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

Good morning, ladies and gentlemen, and welcome to the Arvinas and Pfizer conference call. [Operator Instructions] I would now like to turn the call over to Jeff Boyle, Vice President, Investor Relations at Arvinas. Please proceed.

Thank you, operator. Good morning, everyone, and thank you for joining us to discuss the ARV-471 dose escalation clinical trial results presented this morning at San Antonio Breast Cancer Symposium. Earlier this morning, we issued a press release highlighting these data, which can be accessed in the Investors 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 Oncology Chief Development Officer, Chris Boshoff. Ian Taylor, our Chief Scientific Officer, will join for the Q&A portion of the call. Before we begin the call, I'd like 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 our presentation, in today's press release and in the company's recent filings with the Securities 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 our CEO, John Houston. John?

Thanks, Jeff. Good morning, everyone, and thank you for joining us today. We're very happy to provide this exciting update from our ARV-471 program. I'll begin with a brief introduction before handing the call over to Ron and Chris for a detailed review of the data presented at the San Antonio Breast Cancer Symposium this morning. We'll then open up the call to your questions. So if you could turn to Slide 4. At Arvinas, we've developed our proprietary PROTAC discovery platform to engineer proteolysis-targeting chimeras or PROTAC-targeted protein degraders that are designed to harness the body's own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. ARV-471 is a PROTAC-targeted protein degrader that induces degradation of the estrogen receptor, or ER, a well-known driver of breast cancer. You may recall last December, we presented interim data from this Phase I dose escalation trial. And the poster presented this morning now includes data from nearly 3x as many patients. We are pursuing a robust development plan for ARV-471, and I believe these completed Phase I results reinforce our decision to move this program forward expeditiously. As you may know, we initiated the ongoing VERITAC Phase II expansion trial in locally advanced or metastatic ER-positive HER2-negative breast cancer earlier this year. We also have an ongoing Phase Ib trial in combination with Pfizer's IBRANCE, which is a dose escalation study intended to identify the right dose of 471 for combination in later trials. And in 2022, we look forward to beginning 2 Phase III pivotal studies of ARV-471 in metastatic breast cancer. If successful, the clinical program is designed to position 471 as a best-in-class endocrine backbone therapy across the breast cancer treatment paradigm from the adjuvant setting through late-line metastatic disease. Despite advancements in oncology in recent years, there remains a considerable unmet medical need for the treatment of breast cancer. Breast cancer is the second most prevalent cancer in women. And 1 in every 8 women will be diagnosed with breast cancer at some point in their lifetime. The combination of targeted therapies with existing endocrine treatments have become commonplace in the management of advanced ER+ breast cancer, but success is still limited. This is particularly notable for CDK4/6 inhibitors, which have become firmly established as a standard of care for the initial treatment of advanced ER+/HER2- breast cancer. Despite these 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. We believe ARV-471 is fundamentally different from any other therapeutic in development and has the opportunity to become a future standard of care in ER+ breast cancer, first, for patients with metastatic disease, and ultimately, for patients with early-stage breast cancer. Now moving to Slide 5. If you recall, in December of 2020, we reported a clinical benefit rate of 42% in 12 eligible patients. Today, we're reporting an equally compelling clinical benefit rate of 40% in 47 eligible patients. And this is in a patient population expected to be resistant to ER-targeted therapies, which Ron will talk about in just a few moments. As a reminder, CBR is the standard primary efficacy endpoint in Phase II studies evaluating new therapies in patients with previously treated ER+/HER2- breast cancer. In order to qualify as a clinical benefit responder, patients must either have achieved a confirmed RECIST response or durable stable disease, defined as disease stabilization of at least 24 weeks duration. This study enrolled the most heavily pretreated patients of any trial of an ER-targeting therapy, with all patients required to receive prior treatment with CDK4/6 inhibitors. Despite the advanced stage of disease and heavy pretreatment, the data we presented today reflect a high clinical benefit rate and deep ER degradation with a favorable safety and tolerability profile. While ARV-471 has not been studied against fulvestrant or any clinical stage set, we believe today's data position it strongly among these current and potential future options. Now before I turn it over to Ron, I want to reflect back to last December when we first shared what we believed was quite remarkable interim data with 471. We told you that we believe 471 was tracking to have the best-in-class profile, including safety, efficacy and ER degradation for any ER-targeting therapy. Now nearly 1 year later, I couldn't be happier to reiterate that the data continued to support this potential position. ARV-471 continues to demonstrate a compelling clinical profile, and I'm more confident than ever that we have an opportunity to provide a significant advance in treatment options for patients with ER+/HER2- breast cancer. Now with that, I'll turn the call over to Ron, who will take a deeper dive into these compelling data. Ron?

