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

Good afternoon, ladies and gentlemen. Welcome to the Arvinas conference call. [Operator Instructions] I would now like to turn the conference over to your speaker, Jeff Boyle, Vice President, Investor Relations at Arvinas. You may begin.

Thank you, and good afternoon, everyone, and thank you for joining us to discuss the ARV-471 Phase II VERITAC data. This morning, we issued a press release highlighting data, which can be accessed in the Investors section of our website at arvinas.com. With me today are our Arvinas President and Chief Executive Officer, John Houston; and Arvinas Chief Medical Officer, Ron Peck. Chris Boshoff, Pfizer's Chief Development Officer, Oncology and Rare Disease, Pfizer Global Product Development, will join for the Q&A portion of the call. Before we begin the call, I'd like to remind you today 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 I'm now going to turn the call over to John Houston. John?

Thanks, Jeff. Good afternoon, everyone, and thank you for joining us today to discuss the initial results from VERITAC, the Phase II cohort expansion portion of a Phase I/II study with ARV-471. Although this is not the way we anticipated presenting these data, let me start off by saying we are really thrilled with these interim results, and I expected to begin our Phase III registrational program in the coming weeks. Now Ron will walk you through the data in detail and Chris Boshoff from our collaborators, Pfizer will be here for the Q&A part of the call. So if you could turn to Slide 4, a quick overview before Ron reviews the data, we've seen robust efficacy across the Phase I/II trial. And what is, to our knowledge, the most heavily pre-treated patient population evaluated with an ER targeted therapy. That's 100% prior treatment with CDK4/6 and very high rates of prior chemotherapy and fulvestrant. And you can see the clinical benefit rate across the Phase I/II trial has been very consistent and more than we initially anticipated in the highly resistant and likely ER-independent population, and this will be a key point as we go forward. ARV-471 continues to have a favorable tolerability profile, including at the dose we intend to advance into Phase III, which is 200 mg. So with the consistent and robust efficacy and the favorable safety profile in more than 150 patients evaluated, I'm more confident than ever that we have an opportunity to provide a significant advance in treatment options for patients with ER-positive HER2-negative breast cancer. Now I want to spend a lot of time on Slide 5, but it's important to remind you of the considerable unmet medical need for the treatment of breast cancer from frontline to later line settings. CDK4/6 inhibitors have become truly established with the standard of care for the initial treatment of advanced ER-positive HER2-negative breast cancer and combination strategies with ER treatment is a valuable treatment option. Despite recent advances, breast cancer remains a major public health issue due to the shortcomings of current therapies that we believe can be addressed by more effective targeting of the estrogen receptor. And we believe ARV-471 is fundamentally different from any other therapy in development and differentiated in its ability to provide a differentiated standard of care across the entire treatment paradigm in ER-positive breast cancer. First for patients with metastatic disease and ultimately for patients with an early-stage breast cancer. So for a long time, we've talked about ER independence in the late-line setting. Especially after CDK4/6 and prior chemo and metastatic settings. On Slide 6, we can see some recent trial designs and the associated patient populations for those trials. When looking at our CBR and PFS, it's important to keep in mind the significant differences in patient population. In VERITAC, patients had 100% prior CDK4/6, nearly 80% prior fulvestrant, and 45% prior chemo in a metastatic setting. And while it's difficult to do cross-trial comparisons, it becomes even more difficult with the varying degrees of prior treatment. So when looking to the most comparable trial, when it comes to prior treatment, EMERALD and VERONICA are the closest, but even then, the patients in VERITAC, as shown on the bottom row, have significantly more prior treatment with fulvestrant and chemotherapy and are likely the most treatment resistance. That's why we are confident in the development path for 471 and the opportunity for it to become a future standard of care in ER-positive breast cancer. I'm now going to turn it over to Ron and he's going to give you a much more detailed look at the data, and I'll be back after him. Ron?

