Welcome, ladies and gentlemen, to AstraZeneca's Investor Conference Call, ESMO 2025. Before I hand over to AstraZeneca's management team, I'd like to read the Safe Harbor Statement. The company intends to utilize the Safe Harbor revisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operation 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 presentation and webinar. There will be an opportunity to ask questions after today's presentations. Please use the raise-a-hand feature to indicate you wish to ask a question, and please remember to unmute your line when invited to speak. And with that, I will now hand you over to AstraZeneca. Good evening, everybody. Thank you so much for joining us to share. We want to share with you some of the great ASCO data that were presented. ESMO, sorry. The great ESMO data that were presented over the weekend. I must say it's been really a fantastic ESMO. I was asked a minute ago, how do I feel about ESMO? And I'll say that it was really a great ESMO, lots of great data. But beyond this, what really excited me the most is a couple of days ago, I was told by a very prominent ESMO leader that we have the best team. I don't know if he wanted to be nice to me and to us, but suddenly hearing this was a fantastic tribute to the work this team here around the room has been doing, and of course, people beyond this room. So this is our disclaimer. This is the agenda. Susan will cover the key themes that we went through at the World Lung Congress, but also at this ESMO, then we are very privileged to have Professor Nadia Harbeck with us and Professor Rebecca Dent, who will cover some of the data presented, in particular DESTINY-Breast11 and 5 and TROPiON-Breast O2. Sunil will look at integrating this data, putting them in perspective as far as clinical practice, and Dave will lead the Q&A. We're also going to cover the POTOMAC data. Dr. Neal Shore is joining us to discuss this. We'll do it in the second phase because Nadia and Rebecca have to leave, I believe, early enough to join some other meetings, and so we'll cover POTOMAC and the consequences or the implication of POTOMAC into clinical practice a little later and finish with a broader Q&A. Dave will tell you, but I want to tell you upfront also, if you have any questions as it relates to MFN or broader financial questions, if you don't mind, keep them for the end because we really want to focus the first part on this great data we have with DB11, DB05, and TROPION-Breast02 so I just want to start there and tell you that we are on track for the $80 billion turnover that we are targeting for 2030. Of course, it still depends on the delivery of the pipeline between now and the first half of next year, but so far, we are, as you know, very much on track, both from a financial viewpoint, but also importantly from a pipeline viewpoint. We've had a really great run so far this year with a lot of positive readouts. Beyond oncology, I just want to highlight Baxdrostat that is really looking very good. Not only the BaxHTN data, but the Bax 24 data are really, really exciting, I must say, in terms of the overall blood pressure reduction, but also the 24-hour control and the reduction of aldosterone, which we believe actually will be a very important feature of this product. We think it's a mega blockbuster potentially, and there are other products making progress, of course, but I just wanted to highlight this one very quickly. We're also making very good progress on what we call the day after tomorrow, the post-2030 period with our ADCs, our radioconjugates, but also our cell therapies from really good data that are coming up, and the team is making very, very substantial progress with our cell therapy strategy. This is what we have been able to deliver so far this year. As you can see, a lot of green dots, a couple of setbacks, as you would expect. I mean, we can't win them all. CAPItello-280, of course, was negative. Fasenra and COPD, the resolute study was very disappointing. We expected a positive result there, but again, you can't be successful everywhere. But overall, really a great set of results, in particular in oncology. There's a lot more to come in the first half of next year and the second half of next year. And all of those studies will definitely influence our growth rate between now and 2030. But I have to say we are very much on track with what we told you we wanted to deliver between now and 2030. So with this, I'll hand over to Susan, who will cover the key oncology themes at this ESMO and World Lung. Thank you. Thank you, Pascal. Welcome, everybody. Thank you for your interest. So as Pascal said, we've had a number of important presentations across the World Congress on Lung Cancer and here at ESMO with the pivotal data from DESTINY-Breast11, DESTINY-Breast05, TROPION-Breast02, and of course, at World Congress on Lung Cancer, the FLAURA2 final OS data. But in addition, the POTOMAC data in bladder cancer, the MATTERHORN final OS in gastric cancer. And I'm also encouraged to see the data that's coming out from the early stage of the pipeline with important presentations you can see on the right-hand side from our bispecific volrustomig, both in combination with chemotherapy, but also in combination with Dato-DXd in the TROPION-PanTumor03, and then the emergence of one of our homegrown ADCs, the folate receptor alpha-targeted Fontana, and then the data that we have from sariparib in combination with androgen receptor inhibitors in the Patrana study. So we continue to have a good track record at ESMO with five presidential plenaries in the last three years and lots more coming through the portfolio. So I'm very proud of the representation that we have here. In terms of where this fits, if you remember, I highlighted five themes of things that are going to transform the treatment of cancer at the Investor Day in May 2024. And I just want to say how these data sets that we've currently seen presented line up against those key themes. So you can see from our data, not just our data, but other people's data at the recent congresses, that we are starting to see this advance of multiple antibody drug conjugates having the potential to replace backbone chemotherapy in a number of different settings and tumor types. And you can see this. But one thing that I also want to emphasize is that I think this identifying the right patients to treat with each ADC is going to become a really important part of differentiation. We're investing in our computational pathology QCS technology, not just for Dato-DXd, but across the portfolio. And we had some data here that helps to back up the work that we're doing with the QCS real-world implementation. In terms of the segmentation of the IO space, again, more data from the ARTEMIDE-01 study showing real good durability and good tolerability with a low discontinuation rate for volrustomig. And again, good combinability with Dato-DXd and the TROPION-PanTumor03. Just as a headline, there were going to be data for our T-cell engagers and cell therapy presented at a congress later this year to be announced. The Cinobacibeg CD19, CD3, bispecific, and AZD0120, which is our lead cell therapy, BCMA CD19, dual CAR for multiple myeloma. And then again, putting these together in combinations is a key part of our strategy for our portfolio. And you see a number of examples of how combinations can make a real difference in terms of outcomes with the FLAURA2 data in the first-line EGFR mutant lung cancer chemotherapy plus Tagrisso. I mentioned the TROPION-PanTumor03, which looks exciting in terms of potential activity in bladder cancer and the Patrana data. And then again, we've had multiple examples now building off the AEGEAN and NIAGARA data, and now