Thanks, John, and good morning, everyone. Before I take you through the really exciting data on ARV-471, I'll briefly describe the design of the first-in-human trial, as shown on Slide 6. We employed a traditional 3+3 dose escalation design, and the primary endpoints and secondary endpoints are typical for oncology Phase I trials. We began with the starting dose of 30 milligrams administered orally once a day, and dose escalation continued up to a maximum administered dose of 700. A maximum tolerated dose was not reached. The inclusion criteria for the trial are shown on Slide 7. Importantly, all patients must have received at least 1 prior CDK4/6 inhibitor agent. We believe this requirement is unique to our Phase I trial as compared to those for the various SERDs currently in development. This is a critical point because we now know that patients who progress on or after a CDK4/6 inhibitor display a particularly high level of ER-independent resistance and have aggressive disease that progresses rapidly. More specifically, recent molecular profiling studies show that 66% of patients treated with these agents develop mutations across multiple pathways that are associated with unresponsiveness to ER-directed treatment. Not surprisingly, these patients do poorly with current treatment options, including the standard-of-care agent, fulvestrant. At this year's ASCO meeting, the results of the VERONICA trial demonstrated that fulvestrant had a clinical benefit rate of just 14% in patients who were previously treated with a CDK4/6 inhibitor. As shown on Slide 8, patients in the trial received extensive prior therapy. The median number of prior therapies was 4, 80% of patients receive fulvestrant and 78% received prior chemotherapy. And most notably, 55% of all patients in this trial have been treated with chemotherapy in the metastatic setting, which is well known to be associated with poor outcomes in this patient population. To our knowledge, the percent of patients who received both fulvestrant and metastatic chemotherapy are among the highest reported in the first-in-human trials of novel ER-directed therapies. Together with the 100% prior CDK4/6 inhibitor use, we believe that this is the most treatment-resistant patient population across the competitive landscape. This makes the efficacy we are seeing with 471 even more exciting. Slide 9 outlines the safety profile observed in this study. ARV-471 was well tolerated across all dose levels up to 700 milligrams, and no dose-limiting toxicities were reported among the 60 patients we are reporting on today. Adverse events were primarily Grade 1 and 2, and only 4 patients experienced Grade 3 adverse event that was deemed potentially related to ARV-471. Of these individual Grade 3 adverse events, none were indicative of a true safety signal based on the data to date. Importantly, only 1 out of 60 patients discontinued due to an adverse event, and only 1 out of 60 require dose reduction. Based on these results, ARV-471 continues to demonstrate a highly favorable safety profile that we believe is well suited for patients with ER+ breast cancer across all lines, including the post-operative or adjuvant setting where patients tend to remain on treatment for 5 years or even longer. The key efficacy endpoint, CBR, defined as the rate of confirmed, complete or partial response, plus durable stable disease lasting 24 weeks or longer, is presented on Slide 10. Among 47 evaluable patients, ARV-471 achieved a clinical benefit rate of 40%. Approximately 30% of these patients are still on treatment, 2 of whom have received ARV-471 for more than 1.5 years. Importantly, clinical benefit rate was seen in patients with both ESR1 mutant and wild-type tumors. This CBR result is favorable relative to the rates reported in Phase I trials of the various SERDs now in development and is particularly notable in the context of the extensive prior therapy these patients received. The 40% CBR rate is also encouraging, given that 14% was seen with fulvestrant achieved in the CDK4/6 inhibitor treatment patient population in the VERONICA trial that I mentioned earlier. As shown on Slide 11, ARV-471 also demonstrated promising tumor regression in these late-line patients with measurable disease at baseline. Three patients achieved a confirmed partial response and 1 notable response. To talk about here, just to give you a picture of what this looked like was in a patient who entered the trial with extensive liver metastases after presenting -- progressing through multiple standard agents, including multiple therapies that are targeting the ER receptor, multiple-targeted agents and chemotherapy in the metastatic setting. Patients with large hepatic lesions often do not respond to endocrine therapy and are therefore commonly treated instead with chemotherapy. This patient had a substantial reduction in her lesions as demonstrated in the CAT scans included in the poster and met criteria for a confirmed partial response. Moving to Slide 12. ARV-471 degraded ER up to 89% through the 500-milligram dose level with a median reduction in tumor expression by 67% and a mean reduction of 64%. This level of ER degradation exceeds the mean of 40% to 50% reported in published data with fulvestrant administered at the optimal dose of 500 milligrams. Importantly, degradation was consistent across both wild-type ER and ESR1 mutant protein. And with that, I'll now turn the call over to Chris.

