Arvinas, Inc. (ARVN) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. Welcome to the Arvinas SABCS data presentation. [Operator Instructions] 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 2 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 Investors section of our website at arvinas.com. With me today are Arvina's 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' 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 filings 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 Ib study of vepdegestrant in combination with palbociclib. I'm on Slide 4, 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-positive HER2-negative breast cancer. As we have seen previously that vepdegestrant degrades both wild-type and ESR1 mutant estrogen receptors. More than 350 patients in 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-positive HER2-negative advanced breast cancer patient population. On Slide 5, you will see the vision we and Pfizer have for vepdegestrant  and the expanded development program, which Adam will discuss [indiscernible]. We are currently evaluating vepdegestrant in multiple trials across setting an ER-positive HER2-negative breast cancer. Along with our partner, Pfizer, we are confident in the potential of vepdegestrant to become the backbone ER target 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 a pivotal Phase III VERITAC-2 monotherapy trial, our TACTIVE-E everolimus combination trial and the Phase Ib combo trial with [ 5 ] 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-positive HER2-negative breast cancer. Adam will share more of these potential studies shortly. Turning to Slide 6. But before we get into the details of the recently announced data for the Phase Ib 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 and our San Antonio poster, PO3-05-08 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, and at the time of the data cutoff, 1 patient remained on therapy for more than 79 weeks. From the Phase II VERITAC study, there were 8 patients who 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. And 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 one -- the 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 are expecting a CBR more in the range of what 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 Ib trial with an objective response rate of 42%, a medium 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 and you'll see later in the presentation that the elevated neutropenia 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 4 neutropenia in subsequent cycles. Importantly, no febrile neutropenia was noted through the trial, and there were low rates of discontinuation and the patient's final dose of palbociclib, only 11% of patients had grade 4 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 Ib 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 milligrams once daily, 3 weeks on, 1 week off, regardless of dose reduction on prior CDK4/6 inhibitor therapy. Vepdeg Was escalated from 180 milligrams up to 500 milligrams and majority of patients were treated at 200 and 500 milligrams. The 200-milligram dose was the last cohort to be completed in this cohort study and was selected as the vepdeg dose in the 2 ongoing Phase III study. The patient population that was enrolled in this Phase Ib 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 4 recently completed Phase II studies that evaluated CDK4/6 inhibitor therapy in patients who have previously progressed on a CDK4/6 inhibitor-based regimen. Although we cannot compare data across trials, the fact that they are -- these are not head-to-head studies, and there are differences in study pop -- there are differences in the study populations, therapies and other factors, you should not over-interpret these results. The trial shown on Slide 12 can provide some useful context since the great majority of patients who are treated with vepdeg plus palbociclib had progressed on prior CDK4/6 therapy in most cases, palbociclib. While baseline characteristics for these trials vary between studies as well as within this data set, you will notice that the patient with vepdeg plus palbociclib were on balance more heavily pretreated. Of these 4 studies, PACE in row 1 and PALMIRA in row 4 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 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 Ib 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. The 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 vepdeg and palbo 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 vepdeg results are presented for all 3 key efficacy measures, objective response rate, PFS and CBR on the right side of the page and for the 4 benchmark trials on the left. The vepdeg plus palbo results were consistently robust across all 3 endpoints. Moving on to safety, neutropenia, a common AE associated with palbociclib was more frequent in combination with vepdeg than for the 2 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 4 neutropenia, the lab-related adverse event of greatest clinical relevance was 40% and the combination was effectively managed per protocol, which aligned with the standard label palbociclib dose reduction algorithm as reflected by 2 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 is 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. Swimmers plots for all 46 patients as shown on Slide 17, with an overlay on when palbociclib was dose reduced. Given that palbociclib belated 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 1 palbociclib dose reduction, 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% and in palbociclib registrational studies, PALOMA-2 and PALOMA-3. Either 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 the VERITAC-3 Phase III frontline study that is randomizing 50 patients between a palbociclib starting dose of either 100 milligrams or 75 milligrams in combination with 200 milligrams of vepdeg 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 are able to receive and maintain treatment with the standard palbociclib dose of 125 milligrams. 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 vepdegestrant. Adam?

Thanks, Ron. 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 vepdeg given the increased neutropenia as seen in the Phase Ib. However, as mentioned, the neutropenia was well managed through standard on-label dose reductions of palbo as described in the approved label. And following the dose reduction, we observed a 44% ORR and a 10.2-month median duration of response and a PFS of 11.1 months. 11% 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. And 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 leading 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 2 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 Ib trial data, 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. And with that, I'll turn it back to John to start the Q&A. John?

Thanks, Adam. And 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. And 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. So now let's open for Q&A.

[Operator Instructions] The first question comes from Eli Merle with UBS.

Just in terms of the Phase III VERITAC 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, Eli. Ron, do you want to take that?

