AstraZeneca PLC (AZN) Earnings Call Transcript & Summary

Welcome, ladies and gentlemen, to AstraZeneca's Investor Science Conference Call San Antonio Breast Cancer Symposium 2022. Before I hand over to AstraZeneca, I'd like to read the safe harbor statement. The company intends to utilize the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements. Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this conference call and webinar. [Operator Instructions]. I must advise you that this call will be recorded today. And with that, I will now hand the call over to AstraZeneca.

Thank you. Hello, and welcome, everyone. My name is Morgan Sanford in the Investor Relations team at AstraZeneca. We're pleased to be hosting this investor science conference call where we will discuss key data presented at this year's San Antonio Breast Cancer Symposium. Please move to Slide 3. As part of our panel of speakers today, we are joined by Dr. Nicholas Turner, Principal Investigator on the CAPItello-291 trial, Professor at the Institute of Cancer Research and the Royal Marsden Hospital, London. I'm also joined by AstraZeneca colleagues, who will be presenting this afternoon, including Susan Galbraith, our EVP of Oncology R&D; Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer; and Dave Fredrickson, our EVP of Oncology Business Unit. For Q&A, we will also be joined by Liz Chatwin, Global Franchise Head in HER2 and breast cancer as well as Ingrid Mayer, Global Clinical Strategy Head, Breast Cancer. Now if you could please move to the agenda for today's call on Slide 4. Susan will provide an overview of our presence at San Antonio Breast Cancer Symposium 2022, followed by the presentation of the CAPItello-291 Phase III data by Dr. Turner. Cristian will go through the SERENA-2 Phase II results, which will followed be Dave providing commercial context to our data here at the congress. We will close the call with Q&A chaired by Dave. With that, please move to the next slide, and I will hand the call over to Susan.

Thank you, Morgan. So I'm delighted to be here at San Antonio. If you could just move to the next slide. This represents our strongest showing ever at San Antonio Breast Cancer Conference. In fact, I think it's probably the strongest showing for any company ever, with 56 accepted abstracts for all awaiting presentations and key data highlights across our portfolio. Please move to the next slide. So you can see here that the data that we're representing at San Antonio helps us advance our strategic ambitions across different segments of breast cancer. In the HER2-high setting, we've got new standards of care in this with the DESTINY-Breast03 and DESTINY-Breast02 studies, both showing overall survival benefit. Within the hormone-receptor positive space, we're reshaping the treatment of this segment with the potential to establish camizestrant as a best-in-class endocrine backbone therapy across different settings and capivasertib extending benefit of endocrine therapy for ER-driven disease by targeting a key pathway of resistance by the AKT pathway. Plus, we have best-in-class ADCs to replace chemotherapy in HER2-low segments as new targetable subtypes for both the HER2-targeted and HER2 DESTINY-Breast04 data and with our TROP2-targeted ADC with the TROPION-PanTumor01 data. And of course, the gBRCA segment, we've already established and are expanding beyond gBRCA with the Olympian data. I'm also excited about the opportunities in what we used to call triple-negative breast cancer, with improved response rates and durability for our ADCs in combination with IO, and I'll go into a little bit more of those data later. Please move to the next slide. Of course, within hormone receptor positive breast cancer, we have a strong legacy at AstraZeneca of developing medicines in this segment, first, from the 1960s where Nolvadex was first synthesized, all the way through Arimidex, Faslodex, obviously, and then through to our next generation SERD. And it's great to also now have the PARP inhibitors with Lynparza and the ADCs coming through in breast cancer, too. So the future, what we're looking for is to transform the paradigm with our next-generation or SERD with ongoing Phase IIIs with capivasertib, and we're anticipating a regulatory filing based on the CAPItello-291 data in the first half of next year. And we're taking an HER2 into the earlier lines of therapy as well as seeing the early data from TROP-2 for Dato-DXd. Please move to the next slide. So how does all this then fit together? I showed a version of this slide at the ASCO meeting when we presented the DESTINY-Breast04 study. But just to update it, this is focusing on the hormone-receptor positive segment in particular. And I think in the early space, you can see that for the gBRCA group we have Lynparza there, but there's a potential for camizestrant to replace current standard of care endocrine therapy in those patients that have intermediate or high-risk hormone-receptor positive early-stage breast cancer. We also think there's an opportunity based on the exciting data we're seeing in the metastatic setting to think about how antibody-drug conjugates could have the potential to replace some elements of the chemotherapy regimens that are typically used in the early space. But for today, we're focusing more on the metastatic setting. And of course, we've got the ongoing Phase III trials with camizestrant, SERENA-4 and SERENA-6. You can then see in the second line that we've now got something that's coming through that can offer a potential new standard of care in the second-line setting with the capivasertib data. And again, we've got the ADCs that have the potential when patients lose their estrogen receptor drive to replace chemotherapy for those patients that are no longer responsive to endocrine therapies. So with that, I'm now going to hand over to Dr. Nick Turner, who is the principal investigator on the CAPItello-291 from the Institute of Cancer Research in London.