with the OS data from MATTERHORN and the disease-free survival data from POTOMAC showing that when we move active drugs into the early stages of cancer, at the earliest point, we're seeing really good improvements in long-term outcomes. So what this means then in the context just of one tumor type, breast cancer with the three pivotal data sets that we've seen represented here is further advancing our portfolio. You can see on this landscape map that in every segment of breast cancer, HER2- positive, hormone receptor positive, triple negative, and germline BRCA, we have a portfolio that's addressing the needs of cancer patients in multiple different segments. And we're moving this portfolio into the early stages of the disease where there's the greatest potential for affecting the cure rate and improving the cure rate. And that's the goal of what we're doing here. So with that, I'm excited to then hand over to sort of have more discussion about the three pivotal trials that we've represented. And I'm going to pass on to Professor Nadia Harbeck. Good evening. I'm a medical oncologist from the National Cancer Center in Singapore. I've been there about 15 years. I'm originally from Toronto, Canada, and also spent some time in the U.S. and Europe, so I don't belong to anywhere in the world, so what that makes it interesting, though, is that medical oncology actually is the same around the world, and I'm very excited to share with you today the TROPION-Breast02 trial, which was eagerly anticipated, so this is a study that was designed a few years ago with the idea that triple negative breast cancer, as many of you know, affects a lot of young women, and certainly in the first-line setting and the metastatic disease, this is a very aggressive disease, and these patients very often don't go on to get second-line therapy. In fact, what we showed more than a decade ago is 50% of them never go on to have second-line therapy. So you need your best drug first. And so in this particular trial, the TROPION-Breast02, we looked at locally advanced inoperable metastatic triple negative breast cancer in the first-line setting. And these patients, immunotherapy was not an option. And what was truly unique about this study is that there was no minimum disease-free interval. What that means is from the time of finishing their treatment in the curative setting to when they relapse, often trials actually exclude patients within the first six months or the first year. But we know that half of the patients with triple negative, that's when they relapse. And these are very young patients. And so we really were very happy that we could include these patients in this trial because this is a huge unmet need. And so patients were randomized to receive Dato-DXd, which is a TROP2 antibody-drug conjugate, Datopotamab deruxtecan, versus investigators' choice chemotherapy. This trial was unique also in that it had dual primary endpoints. So it was powered to look at not just PFS, but also overall survival. These are the curves. Take a good look. They separate very early. That separation is sustained. And what we saw was quite a dramatic improvement in progression-free survival. What you can see there is 5.6 months to almost 11 months with a hazard ratio of 0.57. And you can see that this was highly statistically significant with a log-rank P value of less than 0.00001. Now, what's really important for me is this is a survival advantage. We call this the five-month trial, five-month progression-free survival improvement, five-month improvement in overall survival. And in these really young patients, this is really clinically meaningful. And what you can see here is 18.7 months in people getting chemotherapy. And then this increases to almost two years in patients getting Datroway or Dato-DXd. And you can see that this is highly statistically significant as well. Now, again, what's really amazing is that this data is very consistent. When you're in clinic, what's really important is do you get a response? How do your patients feel when they come to see you? And we see a more than doubling of the response with a delta of 33.2% and a more than tripling of the complete response rate. Now, we can also say on this trial that not only did they see responses, but those responses were sustained. And again, a five-month improvement in duration of response. So is there any cost to this improvement in efficacy? Now, thankfully, what we've shown in this trial is that very similar to other studies that have been done with this compound, there were no new safety signals. What we see are two important findings here. You can see that when we look at Datroway versus standard of care chemotherapy, you can see that the number of serious adverse events was very similar between the arms. There were some increased dose reductions and dose delays, but in fact, more patients getting chemotherapy stopped their treatment. What you can see here is we see higher rates of dry eye, stomatitis, and nausea. But in the standard of care arm, we see more myelosuppression, so anemia, low blood counts, so Datroway really is a potential new standard, and I think anybody who was at the presentation, anybody who's read some of the reports, this clearly is a new standard of care which likely will be incorporated in guidelines in the next six months. It met its two primary endpoints of PFS and overall survival. As I told you, it was the five-month trial, five-month improvement in PFS, OS, and duration of response, and despite this more than doubling of the duration of response, what we saw was very similar side effects between the two arms, and in fact, more patients stopped who got chemotherapy, so we're really excited to be able to use this in the clinic very soon for our patients. Good evening. It's wonderful to see that data, so thank you, Dr. Harbeck, and thank you, Dr. Dent, for an excellent presentation and overview, so I'd like to just share with you how we're thinking about, of course, the clinical context of this information. As Dr. Harbeck walked us through, these are two important pivotal studies in early-stage HER2-positive breast cancer, but they're also two very distinct populations, so DESTINY-Breast11 is really looking at that patient who is coming in for a neoadjuvant treatment, and if we take a look at a G7, that's about 34,000 patients, and about 80% of them are high risk, and DESTINY-Breast11, for four cycles given HER2 followed by four cycles of THP, is really addressing that patient population, and that Dr. Harbeck just mentioned, this is the highest reported pathological complete response rate. And that PCR not only correlates with long-term efficacy, but if you get PCR, you don't necessarily need escalation of therapy thereafter. So that's really clinically meaningful when clinicians have that discussion with their patient. DESTINY-Breast05, of course, represents after neoadjuvant treatment is completed. So if you take a look at 34,000 patients with HER2 -positive, about half of them will have residual disease after receiving neoadjuvant treatment. And this study was specifically looking at those patients who have high-risk characteristics. So that's about half of those patients who have residual disease. And again, for DB05, that's Enhertu is given for 14 cycles. Together, we believe that this is a blockbuster opportunity and, of course, continues to solidify that in clinicians' mind, when to use Enhertu, should I use it in a neoadjuvant setting, or should I use it in the post-neoadjuvant residual disease setting? Furthermore, it really spans the continuum that we have seen for HER2-positive breast cancer, where Enhertu has consistently shown a clear benefit. As you know, for DB1 and DB2, we have that approval