Thanks, Ron. Turning to Slide 13 to summarize in this Phase I trial with a heavily pretreated patient population, including 100% of patients previously treated with the CDK4/6 inhibitor, 80% with prior fulvestrant and 78% previously exposed to chemotherapy, ARV-471 demonstrated early clinical benefit and is well tolerated. A robust efficacy segment was observed in this population, which we believe is the most heavily treated compared to other recent studies with ER-targeted degraders or modulators. In this setting, only approximately 34% of tumors would be expected to be driven solely by estrogen receptor signaling. But even in this very advanced stage patient population, we saw a clinical benefit rate of 40%, which included 3 confirmed partial responses and with demonstrated impressive ER degradation. As a reminder, only 1 out of 60 patients discontinued due to an adverse event, demonstrating a favorable benefit risk profile and supporting the further development of ARV-471 as a monotherapy or as a suitable combination partner to test in earlier lines of treatment. Turning to Slide 14, which outlines our clinical development plan. In partnership with Arvinas, we will jointly develop ARV-471 through a broad clinical program designed to generate data that, if positive, could position ARV-471 as a best-in-class endocrine backbone therapy across the ER+ breast cancer treatment paradigm from the adjuvant setting through to late-line metastatic disease. ARV-471 is currently in 2 ongoing clinical trials for ER+/HER2- metastatic breast cancer, a Phase Ib combination study with IBRANCE or palbociclib and the VERITAC Phase II monotherapy dose expansion study, which I'm pleased to announce is now fully enrolled. In 2022, we expect to share data from the VERITAC monotherapy Phase II study as well as data from the Phase Ib trial in combination with IBRANCE. We also intend to initiate Phase III studies next year across multiple lines of therapy in both monotherapy and in combination, as well as expand an umbrella study with other targeted medicines, including our next-generation highly selected CDK2 inhibitor, our CDK4 inhibitor and our specific KAT6A inhibitor. With that, I'll turn it back over to John.

Thanks, Chris. And if you all turn to Slide 15, I hope you share in our excitement for the data we presented today at the San Antonio Breast Cancer Symposium. With a strong efficacy signal, compelling ER degradation and a well-tolerated safety profile, these data further demonstrate that ARV-471 has a consistent, potentially best-in-class profile and is well positioned to become the future of go-to choice for ER-targeting therapies. And as Chris outlined, we have a clear development path for ARV-471 with a data-rich 2022 ahead. We look forward to reporting data from multiple studies, both monotherapy and in combination and to initiating 2 Phase III studies in the upcoming months. Now before we open the call for questions, I want to thank our employees for their continued dedication and importantly, the patients, their caregivers and physicians who participated in this trial. Thank you again for joining us this morning. And operator, we're ready to open the call for questions.

[Operator Instructions] Our first question comes from Ellie Merle with UBS.

Just in terms of safety, could you elaborate a bit on the QTc elongations seen in 1 patient as well as sort of the liver elevation seen in 1 patient that were Grade 3? And then just in terms of the planning for the Phase III, could you talk a little bit about how you're looking at the AMEERA-3 data as well as the data from Radius? And any implications in terms of your trial planning?

Thanks, Ellie. Some nice questions there. Yes, we're very pleased with the safety profile we're seeing at this stage of the Phase I and moving into Phase II last year. Let me hand over to Ron, who can take you through those examples you mentioned.

Thanks, John. Yes. So I'll start with the QT. So this is an isolated event. This is a Grade 3 event. And I just -- the point about that is based on the thorough evaluation of the data, we don't believe this represents a signal. This is not unusual to pick up in a Phase I trial. And so we don't see this as a signal. There were -- for this particular patient, the patient was on a couple of medicines that could be associated with QT prolongation. And the other point I'd like to make here is that preclinically, we have not seen a preclinical signal that -- around QT prolongation, either in the hERG assay nor in the dog studies. So we don't see this as a signal. And with regard to -- I think you mentioned liver, but I just have to make a correction. You probably are referring to amylase lipase. We haven't had any Grade 3 liver events. The amylase lipase is similarly an isolated event. This is a patient who had elevation in 1 lab test. A subsequent lab test was unremarkable. Both cases for the QT and the amylase lipase, these were asymptomatic findings. So this is another case where we don't see this as a signal based on the data that we have today.