Thanks, John. So I'll start on Slide 8, which outlines the trial design for the Phase II expansion. Just a couple of points to highlight here is, number one, the eligibility. So as John highlighted, this trial required that patients have progressed on or after a CDK4/6 inhibitor. So that's an important differentiation about this trial design. In addition, there was no restriction on prior endocrine therapy. That includes -- that means that patients could have received fulvestrant or any other endocrine therapy. And then also the trial permitted prior chemotherapy, including the use of chemotherapy in the metastatic setting. The second point, just to highlight is the primary end point of clinical benefit rate, which is a standard endpoint in Phase II trials in -- with endocrine therapy in this late-line setting. And then the third point here is that we selected 2 doses to test in Phase II. The first dose was 200 milligrams, which actually was enrolled initially before we had determined in parallel what a second dose would be suitable for enrolling in this trial, and that was the 500-milligram dose. And so the 200-milligram dose, it actually enrolled before the 500, which will come up as we talk about the PFS results later. Slide 9 details the baseline characteristics for the patients in this expansion cohort. And there are a couple of points that I want to really highlight and it goes back to John's presentation of Slide 6 and the differences in the prior therapy for the different trials that have been conducted in this setting. So importantly, 100% of patients had gotten CDK4/6 inhibitor, at least 1 therapy and maybe sometimes more than 1. We had 75% of patients who have gotten chemotherapy across any line. And importantly, as many as 45% of patients had gotten chemotherapy in a metastatic setting. And then lastly, the other point I want to highlight is that 80% of patients had gotten fulvestrant. So all told, this is a very unfortunately sick population of patients to evaluate 471 in, and it goes back to the points that John highlighted on Slide 6. All right. Slide 10 now highlights the primary efficacy endpoint, and that's the clinical benefit rate, defined as confirmed partial or complete response by RECIST criteria and also the inclusion of stable disease that was of at least 6 months' duration. And as you can see, across both doses, we had a clinical benefit rate that was pretty much in line with what we showed in Phase I in a population that was similarly heavily pretreated, a clinical benefit rate of about 38%. This is robust in this post-CDK setting. And then also just to understand that the CBR rate was similar between the 200 and the 500-milligram results. So importantly, and not surprisingly, the results were a little bit better in the ESR1 mutant subpopulation. That's very consistent with recent data that is across all of the recent novel ER therapies that have been tested, which indicates that this is a population that may have slightly more ER dependency in a setting where there's extensive ER-independent resistance and as a corollary to that, the CBR in patients with ESR1 wild-type tumors was around 20% when you pull the 2 doses together. And so that is also in the context of the extensive prior therapy. Importantly, even those patients with wild-type still had benefit. You still had some of these patients that have been on therapy for quite some time. Now to put all this into context, if you look at the trials that John had described as being the most comparable to this in regards to the fact that they were both completed in patients who were all post CDK4/6 and you look at the results for fulvestrant. So those are namely the VERONICA trial and the EMERALD trial, if you look at the control arm, fulvestrant performed very similarly between these 2 studies in all comers, the CBR was between 11% and 14%. And then if you look at the ESR1 mutant subsets, mostly defined in the EMERALD publication, you can see that the results are actually quite similar to that. There wasn't really much difference in ESR1 mutant group for fulvestrant. So very poor outcome in this very difficult-to-treat population. Now turning to Slide 11. These are the waterfall plot results for RECIST data and not surprisingly consistent with trials of endocrine therapies in ER-positive HER2-negative. Patients' response rates are not common in this setting. Even with fulvestrant, you'll see single-digit response rates and less resistant populations. But importantly, the activity that you see for 200 and 500 are quite similar, and that includes some patients' response. And notably, 1 patient who was treated at 200 milligrams had a confirmed partial response who actually had an ESR1 wild-type tumor. Now turning to Slide 12. These are the results for progression-free survival at this stage. And I just want to orient you to the slide. On the left side are the results for all comers. So we'll call it the intention to treat group, and on the right side, you see the results for the patients who had ESR1 mutant tumors. And also just to point out that we're presenting results here for both the 200-milligram cohort and also the full group of patients who had both 200 and 500. The results at 500 were not mature at this data update so we will present those results at a later time. But importantly, the results for all comers -- I'm sorry, the results for the poll patients across the 2 doses and the 200 proforma quite similarly. So as you can see on the left side, the results for all-comers range between 3.5 and 3.7 and on the right side, for ESR1 mutant tumors, you can see that the results were between 3.5 -- I'm sorry, 5.5 and 5.7. And again, I just want to put these in context, again, the closest population to this would be the trials completed in the post 100% CDK4/6 therapy patients, again, VERONICA and EMERALD. And if you look at the control arms for that, for fulvestrant, you'll see that progression-free survival for fulvestrant was about 2 months, whether it was in the ESR1 mutant population or the all-comers. So this -- between these results and the clinical benefit rate results, we see that 471 had demonstrated robust activity in this setting and very much consistent with what we showed in the Phase I population. Now I'm going to turn to Slide 13, which summarizes the latest data that we have on ER degradation now focused on patients who receive 200 milligrams, which is the recommended dose and the dose that we're taking into Phase III. We have now a total of 9 patients that's pulling between the Phase I trial and the VERITAC expansion trial. And as you can see, very consistently, we're showing degradation in all patients. And you can see many of the patients had degradation down to the lower limit of detection as you can see at the dotted line at the bottom. We can see a mean ER degradation of about 71% and a median of around the same thing. So again, very consistent results with what we have shown before and numerically higher than has been reported for fulvestrant. So again, this all is very consistent with our expectations based on the mechanism of the drug and what we have shown preclinically. Now turning to safety. I'll start with Slide 14, which summarizes the key takeaways from the treatment-emergent adverse event summary. And so a couple of points to highlight here is even for treatment-emergent adverse events, which are adverse events that are regardless of relationship to treatment, we only have 20% of patients who had Grade 3, 4 adverse events, whether they were determined by investigators as being related to treatment or not. Which is a very low number, especially in this very advanced sick population that will normally have adverse events just by nature of their disease and prior therapy. The other thing to point out here is that discontinuations and dose reductions were quite uncommon and specifically at the recommended dose of 200 milligrams, we only had 1 patient who had discontinued that was a patient with QT prolongation that had some confounding effects relative to the fact that they had baseline elevation of the QT. They also had electrolyte abnormalities and had been on therapies that are known to prolong QT, and that was the only discontinuation at that dose. Now turning to Slide 15 to provide more information around the safety profile. This is summarizing the treatment-related adverse events, the most common, which are those that were greater than or equal to 10% in frequency. And you can see between the 200 and 500-milligram doses that there was actually quite -- the safety is quite similar. Both were well tolerated. And if you look at the events that had a frequency of about 20%, the only one that you'll find that is in that range is fatigue. And just to make the point that in this very advanced population, it's very difficult sometimes to discern fatigue and it's quite common in this setting. That was the only one where we had approximately 20%. But if you look at the other adverse events, they generally fall around approximately 10%. So again, overall, well tolerated. And then I'm going to finish by just describing the Phase III trial design. We're very excited to get started with our Phase III program. This is the first study that will start. It is due to initiate before the end of the year. This is called VERITAC-2. And this is the Phase III study in second-line plus patients. And importantly, the population will be a less treatment experience population than had been treated in both the Phase I and the VERITAC Phase II expansion. Specifically, the trial will exclude prior chemotherapy that have been administered in the metastatic setting and also excludes fulvestrant since fulvestrant is the control arm. So we expect that this is a population that may potentially do better with 471 and may give the best chance for showing its potential in patients, not just with ESR1 mutant tumors, but also those with wild type. But importantly, the trial has co-primary endpoints. One primary endpoint is focused on those patients who have ESR1 mutant tumors. And then there's also a second primary endpoint that's focused in all-comers. So the trial can be a successful trial as long as it hits at least one of these primary endpoints. Okay? And the trial was designed as a fully robust Phase III study with a sample size of over 500 patients. With that, I will hand it back to John.