for Enhertu in late-line setting, and there is consistent PFS and overall survival benefit. DB03, we have benefit for PFS and OS. And more recently, at ASCO, we presented the DESTINY-Breast09, which showed quite remarkable efficacy versus the standard CLEOPATRA with a PFS that now exceeds 40 months. And now, of course, with these two important studies, it solidifies Enhertu across all stages of HER2-positive breast cancer, again, giving confidence to the clinical community to use the best agent, of course, hopefully upfront now with the early-stage setting. Furthermore, as Dr. Dent highlighted, of course, this remarkable study that we saw with TROPION-Breast02. A couple of important elements, of course. Now this is the first and only therapy to significantly improve overall survival, as was highlighted by the discussant and also Dr. Dent, that this standard of care has not really shifted for more than a decade, and to show this meaningful improvement in five months is quite remarkable. Of note, there's about 24,000 patients in G7 who would be treated in the first-line TNBC, and as Dr. Dent highlighted, about 70% of them are not candidates for immune therapy, so this is really addressing a significant unmet need where the standard of care remains chemotherapy, and this is where TROPION- Breast O2 was studied and really is positioned, and what's remarkable in the data that was shared by Dr. Dent is that not only the efficacy, which shows this consistent improvement in PFS and OS and duration of response, but also safety is, I think, a clear differentiator versus other possible therapeutic options. We further are, of course, emboldened by the data that we have seen with BEGONIA, which was done in phase Ib/II setting, looking at now a combination of Datroway in combination with Imfinzi, showing a remarkable response rate of 80%. We have three really important studies in TNBC based on this combination of Imfinzi in combination with Datroway, of course, the TROPION-Breast03 setting, which is being done in the residual disease setting, the TROPION-Breast04 in the neoadjuvant, and the TROPION-Breast05 for those PD-L1 high patients in the metastatic setting. So along with, of course, the strong data that we have seen with TROPION-Breast02 and also encouraging data that we have seen with BEGONIA that gives us confidence for TROPION-Breast03 or four or five. So with that, I think we're going to open it up for Q&A, and I'll pass it to Dave. Thank you. Please go ahead. Thank you, Sunil. Thank you also, Doctors Harbeck and Dent, for those great presentations. Okay, so we will open it up here in the room. We'll also take some questions online. We can start here. Andy, I'll hand the microphone around, please. Thanks, Andy. Two questions, please. Great data. I hope you don't mind, Susan. I want to go into the SERD space because on one hand, we had Prof. Johnston saying SERDs are going to be practice-changing in the adjuvant setting. And on the other hand, you've got competitor data presented over the weekend. The market is still quite, shall we say, conservative as it relates to the potential of SERD. So how does that AMEERA data change, if at all, your view on the opportunity for SERD? That's question number one. Yeah, sure. Do you want to just ask your second one now, and then we'll work through? All right. The second one is, look, commercially, this has implications, but I had Professor Dent and others over the weekend talking about treatment de-escalation, reduced dosing, even stopping treatment. How is that going to be incorporated? Because that is a growing that became very clear over, that said, not just by Professor Dent, but other doctors, that that needs to be incorporated into future trials. Okay, perfect. Thanks. Sunil, do you want to start with the question about the oral SERD and the AMEERA study and how that reflects on our program? Yeah, no, happy to do it. So I think, so first of all, those results are, I think, as expected. We have seen data from SERENA-2, which was very much in line and consistent with what we saw with Avera. And furthermore, I think it just gives us even more stronger confidence in the SERENA-4 setting. So it's important to note the SERENA-4, of course, in the endocrine-sensitive setting, and Avera and some of the other reported studies were in the second-line endocrine-insensitive setting. So I think given the data that we have seen in the endocrine-sensitive, we think we have a great SERD, and we have confidence in the SERENA-4 based on both the data from SERENA-2 and, of course, other competitor data as well. All right, thank you, Sunil. Dr. Dent, do you want to comment on the question with respect to strategies around de-escalation? Absolutely, so as many people know, I'm quite passionate about triple-negative, having been sort of in this space for more than 20 years. I think what's amazing to see is that triple-negative breast cancer used to be really quite fatal, and what we know now is that when they're in the curative setting, we realize we have to have a lower threshold to treat, and so finally, we're having survival rates that are really unprecedented compared to where we were 20 or 25 years ago, so we're kind of where we are with HER2-positive breast cancer about 10 years ago, so we now have a better idea. Yes, we're in the curative setting. The chance of cure is higher. We're having to treat fairly aggressively, and now we have to figure out which part of the treatment we can actually de-escalate. Who needs immunotherapy? Who needs platinum? Can we potentially displace the anthracycline with an antibody-drug conjugate? And many of the trials right now are actually going to address those questions. I'm also hopeful that truthfully, I know we all talk about artificial intelligence, but we really are going to potentially use technology to better identify which patients need which part of the treatment. And that's really just begun. So the fact that we are now approaching 90% overall survival for TNBC is a monumental change. And even in the metastatic context, what's unique about Datroway, to be honest, is that we do see some activity in the brain. And very often in the curative setting, we used to see isolated brain metastases that would recur also in the metastatic setting. So if we're able to incorporate that into the curative setting, that might mean the chance of cure is not just systemic, but also in the CNS. Perfect. Thank you. And then maybe, Sunil, do you want to comment just in terms of the HER2- positive setting on this in case the question was covering that as well? No, thank you. I think it's a great question, and I think it's certainly something that's ever coming up. DB09 was really designed as continued HER2 until progression, and we saw really remarkable data. We have not seen data like that with a hazard ratio of 0.65 and a PFS reaching and exceeding 40 months, so I think there is the dialogue as to which patients and how long to give HER2 for. But I think those who look at the data and say, "We want to be able to replicate that clinical data in real-world practice," then I think the best way to do is, of course, keep patients on HER2 until progression. Great. Thanks, Sunil. Maybe, Andy, while we wait for a question here, I'll go just online. Luisa Hector, going online to you for a question, please. Thank you, Dave. Can you hear me? Yeah. Great. So yeah, my question is on TB02. So Susan, you started with the comment on really trying to identify the target patient for ADC, and we've just heard about intensity of dosing. So I'm just wondering whether the TROP2 status is relevant here. Did you look at it within breast cancer? And then perhaps we could hear some comments on the toxicity profile, the ability to manage