And Ron, do you want to talk to the second half of Ellie's question related to plans for Phase III as it relates to Radius? I mean generally, we are actually pleased to see other companies with SERDs showing positive data. I think that bodes well for our compound because of the profile of our compound are a similar stage of development, and the Phase I clearly looked very, very good. So we're pleased to see that. Ron, do you have anything about any change with plans? I don't think we have a change of plan, but thoughts about the overall planning for Phase III?

Yes, certainly, no. We don't have any -- this doesn't affect our plans. I mean for us, we're thrilled that we have activity both in ESR1 mutant and ESR1 wild type. And also, I mean, just as we have been talking about, we're very excited by the efficacy data, especially in the context of the extreme prior therapy that these patients received. So we feel that this is something that makes perfect sense for us to move into the second line, and our strategy doesn't change as a result of these results.

Our next question comes from Joon Lee with Truist Securities.

Congrats on the very impressive data. In the swimmer plot data, there are 5 patients with stable disease past 6 months who are no longer on 471. What's their disposition? And I have a follow-up.

Ron, do you want to take that?

Yes. Can you restate your question, please?

He says there's 5 patients in the swimmer plot that had stable disease. What's their disposition?

Yes. So in the swimmers plot, when patients are still on therapy, they'll have an arrow. If they don't have an arrow, that means that they've stopped usually for progressive disease. But I think one thing that is -- with regard -- I guess stepping back, overall. The thing that we're excited by is that we have approximately 30% of patients who are still on therapy, including some patients who have been out for a pretty long time.

Got it. And the other question is post CDK4/6 is expected to drive high rates of your ER-independent resistance mechanism. Yet a lot of people -- is 100% of patients were on CDK4/6, yet you have high rates of response. So what's the mechanism by which ER is having an impact in these presumably resistant patients?

Well, I'll just begin. Ron can talk to that. But overall, we know, we believe in these patient populations, this late-stage patient population, over 65% of the patients probably have tumors that are ER-resistant. That does leave a significant number that still potentially could respond. And that's why we're so excited about our data. To have a 40% CBR in a highly resistant patient population is really significant. Ron, do you want to talk in relation to the ESR1 mutant versus wild type?

Yes, certainly. Yes, I can. So one thing just to -- yes, we talked about the activity there in the mutant and the wild type. The clinical benefit rate in the mutant population is actually 50%, which is pretty remarkable, especially with all the treatments that these patients have gotten. In the ESR wild-type patients -- and remember that this is a -- seem to be a signature for lack of responsiveness or under responsiveness to estrogen-directed therapy. We still have a clinical benefit rate of 30%. And just to put that into context, if you look again back at the VERONICA trial, which had a 14% clinical benefit rate, we're still seeing double the clinical benefit rate that would be expected in this population with the current standard of care.

Our next question comes from Ted Tenthoff with Piper Sandler.

Great. My congrats on the data today. It's really cool to see how far the technology is coming, and I really love the broad development plans. I wanted to focus in on the Phase III trials and get a sense. It seems like this is going to be building on this experience in later-stage women. Can you give us any idea of patient population, maybe even size of a potential Phase III trial? I appreciate you guys answering the question.

Thanks, Ted. And of course, we are very excited to have a great partner now for ARV-471 with Pfizer. And Chris Boshoff's on this call. So maybe, Chris, I could turn to you and talk about our early thinking on Phase II plans.

Thanks very much. Good question. So overall, we are working very closely with Arvinas to design the Phase III study, and we will provide additional information or further information in 2022 regarding the -- our strategies. We believe the Radius data, as referred to earlier, provides proof of concept and confidence in these next-generation class of ER-targeted medicines. But we also believe, of course, that ARV-471 could be potentially a best-in-class molecule. We will incorporate any lessons from their studies, obviously, into our trial designs, both in the later and earlier lines in combination with CDK4/6, but also for the adjuvant onsetting.

The next question comes from Alethia Young with Cantor Fitzgerald.

Congratulations on the data. This is [ Manan ] for Alethia. Why did you decide to design your trial with 100% of patients requiring prior CDK4/6 treatment while other trials have not? And how do you believe that your levels of prior chemo and fulvestrant treatment compares to other trials?

Thanks, Alethia. I mean, I'll hand over to Ron for a broader answer. But that was a requirement from the FDA in terms of the 100% CDK4/6. That's why we know that we're in one of the latest patient populations, not only 100% post-CDK4/6, 80% post-fulvestrant and 78% that had prior chemotherapy, so an incredible late-stage population. Ron, anything you want to add into that?