Thank you, Susan. It's a pleasure to be on this call today to present the primary results of the CAPItello-291 study. Next slide, please. CAPItello-291 recruited patients with hormone receptor-positive HER2-negative advanced breast cancer who had all progressed on previous aromatase inhibitor therapy. The study allowed patients to have add up to 2 lines of prior endocrine therapy for advanced breast cancer and one line of chemotherapy. Prior CDK4/6 inhibitors were allowed, and at least 51% of patients had to have a prior CDK4/6 inhibitor. And in addition, patients with diabetes not requiring insulin were allowed to enroll. The study randomized 708 patients between fulvestrant and capivasertib, and fulvestrant and matching placebo. And randomization was stratified by the presence of liver metastases, prior CDK4/6 inhibitor use and region. And capivasertib was given as standard regimen of 4 days on, 3 days off, which was selected early in development to maximize the therapeutic window of AKT inhibition. The study had dual co-primary endpoints, PFS by investigator assessment, overall, and an AKT pathway altered tumors, which was at least one of the qualifying alterations in PIK3CA, AKT1 or PTEN, that was the determined on tissue using the FoundationOne CDx assay. Key secondary endpoints were overall survival and objective response rate. Next slide, please. So first of all, the data on the two co-primary endpoints. This first one is investigator-assessed PFS in the overall population. Median PFS on placebo and fulvestrant was 3.6 months, and this increased the 7.2 months on capivasertib and fulvestrant with an adjusted hazard ratio of 0.6, which was highly statistically significant. And as you can see, the curves separate early and then stay separated for the duration of follow-up. Next slide, please. This is the second co-primary endpoint, which was investigator-assessed PFS in the AKT pathway-altered population. So 41% of patients had AKT pathway alterations. In this population, Median PFS was 3.1 months on placebo and that increased to 7.3 months on capivasertib with an adjusted hazard ratio of 0.5, again, highly statistically significant. Next slide, please. I'll show you here an exploratory analysis of investigator-assessed PFS in the non-altered population, which per protocol included unknown 15% of patients at an unknown status. In this population, the hazard ratio was 0.7, and excluding unknowns, it was 0.79 with very similar curves. Next slide, please. I show you here a planned analysis of overall survival, which was requested by the regulators at this time point to assess for no detriment. Overall, the hazard ratio was 0.74 and in the AKT pathway-altered population, it was 0.69. Next slide, please. So we have key subgroup analysis in this first plot. So this is looking at prespecified subgroups, and across the subgroups, there was broadly similar efficacy. I've highlighted two on the slide, patients with or without liver metastases at a very similar benefit and also patients with or without prior use of CDK4/6 inhibitors had very similar benefit. And as you can see on the right of the slide, 69% of patients had prior CDK4/6 inhibitor use in the advanced breast cancer setting in this study. Next slide, please. In terms of the safety, on the left-hand side are adverse events that occurred in over 10% of patients in the capivasertib group. The most common adverse effect was diarrhea that occurred in 72% of patients, predominantly Grade 1, although 9.3% of patients had Grade 3 diarrhea. There were two rash terms included over 10%, and we, therefore, generated a grouped rash term, which occurred in 38% of patients on capivasertib Grade 3 and 12.1%. But I highlight that both hypoglycemia and stomatitis were relatively uncommon with only 2% of patients having Grade 3 adverse events of hyperglycemia or stomatitis. And then the safety summary is on the right-hand side. If we focus on serious adverse events, this occurred in 16.1% of patients on capivasertib compared to 8% of placebo. And if we focus on adverse events leading to discontinuation, this occurred in 13% of patients on capivasertib compared to 2.3% on placebo. Next slide, please. So if we look at the conclusions, capivasertib plus fulvestrant statistically, significantly and clinically meaningfully improved PFS overall and in AKT pathway-altered population. Benefit from capivasertib was consistent across clinical relevant subgroups, including patients pretreated with a CDK4/6 inhibitor and with liver metastases. Ongoing survival follow-up is ongoing for the future planned analysis of overall survival. And capivasertib and fulvestrant safety profile was consistent with that previously reported with relatively low discontinuation rates due to adverse events, and therefore, capivasertib plus fulvestrant is a potential future treatment option for this group of patients. Thank you.