it, and the profile relative to competitor ADCs for Datroway. Thank you. Perfect. So Susan, maybe you can comment on the TROP2 identification. And Dr. Dent, if you would comment on how you see the toxicity profile across the studies, that'd be great. Yeah, thanks for the question, Luisa. So as it happens in the triple negative breast cancer setting, there's a really high level of TROP2 receptor, both expression and internalization. So I think, and that's reflected in the data sets that you've seen. So we are routinely looking across multiple of our trials for what the computational pathology data show, and we will do that as well. But I think the data overall show that you've got activity across the spectrum that is leading to that overall survival improvement. I would say as well that we're looking across different tumor types for that. My comment was really reflecting that in a world where you've got multiple ADCs available with different targets in different tumor types, which is a world that's coming, there are going to be the next levels of approach to computational pathology, which might include, for example, multiplex testing. We're already working on looking at that because I think that's going to be an important part of the future. Thanks, Susan. Dr. Dent. So I guess I have three points. It's a great question. The first one is when it came to the risk of, let's say, ILD or pneumonitis, we were very reassured that these were rare events in both arms. And obviously, that's something that we've seen with some of the ADCs. What we did see, let's say, with sacituzumab govitecan, what we're quite familiar with using in the ASCENT-03 study, is that there were actually patient deaths in that study that was presented in the same session, and that was related to the compound. And we didn't see that in the TROPION-Breast02 study. What we did see were side effects that we'd seen in some of the prior studies, which were ocular surface events and mucositis. And when it came to mucositis, there was recommendation for prophylaxis. You couldn't necessarily mandate it. But what we know is at the time of data cutoff, 90% of the patients had resolved, and no patients stopped therapy due to mucositis. So for those of us in clinical practice, we know that this was something that we can anticipate. We know how to manage a side effect we're quite used to. When it comes to ocular surface events, the majority of these were dry eyes. I think it's something we're going to have to follow. But what's really interesting is that there is TROP2 expression in the epithelium of the cornea. And so with dose reductions, this seems to be, again, more than 70% of them resolved at the time of data cutoff. And the last thing I want to talk about is time toxicity. So what's unique about this is that we know that the infusion, the first one is 90 minutes, and then it's 30 minutes thereafter. And with some of the other compounds, the first infusion is four to five hours, followed by two hours. And so for my patients and for someone who runs a hospital, the time toxicity makes a real difference. And certainly for patients that are on treatment for longer than a year, time toxicity is important. Thank you, Dr. Dent, very much. Let me go online to Michael Lipton, please, from Jefferies. Thank you, Dave. Two questions, please. DB05, it looks like the percentage of patients from the U.S. were 7%, 8%. Just wondering how that reflects on the commercial opportunity in terms of the geographic split. And then if I could maybe ask Susan on DB11, the mono arm that was discontinued, I was trying to make sense of why we wouldn't see a better signal out of using eight cycles of enhertu in that setting instead of followed by THP. I couldn't quite tease it out of the data. Just wondering if you had any thoughts. Thank you. So just with respect to the commercial question, I think, I guess maybe two parts, Michael. I don't know if part of your question has to do with, is that number of patients enrolled adequate. I think that it is absolutely adequate. If the question is, what does that mean for the size of the population that we might see that is a DB05-like population, I think that Dr. Harbeck answered to that in many respects. And I would take a look at 11 and 05 together representing across the G7 countries, about 40,000 patients that have the opportunity to be able to benefit from treatment within HER2 in the early setting. And I think Dr. Harbeck quite nicely outlined the opportunity to use your best option early is one that we certainly think is going to be an important part of many of the discussions that are being had. Susan. So in terms of the performance of the monotherapy T-DXd arm, you've got eight cycles of T-DXd in that sense up against five different chemotherapy drugs with the dose density four cycles followed by the THP for four cycles. So the other thing is if patients were switched onto a different chemotherapy during the period of the eight cycles, that would count as not having a PCR. So that would, if you like, dilute the overall PCR rate. For those patients that did complete eight cycles of T-DXd, actually, their PCR rate was very similar to that five-drug regimen. So I think it speaks to the potency of the drug overall. But obviously, what we were looking for was an improvement in PCR, so it didn't meet that. So I think that was the context. And I think what you did see is that you can achieve the best-ever PCR rate that's been seen in this HER2-positive rate with a 67% rate. And again, if you achieve a PCR, the chances of five-year overall survival are then 95%. So I think that's one of the reasons why we think that optimizing the chance of achieving a pathologic complete response, which then spares you from subsequent therapy, and it's only four cycles of enhertu, is probably the best strategy. Yeah, and indeed, as Dr. Harbeck also said, it comes with an improved safety profile, which I think is an important part of the benefit-risk in general. Do we have another question here in the room that I see? No? Okay. J.P. Morgan, Richard Vosser, please. Hi, thanks for taking my question. Maybe I could build on Luisa's question and ask Professor Dent about her view of the overall profile of Datroway versus Trodelvy on the basis of the data in TNBC, thinking about the efficacy and the safety together and how she thinks that would influence her decision in terms of which one to treat with, and just one other quick question. There was a little bit of an imbalance in overall survival, just obviously not statistically different, but just the other way in Canada and Europe. Just any further thoughts? I know it was early in the presentation, there wasn't anything to be said, but just thoughts on what might be going on in Canada and Europe as well. Thank you very much. Why don't you go ahead with the first question? You can address the second one. Susan can also address the second question as well. So, great questions. So maybe I'll address the last one first. So I think the first thing is, like you said, the data is very consistent in terms of PFS, overall response, and duration of response. And in those geographic distributions, the results are very consistent. When you look at the overall survival subgroup analysis, as you said, in the Canada-USA-Europe subgroup, there did seem to be a difference there in terms of the benefits. What you can say is that this is a post-hoc analysis. We're not sort of entirely clear. But to be honest, we actually already had a chance to look at the US subgroup, and it looks very similar to the overall ITT population. So as we know, we'll have to spend some time now digging a little bit deeper into the Europe sort of subgroup of that. But as I said, the other subgroups