Yes. I think maybe just to -- I think just to add to the point that we assume that the FDA put that requirement to us because we were coming in with a new modality. And then the only other thing that I would say is we've, of course -- to understand our data, we also have to put it in context with the others. And so as we've looked through this very carefully, we do see a difference. And also, when you look at the literature in the ER+/HER2- setting, you will see that prior chemotherapy fulvestrant, but also chemotherapy in the metastatic setting clearly is a predictor for much worse outcome.

Our next question comes from Michael Schmidt with Guggenheim.

Congrats on the data as well. Just wondering if you could provide some additional comments around the dose response? And you're to select 2 doses for Phase II, the 200- and the 500-milligram once a day. And how you will select the Phase III dose based on that?

Thanks, Michael. Great question. And I'll hand over to Ron to talk about dose response and our initial thinking about Phase III dose.

Certainly. So with regard to -- I'll start with the Phase II doses. So Mike, you brought up that 200 and 500 we had selected for the Phase II. 200 was selected initially based on the exciting data that we had around the time that we had last year's disclosure. And 200, in particular, from an exposure perspective, was giving us a comfortable margin above the preclinical threshold. And of course, we certainly had safety and efficacy and ER degradation at that level. So we felt very comfortable moving forward with the Phase II. We selected 500 subsequent to that based on the continued Phase I dose escalation. And 500 essentially gives us a bookend to investigate whether there could be a dose response relationship as we get up higher in dose, 500 is safe. 500 is the highest exposure that we've achieved. And again, we're seeing activity across the board. What I would say is that this is a Phase I trial, of course. So with small numbers at each of the doses, this is not the trial where you can really discern a dose response relationship. And in terms of us picking a dose for Phase III, it's really going to be dependent on additional data that will come from the VERITAC trial, this dose-ranging study. And that will position us to make a very well-informed selection of our optimal dose for Phase III.

Next question comes from Matthew Luchini with BMO.

Thank you so much for taking the questions and for providing a nice update this morning. I guess, first for me, as it relates to the combo -- the Phase Ib combo study you're going to be starting next year. I was just curious if you have any sense as to, I guess, first, when we might expect some initial results from that study. But I guess more generally, you've talked about maybe looking at CDK2, CDK2/4/6, if there's any of these mechanisms that you think might be particularly synergistic with 471? And then on the data presented today, I was just hoping you might be able to provide or remind us with some additional color as it relates to both the 2 patients who have had, I think it's now north of 18 months of treatment, as well as the patient that achieved a partial response with the -- despite having liver metastases since that certainly is an interesting result given the patient population.

And we can split these components to the questions between Ron and Chris. So Ron, do we start off with the palbo combo and then you can maybe talk about the patients. And Chris, maybe talk about the potential combinations as we move into Phase III. So Ron?

Yes. Certainly, yes. The palbo combination is ongoing. That will, of course, inform our selection of the combination dose. Just one word about that trial is it's not designed for efficacy. We allow prior CDK therapy. Our goal here is very simply to look at safety, ensure that the drugs are combinable without any unexpected findings and evaluate PK. With regard to the questions around -- I think there was a question around the patient with liver metastases, the one that I had described. And just a reminder, there's a vignette in the poster about this with CAT scan pictures. Yes, this patient had a pretty remarkable response. And as you can see in that slide, a patient had in excess of prior therapy. This patient actually had received an investigational SERD that is now in late-stage development and never responded to that prior to going on 471 and actually progressed on that. I think your question was what happened with that patient. That patient actually came off without having RECIST response. The patient did not have toxicity either that drove her to come off. It was more around a patient that was being treated distantly from her home, was referred in for the trial and opted to go back to her referring oncologist. And I think the other question that you had was, was there anything in particular with regard to the patients who are on therapy longer. Yes, you could see, I mean, across the board, these patients are pretty, pretty heavily pretreated. I think it's hard to really discern more specifics, but we are seeing this pattern across the board in terms of the clinical benefit rate.

And Chris, do you want to talk to the potential excitement around 471 plus other mechanisms?

Thank you. That's a good question. So we will -- we are working very closely with our colleagues at Arvinas to design the strategies for the combination studies, including an umbrella trial. As you will recall, 3 years ago now or 4 years, actually, with our collaborators at the Institute of Cancer Research, Nick Turner, we showed that CDK2 is a potential mechanism of resistance to CDK4/6 inhibitors. That was in our palbociclib studies. And we therefore designed and conceptualized, developed this highly selective CDK2 inhibitor, which is currently in Phase I. And we will share data in 2022 with the CDK2 inhibitor. And of course, that provides optionality to also combine the CDK2 inhibitor with palbociclib, and such a study is also ongoing. We are also presenting data at San Antonio Breast Cancer with a CDK2/4/6 inhibitor, and early encouraging data will be shared at San Antonio. Separately, we have a CDK4-specific inhibitor that's currently in Phase I. And again, we'll share data in 2022. The CDK4 inhibitor's particularly designed because we believe that CDK6 play a more important role in the hematological toxicity seen with CDK4/6 inhibitor. So overall, I think this partnership provides us with significant options and advances over competitors in terms of what we can do to combine to really transform the standard of care for patients with ER+ breast cancer. It's a good question. Thank you.