Yes, certainly. So we can't -- we haven't really actually guided on when those results will be available. It's a 50-patient study randomized between the 2 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 in 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 the trial.

The next question comes from Jon Miller with Evercore.

Congrats on the results. Two for me. First, on the planned CDK combo in second-line Phase [ III ] decides as 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 here, what other CDK's 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, John. Certainly, we obviously think our comp is special. And a very targeted protein degrader, such as the vepdegestrant as we believe drives differential biology. But I'll let Ron eliminate more than 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, certainly. For the question about the III class and what we have -- let's put it this way. We use these CDK after CDK 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 SERD -- 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.

Thanks, Ron. So in terms of which specific CDK4/6 and when -- the short answer is it will 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.

The next question comes from Brad Canino with Stifel.

Looking at Slide 18, where you outlined how the dose reduction of palbo 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 mgs? And for palbo, is there any evidence of the exposure response relationship for PFS?

Yes. Great question, Brad. And people giving impressions 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.

And 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 mgs in your estimation?

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 that -- in the bullet on the swimmers 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-milligram daily dose was received by patients. And that's because with the higher rate of neutropenia, there's a much more interruption and dose reduction, for instance, by standard criteria patient who crosses from Grade 2 to Grade 3 has to stop their palbo and then resume it when it goes to -- 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 similar. And what I would say is with regard to exposure response and certainly the Pfizer team has been -- are the experts here. I will say that when you look at publications out there and even the original FDA review document for palbo's initial approval, you'll see exposure response analysis that don't show any meaningful correlation between exposure and PFS at the recommended dose range. So between that and 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, if 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.

The next question comes from Yigal Nochomovitz with Citi.

This is Ashiq Mubarack on for Yigal. Congrats on all the progress. I just had 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 maybe some of the benchmarks you showed us suggested that CDK4/6 wasn't necessarily adding much in a post-CDK4/6 population. And similarly, in your monotherapy experience, you showed that your monotherapy had the best efficacy of the ESR1 population. So I'm curious how you're thinking about the contribution of components, especially in this late-line setting.

Yes. That's a great question. As you rightly point out, this isn't a post-CDK4/6 setting where patients have maybe previously progressed in that setting. So yes, it's really intriguing to see the data set where we believe that there's some kind of synergistic interaction handling. But Ron, why don't you give a kind of more comprehensive answer there.

Yes. So yes, 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 preclinically, 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 2 drugs working together for sure, exactly as you point out. So maybe, Ian, I don't know if you want to add anything more to this?

Yes. I think the synergy between the ER pathway and the CDK pathway has been well established in the PALOMA study clinically. We've certainly shown synergy with vepdegestrant and palbo and other CDK inhibitors, preclinically, we published some of that data [indiscernible] forward. 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. So almost like the synergy is equalizing across those different molecular phenotypes of 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 see some good response in wild-type, but not as much as when you have the synergistic action of the 2 compounds coming together. And on top of that, we've always said, we really believe it that 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 companies.

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.

The next question comes from Michael Schmidt with Guggenheim.

This is [ Ed ] on for Michael. Congrats on the progress. One question from us on the Phase Ib combo data. Have you looked at patients with dose reduced to 100-milligram versus 75 just wondering if you get any preliminary evidence here to show whether the 75 or 100 is a better combo dose given the early dose reduction you mentioned. And then a quick follow-up. The CDK4 combo Phase III, you just announced makes sense. And given the dynamic landscape, it sounds very interesting. What is the level of commitment to continue enrolling VERITAC-3? And how would you balance your resource?

Yes. Thanks. It's a great question. And starting with that second question, both Arvinas and Pfizer are completely committed to continuing the palbo and 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 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 in as our Pfizer to moving forward with the palbo study. Ron, do you want to take the other question there?

Yes, certainly. So the question was around -- yes. I think the question was around whether we can discern from this data set, which how recycled dose is likely to be better between 100 and 75. 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 we -- 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 a being 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 in Pfizer that does modeling to predict what is likely to be the optimal dose of palbo in combination with vepdeg and from that poster, in particular, which is basically based on modeling. It looks like more likely than not, it will be the 100 milligram, but really, the answer is going to be coming from the study lead in.

The next question comes from Derek Archila with Wells Fargo.

It's Sevan for Derek. A quick one from us. Can you provide a bit more color on the neutropenia cases and how were this managed and specifically for the 11% of patients with Grade 4 neutropenia as patients final doses? Can you discuss what these doses were and how do they compare to the Phase III?

Ron, that sounds like a question straight for you.

Yes. Well, yes, I think with -- I mean I'll start with the conclusion, and I'll work back for -- 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 absolutely digital 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. I mean the -- and we expect that with the optimal dose, it will 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 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 in our presentation. And I guess the point was that while neutropenia overall was -- Grade 4, was about 41%. If you look all told, only about 10% of patients had a persistent grade for after dose reduction across the denominator of 46 patients. So all told, we're really confident with the manageability even at a dose we're not likely to go that we would not be going forward with.