Thank you, Dr. Turner. Good morning, good afternoon, good evening, all of you. In the next few minutes, I will try to go through SERENA-2, our Phase II trial in advanced setting HR-positive breast cancer. Go to the next slide, please. This is the design. This is a Phase II randomized multi-dose study in which our next-generation oral SERD camizestrant will be compared with fulvestrant. We compare 3 doses of camizestrant, 75, 150 and 300-milligram. That was fulvestrant standard dose. The 300-milligram cohort was closed prematurely, because not specifically DLTs or safety concern emerged. Simply, the overall safety profile was not deemed to be adequate fitting the setting where we were thinking to develop this drug. This is a Phase II study in which we enrolled a patient population quite similar, I would say, to what just Dr. Turner described you. So patients with advanced disease endocrine HR-positive that, of course, received prior endocrine therapy, at least one line in metastatic setting. Chemotherapy was allowed, and of course, patients could have received the prior CDK4/6 inhibitors. The prior endpoint of this trial was progression-free survival by investigator assessment. And of course, there were secondary endpoints, clinical benefit rate, response rate and safety and survival. Next slide, please. This is the baseline patients and disease characteristics. I want to point out a few things that can help you to understand better probably the data. First of all, visceral metastases. Visceral metastases is lung and/or liver metastasis where certification factors. So you see very well balanced among the 3 arms, and it's about a little bit less than 60% of patients had visceral disease. ESR1 mutation was detecting in 37% of all patients but was not a certification factor. This is the reason why you can see an imbalance among the 3 arms, with more patients with ESR1 mutation in the fulvestrant arm versus some specific camizestrant 75. Then if we move to the next table, you see that most -- also the patients received chemotherapy in the adjuvant setting and about 20% of patients received the chemotherapy -- prior chemotherapy in the advanced setting. I think importantly is the last line is that was the second certification factor in the trial prior CDK4/6 inhibitor use. And you can see that approximately 50% of patients were pretreated with CDK4/6 inhibitors. Next slide. This is the first outcome, the primary endpoint that is progression-free survival by investigator in the overall population. And you can see that camizestrant at both doses, 75 or 150-milligram, produced a statistically significant and clinically meaningful improvement of progression-free survival versus fulvestrant with hazard ratio of 0.58 for 75-milligram and 0.67 with 150, more than doubling the median progression-free survival. I want to point out also that, as you see in the total presentation, the performance of fulvestrant was as expected and actually quite similar to what you have seen in the prior study, around 3.5 months. Go to the next slide. This is a subgroup analysis. I will present you a few slides with some subgroup analysis that are quite relevant to understand also the data and a position the data. This is the first -- one of the first stratification factor, CDK4/6 inhibitors. You see that in the subpopulation of patients that were previously treated with CDK4/6 inhibitors, camizestrant, at both doses, produced a clinically meaningful improvement in progression-free survival with hazard ratio of 0.49 for 75, 0.68 for 150. Go to the next slide, please. Also when you look at the second stratification factor, so patients with lung and/or liver metastasis or visceral disease, in this population, camizestrant definitely produced a better outcome, compared to fulvestrant, it actually performed quite poorly with median PFS and other ratios that were definitely better than the comparator arm. Next slide, please. ESR1 mutation. ESR1 mutation with no stratification factor but, of course, is a very important biomarker in this population, specifically for SERD. And you can see that in the patients carrying tumors with this detectable baseline ESR1 mutation, camizestrant has a very important, meaningful improvement in the outcome in terms of hazard ratios at both doses, and of course, a median PFS compared fulvestrant. Lastly, next slide, please. Last subgroup analysis I want to share with you is related to those patients in which we can define the disease primarily driven by estrogen receptor signal, so endocrine sensitive. These are patients that have an important benefit in frontline with last endocrine therapy in metastatic setting, represent approximately 70% of the patients. And it's important because it is a population that you can translate maybe also into early setting compared to the current setting where SERENA-2 was run. You see that in this group of patients, you have a clear improvement in median PFS and, of course, that translated in a very good hazard ratios for both 75, 150, 0.53 and 0.58. Go to the next slide, please. I'll speak briefly about the safety. Importantly, there are a lot of numbers in this slide. Please focus on the Grade 3 events are higher that are treatment related. And you can see that there is almost no difference between the arms. The events are quite infrequent, and only 2 patients develop Grade 3 at 75 with no patients at 150. And when you look, even more importantly, this treatment-related adverse event that led to those discontinuation, you don't see really differences among the arms. Treatment interruptions were similar between 75 and 150, importantly, very short in duration, just around 1 week. So overall, the safety profile of camizestrant at both doses was quite manageable, quite acceptable and allow the patients to stay on treatment, even in a few cases, there was some interruption. Go to the next slide. When you look then into the granular nature of the events, what is, of course, the most frequent events were low-grade photopsia. It is occasional visual flashes in the peripheral vision and bradycardia. Bradycardia is an heart rate reduction that in almost all these patients were all -- I would say all these patients were asymptomatic. These were -- these are the two most frequent adverse event. But when you look then some of GI toxicities that could be quite important in this specific setting, with this specific class of drugs, 75, 150, you see very few events in terms of diarrhea or minimal liver toxicity or dyspepsia. And here, when I bring back the discussion on 300, when you look at the 300 column, of course, the quantity, the number of events is substantially higher, and what is higher also is the number of GI toxicities. So camizestrant higher doses can induce GI toxicity, but 75, 150, it is minimum. And this is, in our view, a big differentiator compared to the other agents in the same class of agents. So go to the next slide. To conclude, I think SERENA-2 clearly met the primary objective of showing superior statistically and clinically PFS over fulvestrant in these HR-positive postmenopausal population with advanced disease. These clinically meaningful PFS was observed across the prespecified subgroups and was also quite relevant in those subgroups that are a higher medical need, like post CDK4/6 inhibitors and in the presence of visceral disease. It was very dramatic, I would say, in ESR1 mutation tumor, but we observed the benefit with a reduction of progression-free -- or progression between 22% and 25% also in those patients carrying tumors without ESR1 mutation. And of course, very promising is the activity, the superior activity in those patients carrying a tumor endocrine sensitive. So both doses of camizestrant, 75, 150 were very well tolerated, with very infrequent Grade 3 events or more or higher, very infrequent dose reduction and very few discontinuations. So this supports, of course, the further development of this drug that, of course, is currently ongoing in the context of large Phase III studies like SERENA-4 and SERENA-6 and eventually additional future studies. With that, Susan, I'll give back to you.

Thank you, Cristian. Please go to the next slide. So in addition to the camizestrant and capivasertib data that we just described, we also had data presented yesterday from the Enhertu DESTINY-Breast03 data set. This is updated data with the key secondary endpoint of overall survival. And as you can see from the curves here, very clinically meaningful improvement in overall survival with a hazard ratio of 0.64, so a reduction of 36% in the risk of death. 78.5% of patients had a confirmed response and impressively 21% of patients had a complete response. Remember, this is a second-line metastatic setting. And so the median PFS here within Enhertu is 4x longer than the control arm of TDM, 29 months almost versus 6.8 months. Next slide, please. In addition, we're presenting later today and tomorrow updated data for the datopotamab deruxtecan, our next antibody drug conjugate, which we're developing in collaboration with Daiichi Sankyo. This is one targeting TROP2. And again, from the Phase I TROPION-PanTumor01 study, we're showing data with a response rate of 27%, disease control rate by BICR of 85% and very durable responses with a median PFS of 8.3 months. The Phase III TROPION-Breast01 trial of Dato-DXd versus chemotherapy in second line is ongoing. We're also presenting data from another cohort in the TROPION-PanTumor01 in triple-negative breast cancer, which shows an impressive median duration of response of 16.8 months. In this setting, the overall response rate by BICR was 32% in the overall population. And those patients that are naive to prior to summarized inhibitors is 44%. These data validated the 6 mg per kg dose for this drug for expansion across the program. And again, what you can see at the bottom is the data from the BEGONIA study where we've then taken those data for Dato-DXd together with in the first-line setting of triple-negative breast cancer, and again, a 74% response rate here with high durability of those responses, although the follow-up for median duration of response has not yet been reached. Next slide, please. So now I'm going to hand over to Dave Fredrickson, who is going to put this into context of what it means for our business.