Thanks, Ron. And if you turn to Slide 18, I hope you share in our excitement for these data and the potential of the ARV-471 continued efficacy and favorable tolerability puts the compound on a path to 2 pivotal studies beginning soon. In terms of efficacy, ARV-471 demonstrates strong CBR and PFS and heavily treatment-resistant patients and activity in this difficult-to-treat population, we believe illustrates the potential of PROTAC technology. In terms of tolerability, the favorable tolerability profile at 200 and 500 mg qd, a 200 mg Phase III dose, no dose reductions and 1 discontinuation and ARV-471 tolerability is well suited for development across the disease continuum. So in terms of initiating our Phase III trials, monotherapy second-line Phase III and less treatment-experienced patients will be quarter 4 2022 this year and a trial design that you just saw to address the role in both ESR1 mutants and all-comers. The Palbo combo first-line Phase III in patients with ER-dependent tumors would be quarter 1 2023 where broader development initiative with other combos and in early breast cancer. So if you go to Slide 19 and my final slide, our 2020 data is what kicked off interest in 471 with clear signals of efficacy and a favorable tolerability profile. A year ago, we updated the Phase I data and confirmed this profile. And we then at that time said, 2022 would be a significant year for execution and it has been. We've initiated Phase I in Japanese patients to enable global pathway. We planned initiation of TACTIVE-U and TACTIVE-E combination trials with multiple targeted therapies, on track to add additional agents to establish potential for 471 as a backbone therapy of choice and also plan the initiation of TACTIVE-N designed to evaluate safety and clinical activity in early breast cancer, like neo-adjuvant. And of course, in 2022, our Phase II readout, which we believe shows continued efficacy signals and a favorable tolerability profile to support advancement to Phase III registrational studies. And as I said earlier, our next milestone, the 2 Phase III registrational studies in first line and second line. So hopefully, we've given you a lot more information and data, and we're now going to open up to a Q&A session where we can answer many of your questions. Jeff?