are very consistent, especially the response. And if you look at those distributions. Now, in terms of comparing the two compounds, having used sacituzumab govitecan or Trodelvy for many years already, and then looking at these different protocols, what are the differences? So the first thing is Datroway had 20% of patients that were early relapsers, 15% of those were in the first six months. And in clinical practice, I'll be honest, this is really important because half of our relapses happened early, and this clearly showed benefit in that group. The second thing is we had 10% of patients that had brain metastases, which was more than what we saw in the sacituzumab study. And we already have data from the Tuxedo-2 study that actually suggests that there is activity in the brain. And I think in terms of, as I mentioned, when you look at the efficacy, the doubling, more than doubling of the response and duration of response was really quite profound in the Datopotamab or the Datroway study. So I think all of these things combined, I think we do have a more efficacious compound. We may make choices based on toxicity. But what I can see so far is that after patients have had the KEYNOTE-522 regimen, what I find in clinical practice is we have a lot of myelosuppression. And so trying to deliver sacituzumab is a little bit more challenging, whereas Datopotamab or Datroway doesn't seem to have as much myelosuppression. So for me, that actually means I'm likely better able to deliver it, and it seems to be more efficacious. So I mean, I think that as we listen to that, Richard, as we think about once approved, what we know that oncologists in the community are paying attention to, response rate, where I think we've got a good narrative to tell, progression-free survival, again, a good narrative to tell in a population, as Dr. Dent has described, that includes those patients with the shortest disease-free intervals, statistically significant overall survival and a safety profile that's in the right direction. So we've got teams that are ready for these data to hopefully be approved so that we can move them in. Collin White, UBS, please. Maybe this will be the last question, and then we'll have to let Doctors Harbeck and Dent go. Maybe we'll fit in another one over here too. Let's try. Hi, thanks. Colin White at UBS here. It was a question about the DB11 study and the choice of an anthracycline-based regimen as the competitor regimen. I just wanted to know why an anthracycline-based regimen was chosen, and in practice, what sort of percentage of patients in a neoadjuvant setting typically get an anthracycline-based regimen versus something like TCHP that the discussant mentioned as a potential other treatment, and then my second question is just about some of the other data we saw emerging for antibody-drug conjugates with studies in China. We saw some TROP2 ADC data at this conference for Cezetuzumab-Trimotecan, and we also saw some HER2 ADC data for Trazetuzumab-Resectecan. I just, maybe for the company and maybe the doctors, I just wanted to know what your view was on these potential competitive antibody-drug conjugates that were presented and also how difficult it is to assess the data without global data? Thanks. All right, perfect. Maybe just quickly, and then we'll need to wrap up the Q&A. Leora, can you comment on SAC-TMT? And then Susan, would you maybe comment more broadly on ADCs from China? So the SAC-TMT data that we saw was not breast data. It was the lung data. I think it just reinforces the benefit that you see with TROP2 ADCs in lung cancer patients. We currently have ongoing studies with TROPION-Lung-15 and TROPION-Lung-14, where we've actually been able to combine Dato-DXd with osimertinib. As you heard from the discussant, there was this question around brain metastases and efficacy in the brain. So we think the ability to combine Dato-DXd is more tolerable with osimertinib, gives an advantage for patients with EGFR mutant lung cancer. And I think just in terms of general data coming out of China, first of all, it speaks to the pace of innovation that's happening in China, which we've commented on before. There's plenty of wave of ADCs that are coming through there. But I think it's also very clear that in general, we need global trials to get global approvals with more broader expression of patient populations in multiple regions. That's been the approach so far. I do think there have been examples where European regulatory authority have approved based on established under the care in the class of PD1s, for example, on China-only data. But in general, for a new mechanism, you're going to need data that's from a global representative trial. That's our view. And if I can just add something to what Susan just mentioned, I think it was a question when you take a look at the trastuzumab deruxtecan data that the control arm was with chemotherapy and TKI, and as opposed to DB03, which was T-DM1. So there's a question whether those standards of care are relevant outside of China as well. Great. Thanks, Sunil. I'm afraid that I made a commitment to Doctors Harbeck and Dent that we would get them out six minutes ago, so we'll need to thank them once again for their presentations and great job at ESMO. Congratulations on your presidentials and as we then move on to the next section here, please let me welcome our next speaker, Dr. Neal Shore, up to the stage. Thank you very much. Well, thanks very much. I'm leaving uro-oncology. I'm going into breast cancer. Those great presentations. So I'm Neal Shore. I'm a uro-oncologist. I'm now with START Cancer Research. I head up the GU Oncology. I practice in South Carolina. It's START Carolina. So it's a pleasure to speak with you tonight. It's really an honor to work with the folks at AstraZeneca. They really have a pioneering and innovative approach to GU Oncology. So I've been privileged to be part of it. So I'm going to assume, just for purposes of time, that most of you saw the POTOMAC data. A great honor to be part of this. We started this trial prior to the pandemic and really did a tremendous amount of education in the global sites and had great fidelity and rigor to keeping patients involved in the trial. A real testimony to the leadership from the folks on the POTOMAC team from AstraZeneca. What you can see here is a quick review of the study schema design here. These were NMIBC high-risk patients, meaning they had high-grade papillary disease, carcinoma in situ, or lamina propria basement membrane invasion. That's the T1 disease, or multiple and recurrent large greater than 3-centimeter tumors. The stratification factors, you see them listed here. This was a three-arm equally randomized trial. The bottom control was the BCG induction and maintenance. This is based on the classic paper by Donald Lamm and SWOG that actually went to three years of maintenance. But really, in practical aspects and somewhat of some issues with shortage, everyone pretty much agreed that a two-year maintenance would be appropriate, and also the fact that most patients don't even get through a full year of two years of maintenance. And I think that's important because we really practiced great rigor in this trial. In the Lamm trial that had three years, only 16% of patients actually completed three years of maintenance, just as an interesting aspect. So the key first cohort is the induction of BCG and maintenance, as well as a one-year course of Imfinzi, 13 cycles, Durvalumab once every q4 weeks in conjunction with induction and maintenance. Second cohort, a bit of a real kind of a bigger push towards really provocative potential benefit was only induction, no maintenance. And we knew all along that BCG is a good