The next question comes from Akash Tewari with Jefferies.

This is [ Adrian ] on for Akash. We just have one quick question. How long have patients enrolled in this combo study appreciated by prior CDK because if we look at the post-hoc analysis for EMERALD, it looks like longer prior CDK disclosure since we translate to better efficacy for their third -- so what's your take on the role of prior CDK duration in relation to the efficacy within the current competition?

Thanks for the question, Ron prior CDK exposure.

Yes. Yes, certainly. 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 think that there's not going to be any surprises there.

The next question comes from Christopher Lu with Leerink.

Congrats on the data. Just 2 questions from me. So 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 our venous or 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 for the question. And a couple of different ones there. Ron, do you want tackle the efficacy one? And maybe Adam can talk about enrollment, the lower dose?

Yes. I might actually bring Ian in to answer the question just from a biologic perspective.

Yes, I mean, it's so much what I said before. So I can't speak to what other what the SERD mix show on [indiscernible] 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 -- many times, a degrading is better and having investigator is the best approach, which is what vepdegestrant is. So the fact that when you add in the synergy of the pathway, sitting both pathways with the best degrader that I believe that's why we're seeing this equal efficacy across the wild-type and ESR1 mutant pathways. Synergy plus best degradation equals great PFS.

Enrollment at a lower dose? Any answer there from Adam or Ron.

Yes, happy to, John. I mean the short answer is no. We don't anticipate any enrollment challenges. I mean the doses for palbo 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 palbo assuming that as a control there. So no impact on enrollment from our perspective.

We're just waiting for the next question.

Operator, are you still there?

Yes. Our next question comes from Li Watsek with Canter.

This is Rosalie on for Li. 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 end is too small to draw this kind of conclusion?

Thank you for the question. So related to differential ORR, Ron, do you want to take that?

Yes. I mean I think what I would say is it kind of goes back to the -- I think the question about exposure response. Analysis that we talked about, which is that at least with palbociclib AUC and within the recommended dose range, there hasn't been any clear relationship or a meaningful relationship between exposure and efficacy. So I think that really kind of addresses this. And then also I mentioned earlier in the presentation that there's kind of a wash element here because there's going to be compensatory interruptions and dose reductions to account for the neutropenia. So it kind of works out to be a wash here. So that's why we think that there's no added advantage for 125.

The next question comes from Peter Lawson with Barclays.

This is Shay on for Peter. 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 the second half '24. So should we be thinking that this could be an early 2025 start? And could you help add some color for how these will fit in with the current Phase III trials you have going? And related to that, maybe help touch on the rationale for why adding in vepdeg could help with retreatment of the CDK4/6 inhibitors.

Thanks. Yes, 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 stages already started ongoing, and that would segue into the randomized stage and that will be after that data set. And then planning for CKD4, first-line combination study that's in planning and then the second-line study with palbociclib, that's also in planning. So we'll get 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?

Can you repeat the second question, please?

Yes. If you could add any color for why adding in vepdeg could help with retreatment of a CDK4/6 inhibitor in context from historical...

Yes. I mean I think the first thing is, I mean, the data are the data, right? So it's what we've seen. And it's -- for us, really 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 lead this forward to -- work to get this available for patients.

The next question comes from Srikripa Devarakonda with Truist.

Congrats on the data. I understand that these are 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 different dose exposure of palbo between patients who had prior CDK4/6 and core naive. I'm just wondering how this might impact dose exposure and dose selection, especially for the frontline study?

Yes. I imagine the answer is going to be its LEDs in terms of analysis of that data. But Ron, anything you 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 look at our data as try to learn as much as possible. We haven't done that analysis. The numbers are going to 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 going to inform our dose for the combination with palbociclib.

Got it. And if I can ask a follow-up question. This is about the ESR1 mutant and the wild-type data. With the combination it seems like the response rate and the PFS seem comparable, again, small numbers of patients. But I was wondering if your level of confidence that the combo works across all comers and that this could be an all-comer opportunity. And if there's anything in the baseline characteristics that the regulators might pick at.

Yes. I mean, certainly, we're very confident about the data set, Ian Taylor mentioned earlier on, the combination of an incredibly strong degrader plus palbo synergy with the mechanism, I think, really is leading to the data set we're seeing and this balance -- good balance between wild-type and ESR1. So we're very confident about that data set moving forward. The latter question in terms of regulatory authorities. Well, I mean, obviously, we'll have regulatory interactions going forward. And at some point, we'll be able to describe those. But we usually don't try and speculate by how that interaction will go. But we're very confident about the data set.

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 you for all the great questions and for turning out the meeting. As you can tell, we're incredibly excited about our data set 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.