Thanks, John, and thanks, Ron. I would ask before I turn it over to the operator that you limit yourself to 1 question per cycle, if you want to get back into the queue, please do, but I want to make sure we give appropriate time to everybody. So with that, operator, can you open up the queue?

Our first question comes from the line of Brad Canino with Stifel.

Great. My question is for Chris. The slides today state near-term 471 opportunities in the first line with CDK4/6 and "other targeted inhibitors," could that be in reference to Pfizer's CDK 4, the CDK 2 in the CAT 6 inhibitors and similarly, why are these not listed as potential second-line combination partners with 471? Congrats on the data.

Thanks for the question. Chris, do you want to take that question?

Yes. Thank you very much. So you're absolutely correct. The -- that does refer to our CAT 6 inhibitor, our CDK 4 inhibitor and CDK 2. We're particularly excited at the moment about our CAT 6 and our CDK 4 and we're going to share more data with you in 2023 on these. We're looking forward to start a combinations with ARV-471 with CAT 6 and CDK 4. And to your question with the second line, in fact, we hope in the longer term that ARV-471 could be a backbone also for first line for combinations, including our CDK 4 inhibitor backbone with ARV-471. So we'll expose those studies as well, and we'll share more of that in 2023.

[Operator Instructions] Our next question comes from the line of Tyler Van Buren with Cowen.

Can you help put the 3.5 or 3.7-month median PFS in the context? And specifically, how much quick fulvestrant and chemo use in the metastatic setting have impacted the medium PFS results as we think about comparing it to competitive data?

Thanks for the question. Ron, would you like to take that?

Yes, certainly. I think -- so the context that I mentioned was going back to the 2 trials that were completed in the post-CDK4/6 setting. EMERALD and VERONICA and talking about fulvestrant, again, saying that CBR between 10% or 14% and PFS around 2 months, no matter how you look at it, whether it was in the ESR1 mutant subset as you show -- as you can see in the EMERALD publication or wild type. Your question about prior chemotherapy, which is -- it's a good question, and it goes back to John's Slide 6 which breaks down the different prior therapies. I mean the point about those 2 trials is that they may not be -- it's -- they're similar and that they're both post-CDK4/6, but they're not similar because they've -- they're lower levels of prior chemotherapy in case of VERONICA no prior therapy. What is pretty clear in the ER-positive HER2-negative setting is that prior chemotherapy does seem to impact and is associated with worse outcome in general. Whether that's related to occurrence of multidrug resistance or if it's because patients who get chemotherapy in those settings tend to be the more aggressive patients with visceral disease, but there's no doubt that there is a relationship. An example is if you look at a publication of the PALOMA-3 trial and you look at the subset analysis for patients who have gotten prior chemotherapy in the metastatic setting and those who did not, just for fulvestrant, the results are fulvestrant was like 5.5 months in the chemotherapy naive and 3.5 months in the chemotherapy pre-treated. So no doubt there is going to be an impact of product chemotherapy. Fulvestrant, there's probably a little less information. This is sort of uncharted waters here, but I think that there's at least amongst the experts that we work with, I think there's a pretty good expectation that once you've gone through a fulvestrant that there's more likely to be resistance. And I think for us, we're often asked about how do our results compare to others. I mean we make the point that there's really a lot of apples to oranges comparisons. All we know is that this is a very heavily protruded sick population that was studied here.

Our next question comes from the line of Madhu Kumar with Goldman Sachs.

So kind of to follow up on how to think about the kind of CBR and ESR1 wild type. So I guess kind of what can you tell us about the prior therapies in the patients who had a CBR benefited 6 months who were ESR1 wild type. Did they tend to be patients who has had prior chemo and fulvestrant exposure? Or were they patients who were chemo and fulvestrant naive? Or was it a mix? Any clarity there would be helpful.

Ron, would you comment on that?

Yes, sure. Yes, a good question. I mean what we've -- as you can imagine, we've really poured through our data sets here. And there really aren't any obvious differences amongst the different populations. But as we step back and think about this and try to discern what does this tell us about how 471 may perform in the Phase III. I think the important point is that we purposely designed the trial such that 471 as a monotherapy would have the best chance to show benefit and therefore, potentially be practice changing coming out of this trial.

Our next question comes from the line of Ellie Merle with UBS.

Just for the VERITAC Phase III trial, I guess, what are your plans for the proportion that you plan to enroll with ESR1 mutant versus wild type in terms of the enrollment and stratification?

Ron, do you want to make comments and then maybe Chris may have some comments.

Sure. Yes, certainly. Yes. So the trial was designed in such a way that we would have sufficient power and sufficient patients to address each of the primary end points, especially with ESR1 mutations being the subset. So well, I can't provide all the specific details. This is a very important focus of the trial design, and there was every attempt to ensure that this population will be fully powered.