Thanks, Susan, and thank you, Cristian, and Dr. Turner for the presentation. So just a couple of minutes before we go to Q&A on a few dimensions I want to put into context. Can you go to the next slide? I mean, as everybody well knows, breast cancer is the most cancer -- sorry, the most diagnosed cancer globally. 2.3 million cases are identified every single year globally. And despite all the advances that we've made, unfortunately, there's still a high unmet need as evidenced by 685,000 deaths from breast cancer that happen each year. Can you go to the next slide? Within that context, what you see here and what I hope that we begin to outline is that we are really seeking to reshape. Of course -- excuse me, HER2-positive disease or HER2-high disease through in Enhertu, but we, today, are really talking about efforts to reshape hormone receptor-positive breast cancer. A couple of quick things that I just want to point out. The first is that in the metastatic setting in the front line, we've got about 75,000 patients that are diagnosed in the G7 annually. About 60,000 of those then progress into the second line. As was highlighted before, about 85% of those patients or these patients have ER-driven disease at the beginning of treatment, and they do lose that ER drive over time. And the last thing, because of that ER drive, we see that about 70% of patients are receiving ET plus CDK4/6 in the frontline setting. And this is relevant because as we think about the strategy, we, one, want to be able to ultimately replace camizestrant as the ET backbone as part of the treatment of metastatic disease. And then secondly, we see an opportunity through combinations with capivasertib for us to be able to extend the time that women can benefit who have ER-driven disease from ET-based therapy, and so you get a sense of the size of the opportunity that's here. Next slide. I highlighted some of these pieces, but in terms of CAPItello-291, as I said, about 75,000 patients diagnosed each year with metastatic breast cancer, about 65,000 of those progress on with the second line. And there's relatively rapid progression, with a significant number of patients having received CDK4/6 ET therapy prior to this, these are patients that would be eligible based upon the study design for CAPItello-291. There's also a clear lack of standard of care right now in the second-line setting, which means that oftentimes, a clear lack of standard of care means that there's not some definitive option that should be used. And so therefore, we see an opportunity to be able to create one. We think capivasertib addresses key unmet needs through the data that Dr. Turner presented, and we plan for a regulatory submission in the first half of '23. If you go just to the last slide, obviously, we've talked a lot about ET and ET combos for hormone receptor-positive disease. We also are, as you all know, well underway on both the launches of DESTINY-Breast03 as well as with DESTINY-Breast04. I just want to highlight on this dimension that with DESTINY-Breast03, as I mentioned, at Q3 earnings, we're making very good progress in the U.S. and displacing TDM1 and rapidly have become the standard of care and are approaching 50% share within the marketplace. We've got good launches now underway in Germany and in France as well that are bolstering with that. And then also DESTINY-Breast04, we'll update more on full year here, but we're pretty pleased with what we're seeing in terms of the HER2-low launch patient identification so far seems to be something that has not been a barrier or a challenge. And indeed, perhaps anecdotally, I'd share that we hear a lot of physicians saying that they're looking for patients who they shouldn't be treating with 04 as opposed to struggling to find those who they should. So we found a good uptake in that regard. So with that, we'll go to the next slide. We'll move to the Q&A session right now. If you go to the next slide, again, you can see kind of who the Q&A panel is that we'll draw upon. In terms of the Q&A, please raise your hand via Zoom if you have a question, and then we'll put you in the queue. I do see that we've got a queue already. And so I'm going to get well underway.

So Michael Leuchten at UBS. Please, you can go ahead with the first question.

Two questions, please. One, you had an imbalance in Serena-2 in ESR1 state. Now it doesn't matter in that subgroup. But we do know fulvestrant doesn't work all that well in those patients. So for the overall trial results, how meaningful is that imbalance in the baseline characteristics? And then just going back to the positioning of cami, if I look at where the drug works really well, which is in ESR1 mutated patients and patients with liver and lung metastases in patients that have prior CDK4/6. Like, where's the argument that this is naturally a first-line agents, also if we think about the adverse events like bradycardia that comes in?

Mike, thanks so much on that. I think on this one, maybe I propose Susan and Cristian, I'll go first to you both, and they are related questions. One is kind of specific to SERENA-2 and the imbalance in ESR1, but also if you can answer the second with respect to kind of what gives us confidence that this could be an upfront approach and not just a post ESR1 mutation approach.

Yes. First of all, the question about the imbalance of the ESR1s was asked and answered by [indiscernible], who is the principal investigator. We did a sensitivity analysis on that, and it doesn't alter the conclusions about the estimate of the hazard ratio or the outcome of the results. On the second, in terms of the positioning. So I think it's very clear that in the first line, as I showed on that slide, there's a high proportion of patients that have got ER-driven disease, and in those patients, you have activity, as well as the ESR1 we showed and the subgroup that has the ER-driven disease, and you've got really good impressive hazard ratios within that group. So you would expect that this can do better, not just then fulvestrant but an aromatase inhibitor in that first-line setting. And again, I would remind you about the PT010 study that was presented at last year's San Antonio, where they took patients with rising ESR1 mutation on ctDNA, either randomized them to continuing on aromatase inhibitor or switching to fulvestrant. Now that we know that we can do better than fulvestrant, the fact that they doubled the PFS with fulvestrant in that trial, you would suggest that you can do even better. And I think you can just think about the ESR1 mutations as a surrogate for patients with high ER drive in their cancers. So that's where we would expect, based on past precedent that you're going to have an impact. And that's why we're confident in the profile of the drug in the first-line setting.

So thank you very much, Susan, on that. So now let's go to Richard Parkes with Exane.