therapeutic, despite the fact that it has some issues of shortages in different parts of the world. The primary endpoint was disease-free survival. So that would have been consistent with persistent high-risk disease, even if there was a second induction, metastatic disease, muscle-invasive disease, or a death. The key secondary endpoints, you see those listed there as well. So here's the KM, which really was the most important slide. And I point you to the fact that the curves separate very, very early, really at three to four months. And that curve separation stays consistent at a year, two years, three years. And we even now, we presented, Maria De Santis presented this in a plenary session just two days ago with a simultaneous publication in The Lancet. And one sees a hazard ratio of 0.68. So that's really a real effect size. And we're very proud of that. And we're quite thrilled to see that data. Hazard ratio of P-value, I'm sorry, of 0.015. Looking at the forest plot subplot analyses, by and large, looking at whether it's age, there's some odd notion there on the female side, but there's somewhat less numbers there. As you all know, three to four times more prevalent in male populations. This study was conducted outside the U.S. We're finishing a separate U.S. study. We'll report on that, known as POTOMAC, sometime in 2026. We're excited to present that. That enrolled remarkably fast, largely in community urologic oncology sites. The different mutations in the BCG strains, which is a known prevalence throughout the world, and varying subgroup analyses looking at CIS papillary disease and PD-L1 expression. When we looked at the overall survival, the number of events were quite few. As you can see, the maturity wasn't really particularly great. But I think the bottom line here is there's no decremental effect. We had no grade 5 events. That's known to be an issue in some of the checkpoint inhibitors. And there were no grade 5 events in either the combination arm with induction maintenance or just in the induction arm by itself. Looking at the AE profile, look at the tornado plot here, which is well known to you as well. The take-home bottom line here was that everything was consistent with the known profiles of BCG, which is largely lower urinary tract, annoying, irritative symptoms, very rarely a systemic side effect, as well as the known immune-related adverse events that one would see with Durvalumab and Imfinzi. I think very importantly, as I mentioned, no grade 5 events, and that the fact that there was really very little bit in terms of discontinuation of AEs leading to cessation in either of the arms. In fact, the level of concordance of the induction and maintenance was well north of 90% on the BCG, which is really unheard of in real-world community settings. So the conclusions that Dr. De Santis presented at the presentation, and now it's in The Lancet publication, is that Imfinzi in combination with induction maintenance BCG, statistically significant and clinically meaningful DFS versus traditional standard of care induction and maintenance in this enriched BCG naive as opposed to the unresponsive population, which is a whole separate disease categorization, and a median to longest phase three trial, now over 1,000 patients, most of our bladder cancer studies, particularly in the unresponsive, are predicated on 100-patient studies. This was over 1,000 patients, a little over 350 patients in each arm. The hazard ratio correlates with a 32% reduction in risk of a DFS event. And you see the effect very early, less than four months. The descriptive OS analysis, there was no decremental, no negative impact on survival. And so induction and maintenance had a tolerable and manageable safety profile with Imfinzi, nothing that we hadn't really, quite frankly, anticipated. Our conclusion, as well as our discussion within The Lancet publication, is that it supports a one-year course of Imfinzi in combination with BCG induction and maintenance as a new treatment for patients with BCG naive and high-risk NMIBC. I think it's very important built into that conclusion is the fact that it delays assuredly the issue of developing what's known as unresponsive disease. And when you have unresponsive disease in most parts of the world, you're looking at potential chemotherapeutics or having your bladder removed, a radical cystectomy. In the U.S., there's quite frankly a plethora now of approvals in the unresponsive space. Thank you. Thank you, Dr. Shore. Let me just take a minute to put those data now into context, and then we'll move to Q&A again. So really, what's exciting now about the bladder cancer program is if we look at together with the Niagara data, the POTOMAC data that Dr. Shore has just walked us through, moves us into an earlier stage of bladder cancer. I think also importantly, this is a very large population with an unmet need that's very clear. And I think the commentary on delaying to unresponsive disease that Dr. Shore just provided is very meaningful and important. Also, we know that Imfinzi didn't compromise the ability to be able to complete BCG induction or maintenance. And as a result of that, you can see the high unmet need together with Niagara. Volga is something that we're anticipating. I think that as we take a look at the data that were presented on EV, also here at ESMO, it gives us good reason for having confidence that we've designed a smart study with a good approach in the Volga setting. I think that two important comments on Volga, we do incorporate the possibility of CTLA-4 being meaningful in terms of driving to longer-term outcomes within this population, and within the adjuvant portion of the therapy, we do not have EV as part of this, and that's something that I think is seen as a good opportunity to be able to likely drive to similar outcomes, but with a different type of tolerability profile. Together, all of these studies within bladder cancer represent a blockbuster opportunity for us. And indeed, Niagara has been a really important part of the growth of Imfinzi that we've been realizing through the first half of this year. And something that we're looking forward to have continue on is Imfinzi has really been growing nicely, and we'll update more on it in the third quarter. So just finally, within this, we saw four really very impressive pivotal studies all that were discussed today. They all put us in a position to be able to really say that the roadmap that Pascal laid out for our path to the $80 billion ambition and knowing that oncology plays a very, very important part of that. I think these are four very important studies that give us confidence that we're on the right path together with the multiple other catalysts. We've had 10 positive phase IIIs throughout the year. Our commercial organization is ready to make sure that we are turning these indications into opportunities that are competitively well-positioned, getting rapid uptake. And I think that you heard very nicely from the presentations today how they will actually result in transforming care. So with that, I'm going to turn to the last part of our Q&A. Certainly happy to take questions here in the room. Christopher's up first, so we'll take that. And then we'll also, of course, have some questions that are online. Christopher, over to you. Thanks very much, Chris from SEB. So my question is, I guess, first about the robustness of the data and then the US approvability and ex-US market access scope. But then also, I mean, I think it's a good example here of, Susan, the incredible run of luck you guys have had here over the, I guess, over the years since the day after Mystic, I suppose. So maybe you could comment a little bit on what separates the winners from