Our next question comes from Zegbeh Jallah with ROTH Capital Partners.

Great results. As highlighted, we've seen encouraging efficacy observed in a heavily pretreated patient population. So if I can have you speculate just a little bit. So based on what you're seeing here, can you comment on what you think the resistance mechanisms could be? And what your thoughts are regarding the level of efficacy and the durability we could see in early adjuvant setting relative to fulvestrant, for example, particularly given the reported efficacy in ESR1 mutant patients? And I have a quick follow-up.

Great question. And maybe I could ask our CSO, Ian Taylor, to talk about what's known about potential resistance mechanisms, then we could hand back to Ron for that second part of the question around efficacy.

Sure. Thanks, John. Yes, right now, I don't have any data from the clinic that would point to any resistance mechanisms. But what we've modeled preclinically is that most of the resistance mechanisms continue to be non-ER dependent, not related to the ubiquitin proteasome system or the mechanism of the PROTAC per se, but more other pathways, other mechanisms beyond ER coming up, which, of course, is what we're seeing a lot in our patients currently post-CDK4/6. So it seems consistent with that currently.

And Ron?

Yes, certainly. Yes, I think your question was around efficacy in earlier lines. Yes, I mean, we're especially excited about how this is going to work in earlier lines. We firmly believe that degradation is the most important mechanism. Fulvestrant as the most active therapy in the market today, and it is a sort of a more indirect degrader, just gives us that confidence. Fulvestrant's experience has also shown that having greater degradation matters when they moved from the 250-milligram original approved dose to the higher optimal dose 500, which was associated with greater degradation and greater efficacy. So we're thrilled that -- in where we are right now. We have a safe drug. We have a drug that has really robust activity in the most heavily pretreated population that we're aware of in these studies of new therapies targeting ER. So we really do -- we're very excited. I think -- I probably speak on behalf of Chris, that we're very excited about moving this into earlier lines and adjuvant. And as I mentioned, the safety for 471 is especially suited for long treatment, including the longer durations in the adjuvant setting.

And then just a quick follow-up. I know this is a difficult one. I think you've all been trying to answer this question on the call, but just curious on your thoughts regarding whether the efficacy seen in supposedly non-ER-driven tumors could be something unique about how 471 binds the receptor? Or could it be something unique to the iterative effect of degraders and their ability to kind of be effective under low substrate conditions? So maybe more broadly beyond that, you could talk about how this data perhaps, even coupled with data from ARV-110, influences your conviction and the rest of your pipeline efforts, which is expected to probably become more of a focus during 2022.

Thank you. Yes. Yes, obviously, we're extremely excited about the potential of 471. And you mentioned ARV-110, which is also progressing really well. I'm not sure between Ian and Ron, do you want to try and talk about that, what we think is driving efficacy in the ER resistance. Because we are seeing CBR rates, significant CBR rates in these wild-type patients. Ian or Ron?

It sounds like an Ian question.

Yes. Yes, sure, I can go. Yes, I think the key point to remember about these resistance mechanisms is always put it in the context of tumor heterogeneity, right? So these tumors have -- are not homogeneous at all in terms of their molecular profile. And we see that when we're doing the circulating tumor DNA profile. We see a lot of different mutations. And so in some clones of the tumor may be ER-dependent, and we can see responses there. But other clone -- parts of that tumor might have other driver resistance mechanisms like Aurora kinase or PI3K. So it's kind of hard to tease apart in any 1 tumor, all the things that are going on and which part of the tumor might be driving the response and which part might be driving resistance. But clearly, because we're seeing responses and significant clinical benefit rate in most of these patients, there are certainly regions of the tumor that are responsive to ER and that are responding to ARV-471. And we think that's really linked to the degradation mechanism. And that does flow over into 110 as well and the rest of our pipeline. So I think we're seeing that if a tumor can respond, if it's -- even in resistant setting, it's being driven by ER, the degradation can drive that benefit to the patients.

Our next question comes from Brad Canino with Stifel.