First question is just for Dr. Turner. I just wondered if you could talk about how he feels that capivasertib's tolerability compares to alpelisib? I mean, it looks to be quite a lot better tolerated, but just wondering how it feels about that in practice. And then if you could also just help us understand how the overlap between your definition of AKT pathway mutations overlaps with PIK3CA mutation is used in the selection of treatment with alpelisib? That would be helpful. I just wonder if those populations totally overlap. And then my second question was for Cristian on the camizestrant presentation. The effect in ER-driven disease, I'm just wondering how much of that was driven by benefit in patients with ESR1 mutations. Do you see still see that consistent if those patients are excluded?

Thank you, Richard. So maybe Dr. Turner, if you can take the first two. Cristian, you can take the third. And then Cristian, I think also maybe we can come back and hit on the bradycardia question that was asked by Michael also as you get in your answer.

Thank you for the questions, Richard. So of course, we have to be careful with cross-trial comparisons between studies, also where different CTCA versions are used. But one thing that is very clear looking at the study is that hyperglycemia is substantially less common with capivasertib than it is with alpelisib. And also, it's clear that there's less stomatitis and less rash with capivasertib. And although there's diarrhea on capivasertib, overall, the majority of this was Grade 1 and only 2% of patients stopped capivasertib because of the diarrhea. I can speak to my personal experience of using both because we've used capivasertib a lot in a number of trials is that I have found capivasertib easier to use in the clinic than alpelisib. Your second question was about the AKT pathway alterations. So absolutely, as you said, PIK3CA is the most common mutation in the AKT pathway definition, which is as anticipated. But 5.2% of patients overall had AKT1 alterations and 7.1% had P10 alterations. So there is quite a large additional segment as well as PIK3CA mutations that are included in that overall AKT pathway-altered group.

So Richard, going to your question on ESR1 and ER. First of all, let me reinforce the message that, of course, the benefit is very substantially answered by mutation. We see a reduction in risk of progression in also ESR1 non-mutated patients, because it's 22% and 24% at 75, 150. So there is benefit or fulvestrant also in the population. The analysis is done on the ER-driven disease, it is taking in consideration not all the patients that are ESR1 mutated but also patients that have non-mutated disease because it's much bigger sample size. And there was some sensitivity analysis performed showing that this is not driven only by the mutated tumors, but also by -- is a benefit observed across. So we believe that this is an important aspect that give us confidence that when the disease is endocrine sensitive, this drug can provide definitely superior benefit versus fulvestrant. Then your question on bradycardia, we received the question before on bradycardia. I want to comment that the safety profile for camizestrant now is very well consolidated. We have more than 1,000 patients treated in the program. Bradycardia is asymptomatic in the vast majority, if I want to say, all patients. It's just a finding that you got in the clinic, and it's simply solved just the way the patient taking a look. It is something, of course, that we will monitor in the context of a larger Phase III studies, but they are ongoing in the Phase III studies, and this is not emerging as a problem. I want to emphasize the fact that one adverse event that is favorable with the camizestrant compare with other drugs in the same class is lack of GI issues. This will be very important in the context of trials where the duration of treatment is very long because keeping the patient on when diarrhea or some of the GI [indiscernible] that are emerging can be more complicated. And we see very favorably the current safety profile of camizestrant in this light.

Thank you, Cristian. I appreciate that. I mean I think the other piece just on the ESR1 piece is that -- I reflect on the conversations that we've been having with investigators is an acknowledgment that ESR1 mutations are indeed a surrogate for endocrine sensitivity, but there is a group, as Cristian has pointed out and Susan did before, of patients with ESR-driven disease that are ESR1 wild-type. And so it's a broader population from within that. Now moving over to Andrew Baum from Citi.

The commercial opportunity for the SERD is obviously greater upstream given the duration of use, given the low ESR1 mutation rate. If you're going to demonstrate superiority on efficacy, it's got to be driven, I would imagine by greater tolerability. So could you talk to how you're thinking about the relative tolerability and how that may drive efficacy, particularly in the adjuvant setting? And then second, again, in the adjuvant setting, could you talk about how you're thinking about patient selection in your forthcoming Phase III trial? Are you going to use ctDNA? Or are you going to stick with classical approaches to select patients at the highest risk of recurrence?

Thank you, Andrew. Susan, would you like to take those two together with Cristian?

So I think in terms of the differentiation in the early stages of breast cancer, really, what you're doing is comparing with aromatase inhibition. That's the place that you're going to be largely using to have camizestrant replaces as the backbone endocrine therapy. And given that -- with the Falcon data that was already previously presented, showing that fulvestrant in the first-line setting is superior to an aromatase inhibitor in progression-free survival are now showing that we can beat fulvestrant on progression-free survival in the second-line setting. That builds confidence about the differentiation for efficacy in the earlier stages. But again, it's also about keeping patients on therapy and minimizing these kinds of side effects that could cause people to have interruptions or discontinued study drugs. So adherence is incredibly important in the adjuvant setting. And that's why the safety profile that we have is so important. And in terms of the adjuvant patient selection, I think the -- what we will use is clinical characteristics that will help to identify the intermediate and high-risk patients for whom endocrine therapy intensification represents an opportunity. So it's not just going to be based on ctDNA.

Thanks, Susan. Okay. Next, please. Simon Baker, Redburn.

Two questions, if I may. Firstly, on camizestrant, you gave a PFS data prior CDK4/6 use. I appreciate the numbers are going to be pretty small, but did you see any difference depending on which CDK4/6 was used prior to camizestrant? And a second question on Cami. The discussion this morning talked about the significance of looking at the clonality of ESR mutations. I just wonder what data you have in your perspectives on the importance of that? And then secondly, moving on to HER2. There was a lot of debate today on quantification as opposed to IHC scores, particularly given the levels of discordance on IHC 1. I just wonder, do you have plans to look backwards and forwards in terms of quantifying by atoms moles per millimeter squared HER2 expression in any of the previous or future studies? And related to that, one of the sessions yesterday was asking the question, is HER2 low a separate entity. I'd be interested to get your perspective on all that.

