pfizer, it looks like you're looking to get feedback from the regulatory agencies in second half 2024. Should we be thinking that this could be an early 2025 start? Could you help add some color for how these will fit in with the current Phase III trials you have going? Related to that, maybe help touch on the rationale for why adding in abemaciclib could help with retreatment of the CDK4/6 inhibitors. Thank you. Thanks. Yeah, we haven't guided to when the trials would start. We're in the planning stages with Pfizer. Clearly, with the first line study with palbociclib, that study lead-in stage has already started ongoing, and that would segue into the randomized stage, and that would be after that dataset. And then planning for a CDK4 first line combination study, that's in planning. And then the second line study with palbociclib, that's also in planning. So we'll give more guidance as we get through kind of regulatory interactions. But clearly, both Pfizer and Arvinas are moving really fast to get to those new plans. Ron, do you want to take the second part of this? Okay. Can you repeat the second question, please? Yes. If you could add any color for why adding in vepdegestrant could help with retreatment of a CDK4/6 inhibitor in contrast to some historical documentation? Yeah. I mean, I think that the first thing is, I mean, the data are the data, right? So it's what we've seen, and it's, you know, for us, really, it has really shown something that we hadn't frankly even anticipated because and I think the other piece of this is what, Ian was saying before, which is scientifically and mechanistically, we believe that this degrader is synergizing with palbo, even in patients who've had clinical resistance here. So between the mechanistic premise and the clinical data that we see in front of us, it's the obvious choice to base and move this forward to, work to get this available for patients. Please stand by for the next question. The next question comes from Srikripa Devarakonda with Truist. Your line is open. Hey, guys, congrats on the data, and thank you so much for taking my question. I understand that these are, you know, small numbers, but given the subset analysis in the CDK4/6-naive patients, and you showed 19 months of PFS, I was wondering if there's any—if you've done any analysis yet about difference in dose exposure of palbo between patients who had prior CDK4/6 and who are naive. And just wondering how this might impact dose exposure and dose selection, especially for the frontline study. Thank you. Yeah, thanks very much. And I imagine the answer is gonna be early days in terms of analysis of that data. But, Ron, anything you'd want to add there? No, I think that's exactly right. We're getting into small numbers. We haven't done that analysis. We tend to, you know, look at our data, try to learn as much as possible. We haven't done that analysis. The numbers are gonna be small, though. And as I mentioned earlier, really, the proof will be in the pudding from the study lead-in, that's really what's gonna inform our dose for the combination with palbociclib. Got it. And if I can ask a follow-up question. The, this is about the ESR1 mutant and the wild- type data. With the combination, it seems like the response rates and the PFS seem comparable. Again, small numbers of patients, but I was wondering if, you know, your level of confidence that the combo works across all comers and that this could be an all-comer opportunity, and if there's, if there's anything in the baseline characteristics that, you know, the regulators might pick at. Yeah. I mean, certainly, we're very confident about the dataset. Ian Taylor mentioned earlier on, you know, the combination of an incredibly strong a degrader plus palbo synergy with the the mec- the mechanism, I think really is leading to the dataset we're seeing and this balance good balance between wild type and ESR1. So we're very confident about that dataset moving forward. The latter question in terms of regulatory authorities, well, I mean, obviously, we'll have a regulatory interactions going forward, and at some point, we'll be able to describe those, but we usually don't try and speculate about how that interaction will go. But we're very confident about the dataset. Great. Thank you so much. I show no further questions at this time. I would now like to turn the call back to John Houston for closing remarks. Well, thank you so much, and, thank, thank you for all the great questions and for turning up the meeting. As you can tell, we're incredibly excited about our dataset here and looking forward to a very exciting 2024 as we move forward in these various trials and planning for the initiation of some new interactions with vepdegestrant. So thank you so much for your time this morning. This concludes today's conference call. Thank you for participating. You may now disconnect.