the losers in the context of NMIBC and how that relates to the rest of your portfolio. But just in terms of robustness, what I'm really wondering about is if you could comment, Dr. Shore, on the rate of cystectomy prevention and what you can say about sensitivity analyses around censoring. censoring. Yeah, I guess, particularly in terms of the number needed to treat to prevent a cystectomy. Yeah, thanks. Perfect. So Dr. Shore, if you wouldn't mind commenting, as Christopher has asked, on the robustness of the data and how you look at it through some of the dimensions that he described. And then we'll come to Susan. Susan, you can talk about US approval. I mean, if you want to refer to it as lucky, I guess you can go with that. But I'll let you address that on your own. I was going to say, you have to be a little bit lucky, but you have to be good in life, and the days when we failed on Mystic are far behind, and the team is very different from the team we had at the time, and we've learned a lot since then. So, Dr. Shore, please, on the robustness of. Yeah, I appreciate Pascal's comment because I was going to bristle a little bit and say, look, I don't work for AstraZeneca, and I don't have any equity in the company. But I bristle, I bristle. It's not luck. It's called vision. It's called leadership. It's called thoughtfulness. I take pride. I've done over 500 clinical trials. And I take pride in trying to pick the MOA, pick the trial design, pick the team. And that's why you get success. It's really not as. I know you're probably kidding in the comments. But I do think that's what separates winners from losers oftentimes. Regarding, look, effect size here is impressive, isn't it? You've got over 1,000 patients in this study. And looking at the intent to treat population, curve is separating very early and consistently throughout five-year follow-up. This is rather impressive. So I think the sensitivity analysis, as we continue to perform it and look at some of the typical forest plots, the numbers start to get small. They get a little bit wonky for sure. But overall, the effect size is, you can't argue with that. Number two, the cystectomy-free rate is remarkably low. There's a 40% two-year recurrence progression rate, traditionally, historically, in patients on induction maintenance BCG. And we basically kind of really blew that away with the fidelity of the patients getting such rigorous induction and maintenance. I mean, BCG is a good drug. So on top of the beneficial effect of BCG, we outperformed induction and maintenance by adding Imfinzi. I think that's an incredibly important take-home message. So did we have some additional adverse event profile? Of course we did. Nothing unexpected from what you'd know in using other IOs throughout other tumor streams. And certainly similar to what we saw with Niagara, which is an excellent study. But having said all that, I think that we'll continue to look at the cystectomy free rate. We did not have much progression whatsoever in this analysis. Mostly what we saw, DFS, it was largely on the level of recurrence. Thank you, Dr. Shore. Susan, do you want to speak to the approvability in the absence of U.S. patients? So of course, the topic of U.S. patient participation in clinical trials is one that's of interest. In this particular case, there was a good reason why there were no U.S. patients because there was not the availability of the BCG during that particular time of the conduct. So I think in that context, it's possible for us to still discuss the relevance of these data to a U.S. patient population with the regulatory authorities. Perfect. Thanks, Susan. Let's go to a question online. Simon Baker at Redburn, over to you. Thank you very much for taking the questions, Dave. Two, if I may, please. Firstly, on POTOMAC, just some thoughts from Dr. Shore on any granularity on patient selection. The result looks very robust and broad, with that possible exception based on gender. So just any thoughts on exactly how you would use this in the clinic on approval. And then second, just changing the subject slightly, you also presented some impressive data on AZD5335 in platinum-resistant ovarian cancer. I just wondered if you could update us on your plans going forward for that asset. Thanks very much. Perfect. So Dr. Shore, please, if you could comment on patient selection. I think Simon's asking about, kind of in the clinic, how you think about the selection of patients to put on a POTOMAC regimen. You don't want me to talk about my ovarian cancer experience. Oh, wow, you could, but we'll let Susan take the first crack at it, if you don't mind. Yeah, yeah. Thank you. So it's a really good question. And look, I'm an enormous proponent of this sort of, I don't think it's hackneyed to say it, but shared decision-making. There's not necessarily going to be a one-size-fits-all on this high-risk NMIBC population. But we know that this is a particularly more biologically virulent population than the intermediate risk and the low-risk patients. They're really kind of very different diseases. So if I have a patient in the clinic who presents with high-risk NMIBC, may also have some variants as well, I'm going to look at that patient and have the discussion with him or her that you have a disease that has a very 40% two-year likelihood of recurrence/progression. We could go with induction maintenance BCG, but we now have level one evidence that we could add a combination by adding in a checkpoint inhibitor, a PDL blocker such as Imfinzi, to enhance your treatment response, so that could certainly be, honestly, just to really put it out there, if I have patients with T1 disease, multifocal CIS, potentially very difficult to resect, high-grade TA papillary, patients who are really refractory to wanting to undergo that procedure on a repetitive basis, and I wouldn't even say that they necessarily have to be younger. They just have to have a preference value for saying, "Give me my best shot, my first shot, best shot." I think that's a phrase you'll start to hear more and more in virtually all tumor types. I think this is what, if you add the combination of Imfinzi and induction maintenance, you're diminishing the likelihood of developing unresponsiveness and then what sets into that cascading paradigm of more and more treatments and arguably cystectomy. Thank you, Dr. Shore. Susan, you want to comment on 5335, which, for everybody else, it's just so you know, it's the folate receptor alpha in ovarian cancer, please. Yeah, just before I move to that, one more comment on the approvability. A third of the patients, about 35% of the patients in POTOMAC, received the OncoTICE BCG strain, which is the strain that's approved in the U.S. That also speaks to the approvability. But to move on to AZD5335, which we're naming Torvusam, Sam, just to help you decode. It's a folate receptor alpha. Again, it's our proprietary linker payload with the topoisomerase inhibitor. It has a very stable linker. And I think we've seen that linker payload perform also with the Puxisam B7-H4, as well as now the Torvusam data set. Really nice durable response rates. We've got good, nice flat spider plots that were shown in that across the different dose levels. And we see good activity in both the folate receptor alpha high and the folate receptor alpha low patient populations, which is important. Obviously, there's a competitive space here. We're moving at pace, and we're excited about the potential. Obviously, ovarian cancer is a setting that we've got good history and good relationships with investigators globally as well. So you can be assured that we will be getting behind this and eager to enter that competitive race. Super. Susan, thanks for the update