Okay. Thank you, Simon. So maybe between Cristian and I don't know if with Ingrid if you've got answers that you can provide on whether we looked at the PFS that Simon is looking for and also insight on the clonality dimension? And then maybe also ask the same, Cristian, to you to address her HER2 expression component. And maybe it'd be interesting to get Dr. Turner's perspective on the last HER2-low question if we have the opportunity for that.

So -- go ahead, Cristian.

No, no, please, Ingrid, go ahead.

No, I was just going to say that, indeed, the numbers are small. But nevertheless, the data on PFS differentiated by CDK4/6 inhibitor is not yet available. So I'm not sure we can comment on that. And again, in terms of ESR, it's more about the very little fraction of clonality. So again, not much of a difference is seen in that.

And then maybe, Susan, do you want to comment on the HER2 quantification question?

Yes. So I think I've indicated before, and it was actually mentioned by the presenter in that session, David Rimm, that we are working on a quantitative immunohistochemistry capabilities using our computational pathology capabilities to improve on the kind of ordinal characterization of IHC 1+, 2+, 3+. We've also got sensitive mass spectrometry data that does measure in atmos moles per microgram, the level of HER2 expression. I don't think that, that quantitative mass spec is an assay that you could roll out extensively into clinical practice because it requires laser capture microdissection of the slides, which is something that is difficult to do. But what it can do is help us get another orthogonal methodology to understand what the right cut points is for the different settings. So absolutely, we're looking at these ways of improving on the current methodologies for identifying the right patients. And it's applicable not just for HER2, but also for the other antibody drug conjugates that we're developing. I think it's an important piece of our overall development plans for this portfolio.

Thanks, Susan. And I think that Simon's last question was really asking is, is HER2-low of its own entity in itself? Is it maybe a question around kind of how does it fall into the evolving differential diagnosis and patient identification that you're going through as a patient presents to you, Dr. Turner.

Yes. Thanks for the question. I think from a sort of biology perspective, it's not a separate subtype in the same way that luminal and basal-like breast cancer are separate subtypes. It's clear that HER2-low breast cancer within ER positive has some associations. It's associated with a slightly worse outcome in the number of settings and with slightly different genomics. But from a clinical perspective, of course, it's increasingly a very important subset of patients to be identifying because of the efficacy that we've seen with HER2, in HER2-low cancers. But at the moment, we're uncertain whether HER2 low is a transitory definition with the assay we've got because we've also seen in Phase II studies some efficacy in HER2, in HER2 0. And I think that comes back to the immediate previous question, where we potentially have efficacy in HER2 in HER2 0 cancers and the need to develop better assays in the future to quantify HER2 in the cancer.

Thank you, Dr. Turner. Much appreciated. And I think the point is a well-taken one, which is that as DESTINY-Breast06 results become available, I think that it's going to further create opportunity for us to continue to push in a positive way this discussion on patient identification for this zero to one group that's out there. I'm going to turn now to Emily Field in Barclays.

Just two. For Dr. Turner, a practical question. I was just curious, what do you currently use in the second-line metastatic setting? And how would you expect that to change with the approval of capivasertib? As in, how widely would you use it amongst your patients? And then just a follow-up question from one of the questions following the SERENA-2 presentation. Just a question on dose response and how we mentioned underdosing of fulvestrant in clinical trials. Were you expecting to see a dose response on efficacy for camizestrant? Or is it as simple as just that 75-milligram is the right dose?

Right. So Dr. Turner on the first question, I think that one is fairly straightforward. And perhaps, again, maybe Susan, if you want to comment on the second question on the dose response and the 75.

Emily, thanks very much for your question. So if we focus on current standard of care in my practice in the second-line setting, it depends on PIK3CA mutation status. So patients that have PIK3CA mutant breast cancer, I use fulvestrant and alpelisib as my standard second line. And then for patients that haven't got PIK3CA mutations, it's exemestane or everolimus within the licensed indication or fulvestrant and everolimus. There is also a small subset of patients, especially older patients who've done very well on their CDK4/6 inhibitors where we still use fulvestrant as a single agent, and a small subset of patients with very aggressive cancers where we do use chemotherapy in the second-line setting. What would I -- how would I expect this to change? So personally, I'm certainly expecting to be using capivasertib in the future in this second-line setting, certainly within the pathway-activated cancers. But actually, across the U.K. as well as in the U.S., there's a sizable proportion of patients that don't get tumor profiling. And of course, one of the interesting things we've seen from CAPItello-291 is the activity of capivasertib overall is really pretty good, and therefore, has the potential to be used in those patients as well where they are in settings or situations where they aren't getting the tumor profiling.

Thank you, Dr. Turner, Much appreciated. Susan?

Well, I can make a comment on that. So clearly, in the metastatic setting, which is where SERENA-2 is, as we have been saying, what we're seeing here is not a clinically meaningful difference between the 75- and 150-milligram doses for progression-free survival across the set of analyses that you've seen here. And what you also see is good safety at both 75 and 150 milligrams. And we also have from the SERENA-1 data, and we presented some of the data to post really good combinability at 75 milligrams. So that's really supporting the dose selection that we've had for the SERENA-4 and the SERENA-6 studies. We do have an ongoing window of opportunity study, the SERENA-3 as well, which is also designed to help understand the dose response in the early stage of breast cancer.

Thank you, Susan. Okay. Now I'm going to move on to Seamus Fernandez at Guggenheim.