I appreciate the data update this morning. Just so we have the specific details, can you tell us what number of the -- I think it was 47 CBR-evaluable patients had a documented ESR1 mutation. And then what was the CBR in both patients with mutated and wild-type ESR?

Ron, do you want to go through that?

Yes. I actually -- I don't have the -- what I can tell you, and I don't have the numbers in front of me right now. But what I can say is that the CBR rate in the patients with ESR1 mutants was 50%, and for patients with ESR1 wild type was actually 29%, so about 30%. Unfortunately, I don't have the numbers here, but we can certainly get those.

Okay. And then on your Phase II, you mentioned it was fully enrolled. Can you tell us the end, the sample size there that we will be getting?

Ron?

I'm sorry. Can you restate the question, please?

We've just announced that we had finished the enrollment of Phase II. And I think the total number of patients in there will be 60. Is that correct, Ron?

Yes. Yes, approximately 30 patients for the 200 and 30 patients for 500 milligrams.

Our next question comes from Mark Breidenbach with Oppenheimer.

And very glad to just see the CBR rate holding up in the larger data set. Just a very simple question from me. Since you mentioned VERITAC's completed enrollment, I'm just wondering if you can give us any granularity on when in 2022 we can expect to see initial data from VERITAC as well as the Phase Ib evaluating 471 in combination with IBRANCE?

Yes. So, so far, what we've announced is that next year, we will have the VERITAC Phase II data discussed and released. And we'll have the safety data from the Phase I and IBRANCE combination study. What we haven't said yet is where and exactly when. There'll be more on that in the new year. But yes, we're committed to having those results coming out next year.

Our next question comes from Maneka Mirchandaney with Evercore.

I actually just had a couple of quick clarifications. The first one is aside from the Grade 3 QTc event that you guys flagged, just wanted to double check that there weren't any Grade 1 or 2 QTc prolongation or bradycardia type event? And then on the 2 additional confirmed PRs from the prior cut, from what I can tell, I think one of those was the previously unconfirmed patient as of the December 2020 cutoff and then one is a new patient. But I just wanted to clarify that that's correct as well.

Yes. Thanks for the question. And Ron, do you want to take those?

Yes, certainly. Yes, for Q2, we had 2 other patients that had Grade 1 or 2, but these patients had other explanations. One patient had an elevated QT at baseline. The other patient was on therapies that are well known to prolong QT. And these were also very transient observations. The QT would go down to baseline. So it was not, in our assessment, anything that would support a signal here. And as I mentioned before, preclinically, 471 did not have a signal, either through hERG testing or dog studies. And then the question was around the unconfirmed response from before that is now a confirmed response. Yes, so this is -- as you know, this is an ongoing trial. The database is not going to be final until the study report. This is a case where what was in the database a year ago led to the determination of an unconfirmed response, but with additional querying to the site, the site ended up putting in a correction in the database and that resulted in the confirmed response.

Our next question comes from Yigal Nochomovitz with Citigroup.

I had 2 efficacy-related questions. The first one is are we going to see PFS data at some point? Or is CBR really the critical metric? And if we do get PFS data, what do you think you need to show there? And then secondly, with regard to ER degradation correlating with clinical benefit, I appreciate that the numbers are too small with the current data to draw any conclusions on correlation of degradation with clinical response. But I'm just wondering, once you do have more data, would it be your expectation that you'd start to see the magnitude of ER degradation start to correlate with clinical benefit?

Thanks, Yigal. Certainly, we can -- I'll have Ian talk about ER degradation. You're right, the number so far, relatively small. And of course, even if we're doing 100% degradation in some of these tumors where it's completely ER resistant, you wouldn't see any benefit. So again, that's the confounder at this very late-stage patient population. But as we go into earlier lines, where the more of the disease is driven by ER, these high levels of degradation are probably going to have a more significant impact on efficacy. But I'll let Ian talk about it in more detail. But Ron, do you want to talk about PFS and CBR and what's the best measure and when we start talking about PFS?

Sure. Yes. Yes. PFS is something that will likely wait until the VERITAC study. Remember that, first of all, of course, this is a Phase I study. The other thing is that -- so we have doses. We have -- treating across multiple doses. It's also -- as we've already made the case is that there's a particularly heavily pretreated typical Phase I population. We actually allow up to 3 prior chemotherapy regimens. So Phase II is where we're going to present the PFS data. And yes, so we look forward to having those data available.

Ian, anything you want to add to the ER degradation question from Yigal?

Not really, John. You covered it pretty well. I mean it's really driven by the biology. Post CDK4/6, you have so much non-ER dependents that you can degrade the ER all you want and those tumors won't respond because they're being driven by something else. So in this setting, it's going to be really hard to show that relationship. But in other settings earlier, as John mentioned, where there's more ER dependence, then that's where it would show up.