on Truqap. Steve Scala, Cowen, going to you, and we've got about five minutes left, so we'll try to move quickly through questions if we could. Oh, thank you so much. I have two questions. One is back on breast cancer and then a general question. I'm curious, does the SERENA-4 trial allow for control arm crossover to camizestrant? If yes, then how should we think about the OS endpoint? And then secondly, has AstraZeneca's interest in PD1 VEGF increased or decreased based on data presented at this ESMO? Thank you. Perfect. Susan, you want to answer the PD1 VEGF question, and then Sunil, you can comment on SeERENA- 4 and the study design. Sure, so in terms of PD1 VEGF, I don't think our view has changed from what I've said previously. Very good. Those short answers? No. All right. So no crossover is allowed within that study. All right, Steve, thank you on that. So here, we'll go to questions in the room, please. Yeah, this is Tony Ren from Macquarie. Just want to go back to the HER2-positive early trials again in terms of understanding the market sizing, revenue opportunity. So I think Dave you said DESTINY-Breast0 5 and 11 have roughly the same patient population, right? But one regimen is only four doses, right? The other one is 14. So would it be correct to think the 05 would actually be a larger revenue opportunity? So in terms of these two studies, if you think of them independently, they would be equal in terms of potentially the size. But with the opportunity for DB11 upfront, and based on, I think, what you heard really Dr. Harbeck speak to quite eloquently, we would expect that you would see a large number of that population being treated with DB11 in that neoadjuvant setting. Now, certainly, there will also be patients that will then be better to receive in the DB05 setting. And there will be also some practices that prefer to wait until that. We look at the two of them together as two opportunities for enhertu to be used in early breast cancer. We think together they represent a blockbuster opportunity among them. And we will certainly also be working to drive towards where the best outcomes can be achieved. And within that context, we think using the medicine as early as possible is where the best opportunities are for that. That really is DB11. But DB05 also is a very important opportunity for those that can't benefit in the 11 context. So Rajan Sharma at Goldman Sachs. Hi, thanks for taking that question. I'll just keep it to one. I just had a quick question on Sariparib, and given that we've now seen initial data in prostate, just wanted to get a sense of your confidence that this is an opportunity that can go beyond where Lynparza went? Thank you. Susan, you want to take that? Yeah, sure. So the data that we showed in the Patrana study, which was using the 60 milligram dose of sariparib, which is a dose that achieves 30x the target inhibition level of the approved dose of olaparib, we saw good tolerability in combination with hormone receptor inhibitors, including darolutamide, and really encouraging PSA response data with PSA 50 and PSA clearance, and also radiographic response in those patients that are radiographically evaluable. I think we've got also very good and low discontinuation rates on this study, which are lower than any of the data that have been seen in the hormone-resistant or castrate-sensitive patient populations previously. So I think this reinforces that the profile of the drug is playing out as we had hoped. The EvoPAR-Prostate01 study has been enrolling very rapidly, which again just speaks to the people's interest in this mechanism. And of course, with those studies that we've got, we are going into earlier line settings than we've seen with olaparib with the PROPEL and the PROFOUND data sets. So we're excited about the profile that we're seeing with sariparib and look forward to seeing those trials read out. Great. Thank you, Susan. Let's try to see if we can get a couple more, and Mattias at Handelsbanken, please. Thanks so much. I have two questions, please. First, for TB02, there's been some discussion around how to think about allowing for crossover or not, and its potential influence on the OS data. And the question is asked, of course, in the light of high rate of crossover in the SEM3 trial, whereas TB02 did not allow for crossover. So I'm interested in your perspective on crossover for this setting. And then secondly, staying on crossover, there were recently revised guidelines from FDA on the assessment of overall survival, including the agency's view on crossover. So I'm curious to hear how you think about crossover in general terms within oncology. When is crossover appropriate and when not? Susan, you want to give perspective there? Yeah, sure. So obviously, Datroway isn't approved in the second line setting. So in terms of the context of the study, patients did have opportunity for second line therapy. And about nearly three quarters of patients on both arms received a second line therapy, including the opportunity to have other ADCs, not just a TROP2-based ADC, but other types of ADCs. So it's not that there was no subsequent therapy use. But as I think you heard from Professor Dent, in this patient population, a large number of these patients don't make it to second line. So it's really important to actually see that overall survival data that we've got. Crossover is a really important topic, but I think it's also important in the context of the drug development strategy that we think about the demonstration of endpoints that are not just going to be important from a regulatory authority perspective, but important for reimbursement and general access and uptake subsequently, so these are important considerations to think about. Yeah, I think to put an even finer point on it, in the absence of overall survival in a setting like this, the challenges that we would have with broad access to Datroway in the triple negative setting would be significant. And so certainly, this is an important question on when to include crossover and when not to. But access to a medicine with these types of results would be seriously constrained if we didn't have those results. And so I think in this instance, it was absolutely the right decision for us to design it the way we did. I'm going to go to the last question here. Richard Vosser of J.P. Morgan, back again over to you. Thanks very much, Dave. Question for Professor Shore. Just, Dave, you mentioned the Volga study. And I just wanted to see Professor Shore's opinion on the amount of EV used, I think three months in Volga, and how he sees that relative to the EV data that we saw at ESMO this weekend. Thanks very much. Yeah, I appreciate that question. Having been part of the 905, yeah, I mean, EV is not a benign drug, right? And so I think one of the really interesting aspects of VOLGA is the decrease in the exposure to EV. I think the trem-durva combination has great opportunity. We've seen CTLA-4 and a checkpoint inhibitor come to with great results, particularly, at least from my experience, in metastatic renal. So I think it's a very exciting combination. I'm very excited to see the readout on that. I think it ultimately baked into your question is that it could be a much more tolerable side effect profile for patients because of the less exposure to EV. Thank you, Dr. Shore. Let me use this as an opportunity to once again thank you for joining us today and for your presentation. Thank you very much for that. And my thanks to all that are here and who joined us, as well as to those online. I think this has been, for us, an incredibly exciting ESMO. And we thank you again. We'll look forward to seeing you sometime soon, certainly at third quarter. Take care. Bye-bye.