So I wanted to talk a little bit about the triple-negative data. And Susan, just love to get your thoughts on the opportunity. When we're going to see the -- those that program advanced in triple-negative breast cancer versus sort of the Pantumor data where we're seeing robust response rates across the board? I think I also love to get an update on the lung side if you're willing, just your thoughts from yourself and Dave on the broader opportunity for Dato-DXd. I think in the past, Dave, you said this could be even bigger than in HER2. But I don't know about in the wake of the DB03 data, how we're thinking about that because it seems like DB09 is likely to succeed. So I'd love to just get your thoughts there. Maybe for Dr. Turner, when you look at the choice of HER2-low disease and considering triple-negative disease, just wanted to get your thoughts of choosing between a TROP2 ADC versus in HER2?

Super. Thanks, Seamus. Maybe I'll start and just quickly comment on the Dato kind of potential. I mean when I think about the opportunity for Dato, as we've discussed, the first place that we've been taking, the asset is in the lung cancer. And we know that there's opportunities to replace systemic chemotherapy in the treatment of lung cancer. And most every single patient in the metastatic lung cancer space, either as a monotherapy or in combination, is receiving systemic chemotherapy of some kind. I do think it's going to take, obviously, more studies, more work, but we're making good progress in the clinical development plan to get those underway and launched. And I think that obviously unlocking lung cancer and replacing, like I said, systemic chemotherapy is an enormous option there. And then if through the biomarker work, we're able to bring Dato into other multiple tumor types, I think that this becomes an enormous opportunity. So that's, I think, really kind of putting the whole Dato piece in the context. Maybe Susan, do you specifically want to talk about how you see triple-negative as it pertains to Dato?

Yes. So just a general comment. Clearly, across the spectrum of breast cancer, there are some patients that have relatively higher levels of HER2 expression than TROP2, particularly in the HER2-high group. But if you go down through the HR positive into the, what was called, triple negative, you get lower levels of HER2 expression relatively, but you typically get higher levels of TROP2 expression. And actually, the levels of TROP2 expression in the triple-negative breast cancer patient is about 5x higher on the cell surface than the HER2 expression, just to put it into context. So I think that helps to get at your question about when you use one versus another. But I think when you look at the triple-negative breast cancer data that we've got with Dato-DXd a 17-month median duration of response for that setting, I think, is honestly unprecedented. And the response rate in combination with Imfinzi in that setting, particularly as most of those patients are in the PD-L1 low group is also impressive. So what I would say is, what we're seeing is certainly the potential for TROP2 directed ADC is big because TROP2 expression is high across multiple different tumor types. We're seeing good activity with this drug, overall, and we're seeing good combinability with the IO mechanism. And I think that speaks to the potential not just in triple-negative breast cancer but in other tumor types of which lung is one that we're interested in. I think that puts into some context.

Super. Seamus, can I with apologies, ask you to repeat what your last question was that you had asked for Dr. Turner?

I think it was just for Dr. Turner to comment on what Susan just kind of laid out to some degree, which is, as he is choosing between a TROP2 ADC, and I guess maybe that's the current TROP2 ADC versus perhaps Dato-DXd, how does he sort of assess his patients who happen to be triple negative and choosing in HER2?

You said that Dato-DXd. Did you mean in HER2? That's what I heard you say in the first question.

Yes. So in HER2 versus the current TROP2, obviously, maybe excluding Dato-DXd for the time being.

Yes. Thanks very much for the question, of course, because the label for in HER2 and HER2-low is broad, definitely covers the use of it in triple-negative breast cancer that's HER2 low, and I know some physicians definitely are using that setting. My personal view on this is that Trodelvy has been through a large Phase III study. Whereas, in HER2 has a relatively small Phase II data. So my personal preference in this setting is for the use of Trodelvy. But definitely, of course, the activity that was shown in the Phase II within HER2 is pretty substantial.

Okay. Let's move on, please, to Peter Welford at Jefferies.

Firstly, just coming back to a similar sort of question actually that Emily asked just on camizestrant. But in terms of the opposite, which is given the data that we've seen and the lack of dose response and also obviously, the clear I guess, to some extent, the response there is with the safety, is there any data suggesting you shouldn't go lower than 75 milligrams? And I guess, are you confident you have data to go to FDA as to why you shouldn't go lower than 75 milligrams? And I guess, is there a dose response below that level? Because I think it's only the 75-milligram that's been taken into the 3 to 4 and 3 to 6, which we suggest presumably you do think the efficacy of that is similar to 150 but better tolerated as shown in the full data to justify, therefore, with longer duration. Secondly then, just on the ongoing SERENA-4 ctDNA ESR1 mutant study. Just curious if you can comment there, how enrollment is going? And given some of the commentary you made about not using ctDNA in the adjuvant setting, I'm just curious what sort of sites and how you're using it in the SERENA-4 setting? And then perhaps one, today, just thinking commercially about this and given the sort of comments you made about going earlier and totally understood, obviously, but SERENA-4 -- I mean presumably, the ESR1 mutant population is going to be a relatively small single-digit percentage of the first-line group in 4. And that is potentially the first indication where I think you get data in 2023. Whereas, obviously, then 2025, I think, is probably SERENA-6, and I'm imagining maybe '26 and '27 we're actually having data. So just how do you think about SERENA-4, both in terms of pricing but also in terms of obviously some of the U.S. reforms that have currently come in place with regards to thinking about how you position camizestrant?

Okay. Perfect. So maybe, Susan, can I suggest that you take the question on confidence in the dose and the work that we've done on that on 75, and how we're thinking about taking that to the agency our agencies at some point? And then I think, Cristian, maybe you can talk just about the strategies of SERENA-4 and 6, and then I'll finish up on my view on the commercial elements and the Inflation Reduction Act considerations and how we're working through that.

Okay. So in the SERENA-1 study, we tested a range of doses from 25 up to 450 milligrams actually. And those are the data that we use to justify the dose for the SERENA-4 and 6 study. So I think while there wasn't a robust randomized comparison of 25 versus 75, for example, in that setting, we did see a level of ER degradation and inhibition of target and activity that we thought was why we wanted to take 75, 150 and 300 into the SERENA-2 study.