Do you want me to add, John?

Just anything there .

Yes. Just to add. So as Ron said, the study is certainly derisk with a co-primary endpoint for the intention to treat all-comer population as well as powered for the ESR1 mutated population, and there will be sufficient patients for -- to do that testing for co-primary for the ESR1 population, just to add perhaps that we're looking forward to that the study will appear on clinicaltrials.gov soon. We hope that the first subject visit will occur in December and will recruit very aggressively through 2023 to conclude the studies soon with the readout. We're confident in the trial design and the outcome for this study.

Our next question comes from the line of Rich Law with Credit Suisse.

In the 200 mg dose, how many patients have unconfirmed or ongoing stable disease at less than 6 months for June 6 cutoff. That could potentially change of CBR? And also like how many -- how much more maturing is there for the 200 mg dose left that you foresee any change to PFS? And would there be another presentation for the final data?

Ron?

Yes, sure. The clinical benefit rate is fully mature. In fact, the data cut was designed specifically to capture full data of CBR and PFS. PFS, you should not expect any change in the median PFS. It's fully mature, whatever remaining patients that were censored are far enough out from the median point. So that should not change. And at a future point, I mean, the only thing that isn't mature is 500 milligrams, but we've had sufficient data to choose the 200-milligram dose.

Our next question comes from the line of Joon Lee with Truist.

What led you to choose 200 milligrams for the Phase III trial when the 500-milligram is not yet fully mature?

That's a great question. handing over to Ron again.

Yes. I mean, it was -- honestly, I'll go out of character. It was an easy decision, right? So the data actually -- the only data that's not fully mature is PFS, but we had decided prospectively that we would have sufficient data based on clinical benefit rate. We had that as part of our conversation with the agency as well. And really what it amounts to is that we have similar efficacy between these 2 doses. We have PFS that we're very happy with and this very extensively appreciated population. And from the safety side, there's a slight edge to the 200-milligram dose in terms of only 1 discontinuation, no dose reductions. ER degradation was -- as you can see in the presentation was quite robust. And exposure wise, we had a large margin above the minimum effective dose. So it checked all the boxes for us. And then also met the FDA's interest in lowest efficacious dose. So this was really quite straightforward for us.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

Just wanted to clarify, in Phase III, are you using PFS as your primary endpoint? And what was the rationale for changing it to PFS, if that's the case from CBR? And can you give us a sense of when we might be able to see overall survival data for VERITAC.

Ron?

Yes. Maybe just a clarification. Was the question around the primary endpoint for Phase III?

Yes. The question is around PFS as a primary endpoint.

Okay. Yes. Well, the intent has always been progression-free survival for Phase III. It's well-established, highly precedented end point. And yes, we -- and this is the first disclosure of the design. So we had not -- we did not have a prior version of this that included clinical benefit rate. Clinical benefit rate is a good choice for Phase II -- is the primary endpoint of choice for Phase II, but for Phase III, certainly PFS. And we've gotten advice from the agency and also the European scientific advice. So that all lines up with that.

Okay. Maybe just a follow-up. Is your analysis of that Phase III going to be hierarchical with first intent to treat and then the ESR1 patients?

It's actually a design called modified Hochberg design. It's been used in -- I mean the EMERALD trial had that design. It's been used in a number of oncology settings, a lot of the PD-1 trials have looked at this when they booked it subsets. And so it's not hierarchical. It's considered to be optimal design to get the best chance of success for both endpoints. So we could have -- we did look at hierarchical. We looked at even having a splitting out in a more traditional co-primary endpoint, but this worked out to be the optimal design.

Okay. Got it. And then will we see overall survival for VERITAC?

Yes, certainly, at a later point, I mean we are collecting survival in this population. And whenever we have sufficient data, we'll make sure that it gets out there.

Our next question comes from the line of Michael Schmidt with Guggenheim Partners.

Just another one on VERITAC-2. You obviously have a slightly different enrollment criteria here than in VERITAC, early-stage patients, as you mentioned which you did say may benefit ARV-471. I guess I'm wondering how would you expect fulvestrant to perform in this type of patient population?