Next question comes from Tyler Van Buren with Cowen.

I guess the first one is what do you view to be the most significant safety and tolerability benefit relative to Sanofi's amcenestrant as we think about you both eventually competing in the market? And then just secondarily related to the Emerald data, can you just discuss why you think the PFS and CBR rates were higher in mutant patients versus wild type?

Sure. I'll hand it over to Ron, but just again, to be fair to Ron, just to position, we are -- this is our end of Phase I data we're discussing, and these other companies are discussing data from a later stage of development. And we're very comfortable that when we get to compare our data end of Phase II, we'll be in a good position to compare. But having said that, Ron, anything you want to say about safety benefit compared with Sanofi and the Emerald data with the [indiscernible] compared to other drugs?

Yes. I think the message is that we're very confident. The way that we look at this is, this is the most resistant, most aggressive tumor or patient population that's been studied with an ER -- novel ER therapy. We think that the safety really is -- really good all the way up to 700 milligrams. I mean this is pretty remarkable with no dose-limiting toxicities. Only 1 discontinuation, only 1 dose reduction out of the 60 patients. So we think the safety is really quite conducive to long-term therapy. And then the benefit, we are very excited by a clinical benefit rate of 40% in the most resistant population. So we just are very -- we feel like we're in a really good place as we move into Phase III.

Our next question comes from Christopher Liu with SVB Leerink.

I just had 2. With the first one, I was just thinking about your go-forward doses with 200 and 500 milligrams. When I look at the CBRs here for 200 and 500 milligrams, it looks like -- albeit in small patient numbers, but it looks like 500 milligrams has a meaningfully higher CBR rate. So just wondering if you thought that could mean something, if that kind of leans you towards going towards the 500 milligrams?

Well, again, this is our Phase I data. So its dose escalation, where we're very excited to see responses and clinical benefit rate as we went up the doses, very pleased to see significant degradation through all doses. As Ron mentioned earlier, we chose 200 and 500 because we thought that would be a nice bookend in terms of exposure and efficacy. And absolutely, we'll see what happens at the end of Phase II. At the end of Phase II, I think we're going to have a great, rich data set on 200 and 500. But right now, we're just pleased that going through to the end of Phase I, the choices that we made early in the year were correct. These are the right choices to pick 200 and 500, and we'll see how that pans out and what position it puts us in to select which dose for Phase III next year. So as Ron said, it puts us in a very good position.

Got it. And for my second question, I was just hoping to get additional color on the Grade 3 AEs that you saw in the 500-milligram cohort as well as the 180/200-milligram cohort?

Sure. I'll hand back to Ronald to go over again the Grade 3 events.

Yes. Yes. And what I'm going to just say is that just remember that there's only 4 patients out of 60 who've had Grade 3 related adverse events, and each of these were different. There's not a consistent pattern. And as I mentioned in the presentation, none of these individual events represent a particular safety signal based on the data that we have. The other thing that's interesting is that going from 30 to -- 30 milligrams all the way up to 700, there's not an obvious dose relationship for adverse events, which, again, I think, just reinforces the safety of this compound. And I think back to what John was saying from the standpoint of picking a dose, the VERITAC study will also give us more information about safety at the 2 doses, 200 and 500. So we have to wait for that.

Okay. So is there anything you could tell us specifically on what the Grade 3 AE was in the 200-milligram cohort and then the 2 in the 500-milligram cohort?

I actually -- I'm not sure I have that information right in front of me, so we can certainly provide that.

Ron, you can talk -- you already talked about the Grade 3 events earlier, just you just go through those again.

Yes, certainly. Yes, yes. So yes. So across the study with 60 patients, we had 1 Grade 3-related QT event, which I mentioned does not, in our assessment, indicate a signal. We had 1 isolated case of amylase lipase elevation, also asymptomatic and also not indicative of a signal. We had a third patient who had a thrombotic event. This is -- thrombotic event's very common in oncology in metastatic breast cancer, in particular, and this patient also had another risk factor for clotting. So there's no concern about that one as well. We don't think that's related to this treatment. And we had 1 Grade 3 nausea. It's the only Grade 3 nausea that we had. And so -- and the GI profile looks very good. So we're really not concerned about these events.

And I'm not showing any further questions at this time. I'd like to turn the call back over to John for any closing remarks.

Yes. Thank you very much. And thank you, again, to all of you for joining us this morning and for your continued interest, and great questions. So thank you, and have a great day.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.