So the SERENA-6 is evaluating the efficacy of camizestrant plus CDK4/6 inhibitors, and you have a choice between Abema and palbociclib in patients that are HER positive first-line metastatic disease with detectable ESR1 mutation by ctDNA. So you're right, this is a very innovative design, use ctDNA. And it is the, I would say, the fast-to-market strategy for camizestrant that we guided readout after 2023. SERENA-4, the confidence in SERENA-4 is, I would say, quite confirmed also by what you have seen in SERENA-2 confidence SERENA-6 and SERENA-4, I would say, because SERENA-4 is assessing in a large trial, a very large trial, the efficacy of camizestrant plus CDK4/6 inhibitor versus standard CDK4/6 inhibitor and aromatase inhibitor. So you have seen in the data, the activity of camizestrant, not only in ESR1 mutation and also in non-ESR1 subgroup in patients with visceral disease, in patients that have endocrine sensitive disease. The confidence there actually is reinforced by SERENA-2 outcome. And of course, SERENA, we guided also SERENA-4 after 2023 as a read out. With related to -- there was a question a little bit related to the adjuvant stuff. We will -- we are working on the adjuvant. We are very advanced in the plan for regimen trial. We will share the design and the inclusion/exclusion criteria of the trial when this will be made public.

Thank you, Cristian. So I think that, Peter, if I was to build off of this, I mean, both SERENA-4 and SERENA-6, we've said, readout post 2023, to the point that you're raising sort of the exact kind of timing of those will certainly be a consideration as we think about our overall pricing strategy across the globe. I mean I do think also within this, keep in mind that we've intentionally built a program that has both a switch as well as an upfront approach to it. We think that both switch and upfront could prove to be good clinical strategies and that both of these studies, we believe, have the possibility to be able to change the way that hormone receptor-positive disease is being treated. In terms of impact of Inflation Reduction Act, I mean, I guess the biggest thing that I would say at this point is that, obviously, we will be looking at the U.S. launch price and working to understand as we get to that stage, how the world, particularly of negotiation, unfolds and the implications that some of the rule-making will have on how we want to think about some of the longer-term value. And we'll know more about that, obviously, as we see the data that comes through. I'm going to go to the last question with Tim Anderson at Wolfe.

A couple of questions, if I can. I think it was Jose Baselga once implying that bradycardia was an on-target toxicity of oral SERDs. I'm wondering if you think we have enough data at this point to know whether that is, in fact, true. And then second question on HER2 and interstitial lung disease. In the DB03 update, the incidence of ILD increased to 15%. That was versus 10% at the first analysis of that trial and that's in line with the incidents, more or less, from DB01. And I think Astra, in the past, said that it might be lower and less frequent in earlier lines, but the DB03 update seems to maybe undermine that hope. So should we be -- what incidence rate should we be thinking about in the first-line trial like DB09?

Great. So can I suggest that -- Susan, do you want to tackle the first question from Tim on whether or not bradycardia is an on-target tox of SERDs? And then I think, Cristian, I think if you can talk about DB09 ILD expectations and any views that you've got on the DB03 updated data and what we saw in the 10 to the 15?

Okay. So I think when you look across the class of SERDs, not every molecule in that class that has estrogen receptor-degrading capability has bradycardia associated with it. So I'm not sure that I would describe it as an on-target adverse event. I think it's something that's associated with some of the chemical structures that are -- for some of those molecules. And they have different volumes of distribution and distribution to different tissues across the class. What I would say is that the bradycardia that we see, as Cristian described, is overwhelmingly asymptomatic. And just to put it in perspective, it's about the same order of magnitude as you see with the beta blocker. It's widely used as treatment. And it's also -- you can overcome the level if people just walk up the stairs, then you do have a inotropic response to the stimulation of exercise, so your heart rate can increase. So it is observed, but it doesn't interfere with activities of daily living. And from that perspective, it, therefore, isn't something that we think is limiting to take us into the early-stage setting, if that was into context.

So thank you for the question and also the catch. You're right, it's slightly higher compared to the first cut because, of course, the duration of the treatment is increasing and the follow-up is higher. Also, you noticed that -- let me point out one positive thing. The first data cut, we had a complete response rate in metastatic disease of 16%, and now we see, in DB03, a complete response rate of 21% that really is unprecedented in this setting with any other drug. Then the grade -- the number of grades and the number of patients with Grade 1 and 2 is increasing, but the good news, the very good news is that we have only two cases with Grade 3 and no Grade 4 and 5. This is the main difference compared the initial reports with ILD, for instance, DB01. Where we had a substantial number of Grade 3, but also few Grade 5. So we still believe, and actually, we are running trials in earlier line, not only in first-line DB09 but we're running trial in new adjuvant, DB11 and in post-neoadjuvant DBO5, and we started to have also a lot of commercial use of the drug. The data that we are collectively gaining for ILD are very reassuring specifically in terms of severe grades. This is part of the management of the drug that the investigator and the prescribing is to have because it's a clear adverse event related to the drug, but the most important thing is that we don't observe severe grades. That would probably not make the drug fit to their line but this is absolutely not what is happening today. With the current management, we are minimizing the risk of severe grades and most of the patients are developing Grade 1 and 2 today.

Super. Thank you, Cristian. I appreciate it. So thank you, everybody, for joining us on this call at San Antonio, certainly, an incredibly exciting conference for us. I do want to once again extend my gratitude for Dr. Nick Turner for being with us. If you asked a question in the chat and we were unable to get to it, Investor Relations will follow up with you off-line. Also, the webcast recording and slides will be available shortly. So if you want to access that, please feel free to do so. And with that, we will bring the call to the close. Thank you all very, very much.