Yes, I can take that. Yes. So I think it's a good question. I think what we -- I mean, the inspiration for this, frankly, was looking at some of the recent data being reported in the post CDK4/6 population. And what was clear is that there was a population who progresses very, very quickly. I think that was probably best illustrated in the EMERALD trial. And while they were all post CDK4/6, we know that there was a proportion of patients who also got chemotherapy, I think Radius and Menarini have presented a subanalysis that showed that those who had gotten -- were chemotherapy-naive may have actually done better with elacestrant. And even before that, based on even the data that Pfizer has with PALOMA-3, we already knew that prior chemotherapy was another sort of characteristic that would portend for a better outcome. So we decided that the most important thing is to identify a population where we think that -- where monotherapy could still be an important therapy and practice changing. As for the question about fulvestrant behavior, I think it's hard to tell, the only data that's been published and presented in the post-CDK all shows that fulvestrant alone has a PFS of around 2 months, whether -- regardless of the chemotherapy. So even in EMERALD, that population chemotherapy-naive fulvestrant did about the same 2 months. It seemed like the benefit was more in the -- with the SERD. So that just gives us even more confidence in the design that we chose.

And can I just ask a quick follow-up. Just in terms of -- in order to obtain the broad label in an ITT setting, is there a certain efficacy criterion that will need to be exceeded in the ESR wild-type patient population? Or is the success in the overall population are sufficient?

I can take that. Yes, I think this is -- I think, obviously, something that is under a lot of thought and consideration for how it will work out with elacestrant in their NDA that has been accepted for priority review. As the FDA often says, it's a review issue. We suspect that they're going to be interested in how the wild-type population does. On the other hand, the control arm is a therapy that's given intramuscularly. So there's a benefit risk and the convenience element here. But I think it really will -- I think it's all going to really depend on what the data turned out to be at the end of the day.

Our next question comes from the line of Derek Archila with Wells Fargo.

This is for Derek. Just a quick one from us. Can you discuss how wild-type patients perform relative to the mutant ESR1 patients in terms of PFS?

Okay. I can comment on that. Yes, I mean, while it's not in our presentation, if you were to look just in wild type, and we have -- we've looked at this for 200 -- 500 milligrams just like in all-comers, it's just not mature. It shows PFS around 2 months. Understand that this is a population, it's not just CDK pretreated, but also has gotten 45% of chemotherapy in metastatic setting, 80% fulvestrant and that may not be reflective of how it's going to work in the population that will be the trial population for the Phase III. This is a less treatment experience population. Our hunch and expectation is that it will have a better probability of success in that less treatment exposed population. And then the last thing I'll just say is that we do know that there's still some patients even in the phase II, there's still some patients who are benefiting. I mentioned that even the confirmed response to 200 was in a wild-type patient. So we know that there's still efficacy on the table for the wild types.

Our next question comes from the line of Etzer Darout with BMO.

Great. Just wondered in the 15 patients or so that were fulvestrant-naive, if any data you merged there? And was it enough maybe even to give a sense on the performance of ARV-471 in that population? And just maybe your expectations on the percentage of ESR1 patients that would sort of fall into sort of the VERITAC-2 setting of Phase III.

Yes, I can take it. So -- we have not parsed out the data in the fulvestrant-naive patients. As you can imagine, it's a small number since it's only about 20% the patients broken down across the 2 doses. But we haven't, at this stage, parsed that out. Your other -- I'm sorry, can you remind me of the second question?

Yes, your expectations on the percentage of patients with ESR1 mutations for the VERITAC-2 patient population, sort of chemo-naive, fulvestrant sort of naive.

Yes. Yes, thank you. Yes, it's -- I mean all that we know is that in the recent trials that have completed in the post-CDK4/6 and we'll throw ours in there. It seems to be on average between 40% and 50% of patients post CDK who have ESR1 mutations. As far as we know, that doesn't seem to break down by prior chemotherapy, but certainly, there's limited data there. But that's at least the information that we have today.

Our next question comes from the line of Peter Lawson with Barclays.

Great. Thanks for the sooner than expected data. Around the ESR1 mutant wild-type population, where do you think there is a difference in PFS? And your comment about efficacy still being left on the table. Why do you still think there's efficacy still left on the table for the wild-type ESR1 patients biotype.

I guess John, I'll take that.

Well, yes, I mean I think it's a reaction to your last comment. Yes.

Yes. I think yes, so ESR1 mutation -- I mean -- and we actually -- as you can imagine, we work very closely with the thought leader of community in this space, and we're actually just catching up with one of the top investigators in this whole area. And I think between us and the community out there, I think everybody understands that while ESR1 mutations have emerged as the first maybe a legitimate biomarker that can predict for patients who still have ER-dependent disease. I think everybody recognizes that it's an imperfect biomarker. The results, there is a differential between these. And by the way, this is not relating to anything to do with the drug. This is a biology thing for the tumor, amidst a lot of ER-independent resistance. So it does seem to help predict. But as you -- if you talk to those who treat a lot of these patients, on trials and such and patients who have been on our trials. You can hear that there still are those patients who have long-term benefits that say that there's still some patients where the biomarker is just not telling enough. So and I mentioned in the RECIST data that we actually have -- the one confirmed response that we have at 200 for RECIST was actually an ESR1 wild-type. So it's an anecdote, but it points out that there's -- the biomarkers -- ESR1 mutation is not telling the whole story, right? That's one thing. I think the other thing, and we also often get this question is what is -- what about wild-type in earlier settings? And I just want to make the point that ESR1 mutation, while it's an imperfect biomarker, it at least gives some direction for the previously treated heavily resistant, high ER independent resistant population. But when you get into first line, and we're obviously very excited to get started with the first-line study. That's a population that is treatment-naive and much less resistant. We know that 471 is a very potent degrader against wild type as much as it is against the common mutations. So our expectation is that 471 is going to have much more robust activity as we get into earlier settings.

Our next question comes from the line of Mark Breidenbach with Oppenheimer.

And thanks for this presentation. Probably another one in that Ron. Just wondering if you can explain why we're still looking at a June 6 data cutoff, shouldn't we have adequate time by now to confirm some of those unconfirmed partial responses. And then I'm also noticing that the Phase III combo trial with palbociclib has pushed back a little bit to maybe start in the first quarter of next year instead of the fourth quarter of this year. Are we potentially going to see the Phase Ib combination data with palbociclib before that trial starts?

Ron?

Yes. So the question about the data set. So that -- the data set was specifically chosen to capture the primary endpoint clinical benefit rate. And for -- and so that captures CBR that there may be some of the unconfirmed responses may -- there may be some additional follow-up on those. As I mentioned, in this endocrine therapy pretreated population, response rates are really not very helpful to do certain activity. Clinical benefit rate for ER-directed therapy is really the gold standard there. Now I think with regard to would be not updated the data, really the most important thing because the clinical benefit rate and the safety was all that the June data cut captured all that we really needed. There would be not much difference with data cut, it really gets to the PFS question, right? And so for PFS, what we had was a data set that we first then had to make sure that we had a validated outcome. There's -- making sure that missing scans were obtained and the results were otherwise validated, queried as appropriate. And then it was really just sitting down with Pfizer as our partner to make sure that we had robust follow-up on PFS. And again, for the June data cut, as I mentioned, 200 is solid in terms of the estimate of the meeting. It's not going to change based on our latest information and 500 still would not have been mature. So the June data cut gave us what we needed. I think your other question was -- I'm sorry, your other question was around, will the palbo combination data be released around the time of the start? What we said for the palbo combination data was that it would be second quarter. What we have said in the updated guidance is that we expect that the Phase III study for first line would be starting in the first quarter. So it may be that the first -- that the trial is going to start before the data are available. We -- exactly when data are disclosed versus trial starts are not necessarily aligned. It's just a matter of arranging the venue for presentation.

Our next question comes from the line of Terence Flynn with Morgan Stanley.

I was just wondering if you looked at PFS in the Phase II trial by prior chemo exposure, if you run that cut yet? And if you can provide any insight on that front. And then the second question I had is on the Ibrance combo data that you just mentioned coming second quarter of next year. Can you maybe just help frame expectations there for that study in terms of what you and Pfizer would like to see from that trial and if that's in any way gating to starting up this Phase III trial?

Ron, do you want to take that? And then maybe Chris can add any other color commentary?

Yes, certainly. Yes. So I think with regard to the -- your question about prior chemotherapy, have we looked at the data in VERITAC monotherapy to isolate out the prior therapy -- chemotherapy. And what I can tell you is that we started to do some exploratory analyses, not anything that is robust enough with the follow-up that we have today to present it. But I can -- but I would say that it sort of directionally aligning with what we talked about, which is that patients who had less prior chemotherapy metastatic settings seem to be doing better, but certainly not complete enough data that we can go into detail on that.

Chris anything you'd add?

Yes. Just to add again the reason to believe in the first-line design and the first-line study, as mentioned, the in-early disease, almost all positive breast cancers are ER-dependent and we, therefore, expect increased efficacy for ARV-471 and also based on the mean ER degradation that was shown in Phase I and in VERITAC that's 71%. We've got significant confidence that this could be a best-in-class ER inhibitor as a backbone also in first-line disease. And what also gives us confidence is the data that was shown that is very well tolerated. And as you've seen at the selected Phase III -- recommended Phase III dose, there's actually only 1 patient that discontinued due to treatment-emergent AEs and with very good compliance and also feedback from investigators using ARV-471 and that in their hands, I believe this is a very, very well tolerated medicine. So we now have confidence also in the data that we've seen that we can combine Ibrance with ARV-471 and we're looking forward to saw that study in Q1 and to share data here in 2023 from the ongoing combination studies.

Our next question comes from Yigal Nochomovitz with Citi.

This is Ashiq Mubarack on for Yigal. Can you comment on the choice to utilize fulvestrant of the control arm in the VERONICA-2 Phase III trial versus perhaps maybe something like investigators' choice of endocrine therapy like in the EMERALD trial?

Did you say on the VERONICA trial? .

Yes, I can take that. And Chris...

VERITAC-2 trial.

Yes. VERITAC.

Too many V names. Yes. So fulvestrant was -- if you look at some of these recent trials with physicians choice, fulvestrant was more often than not the treatment that was administered. I mean it only leaves second-line AI therapy, usually things like elacestrant -- I'm sorry, exemestane, tamoxifen, but largely, these are going to be fulvestrant trials. Number two, it's cleaner to have a single control arm versus a physician's choice. It gives more homogeneous results. Number three is really the thesis for developing 471 was as one of our first protect degraders is we went into a tumor type where there was already a degrader on the market, which is fulvestrant a very indirect degrader. And our thesis, as always, we can take this technology and apply it to ER and let's just go head-to-head against fulvestrant. And the data that we have for VERITAC just gives us even more confidence in the choice of the design.

Our next question comes from the line of Zegbeh Jallah with Capital One.

Nice to see the confirmatory data. And then just as a follow-up to question, not sure if I missed it, but do you expect the PFS with ARV-471 to be longer in fulvestrant-naive patients? And any plans or strategies as to how you will enroll these non-fulvestrant treated patients given its broad use and then I'm going to make [indiscernible] just squeeze in the last question there, just about the doses. I know you tested 30 to 700 million and you are peaking at about 200. I think we saw this feeling it back in 110 as well. So I was just wondering, if you learning anything about PROTAC molecules that could kind of help you expedite the escalation to expansion process for other pipeline programs.

Good questions. Ron, do you want to tackle the fulvestrant-naive?

Yes. Yes. Yes. I think the question earlier was about that we isolated out the activity in the fulvestrant-naive patients and the answer to that question was we haven't looked that far to a small data set, and we haven't yet looked at those data. Your question was probably more about expectations. And I mean, between us and the advisers that we closely work with, I think the -- we would have the expectation that it may be even more efficacious than fulvestrant-naive population. But -- and while the other thing is that there's another variable here, which is we exclude prior metastatic chemo, which also gives us where there's more data that tells us that, again, may be a population where 471 may they do even better. And I think your other question relates to the feasibility of enrolling this trial. And this is one of the reasons why we have a partnership with Pfizer. And I don't know, Chris, if you want to just talk in general about the feasibility and the efforts to operationalize the Phase III in this setting.

Thank you, Ron. I think just to emphasize, yes, the study is designed, VERITAC-2 and that -- so the study is enriched for tumors that will be more dependent on ER signaling. Because fulvestrant is a global standard of care in this setting, we expect rapid accrual. And as mentioned, that we didn't want to complicate the study and the statistical design and sensitivities by adding stratification for -- or capping to have various control arms. So making fulvestrant the control arm makes the study very attractive for rapid global enrollment.

And the last one was just about -- apologize, just squeezing in my last one about the dosing. Are you thinking that you might be able to rapidly go from escalation to expansion given what you've seen with both 471 and 110.

Well, I think in general, we're learning a lot of our PROTAC through these clinical trials. The one feature I'd say is that each compound is different. Bavdegalutamide, 471 and ARV-766, all PROTACs, but all have different profiles and behave differently. I think Ron and his team are looking at different ways of going through escalation, taking those learnings but each PROTAC will be looked at uniquely because they do have unique profiles. Would you add anything to that, Ron?

Would have said the exact same thing but probably not as eloquently.

At this time, I would like to turn the call over to John Houston for closing remarks.

Thank you, and thank you, everybody, for staying on for this conversation about 471. Hopefully, you can tell, we are very pleased with the Phase II data notwithstanding the way the market's reacted. We believe it confirms, consolidates everything we saw in Phase I. It tells us we have a profile of a compound that can go into Phase III with confidence. And at a profile, we think, still allows us to have the chance to be best-in-class. It's been very difficult to do these apples-to-oranges comparisons. We want to do apples-to-apples, but it's been difficult because there's not many, if any, compounds there that are in patient populations that have had such late therapies. Having said that, when we move into Phase III, we'll start to be able to compare with others. And I think we're going to be in a very great position. So the tail end of this year and next year is going to be a very exciting time for 471. So thank you for your time and all the great questions.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.