AstraZeneca PLC (AZN) Earnings Call Transcript & Summary

Hi, everyone. I'm Craig Marks from the IR team. Welcome. I'll be moderating the session today. I'd like to welcome you to virtual breakout 1 on Tagrisso and immuno-oncology. Today I'm joined by Dave Fredrickson, EVP for our Oncology business unit; and Cristian Massacesi, Senior Vice President, Late Development Oncology. We have until 5 past the hour, and we'll start with a short presentation with the majority of the time allocated for Q&A. The presentation materials are available on our website as well as recording of this session. This event is strictly for invited sell-side analysts and institutional investors. Therefore, if you are a journalist, consultant, or employee of another pharmaceutical company, please disconnect now. [Operator Instructions] Turning to the next slide, Slide 2. You can see our safe harbor statement and forward-looking statement disclaimer that we are using today. I'm now very happy to hand over to Dave to begin the session.

Thank you, Craig. And on behalf of Cristian and myself, I want to welcome all of you to this session where we take a deeper dive into both Tagrisso as well as into Imfinzi and, more broadly, to talk about, not only the work that we are taking on and underway with right now in the markets but also taking a look at the pipeline and what is next. With respect to Tagrisso, I think that, really, this is, for us, one of the absolute key highlights of the ASCO session. I think that José did a very nice job of sharing the data, which you all heard Dr. Herbst share yesterday at the plenary session. But I do think that it's important to also highlight coming into this particular meeting that we've really seen tremendous success with Tagrisso as we are establishing Tagrisso in the front-line metastatic setting across the globe as the standard of care in EGFR-mutated disease. We talked about achieving sales of almost -- just shy of $1 billion for the quarter, which is putting Tagrisso on a run rate of being a $4 billion medicine. And we're doing that with standard-of-care-level penetration in the U.S., Japan and in a number of countries within Europe. We are also, though, still seeing further growth opportunities as we continue to get an opportunity to get more national-level reimbursement and payer approvals on the heels of our global regulatory approvals. We've shared quite regularly that we've been approved in 80-plus countries. We've got payer-level reimbursement in 20 of those. And we would expect to be able to get ourselves to more like 40 countries that we will be able to get that reimbursement. And so there's still a lot of good opportunity for growth with Tagrisso in rest of world in the front line. But then on top of that, obviously, we take a look towards the future, and as we look towards the future, not only do we have that expansion in the front line that I spoke to as well as the potential for NRDL inclusion in the second half of this year, but we begin to then turn our efforts towards rapid submission of the ADAURA data, which we'll do in the second half of this year and look for that, obviously, to be an important driver of our growth moving forward. If you can go, Craig, on to the next slide, please? So when we take a look at Tagrisso and the program, José quite nicely presented again the panel that you see on the left in terms of the ADAURA data that were just presented yesterday. This unprecedented disease-free survival is of a magnitude that it gives us certainly a lot of optimism that it will translate into overall survival. But this 80% reduction of the risk of disease recurrence, I think that there's a number of really important points about this, and we can get into this into the Q&A. But one that I would like to highlight is that I think that if you take a look across the forest plots that were presented, and if you also take a look at the Kaplan-Meiers that were presented by stage of disease, we see very consistent benefit irrespective of stage of disease or respective of ethnicity and other factors that can sometimes come into play. And so I think that, that is a very important characteristic of this dataset. Obviously, the studies of ADAURA sits in the context of a much broader program of life cycle management. We are awaiting the results in the 2021 plus time frame from the LAURA study, which would be in the Stage IIIb, the nonresectable population. Certainly, one of the questions that we get is, do we think that ADAURA is a good read-through for LAURA. Certainly, the fact that we've got positive results from ADAURA and FLAURA suggest that the LAURA setting is one that we are also optimistic about. Of course, the safety is going to be an important component within that setting. But that's something, obviously, that hasn't come up as an issue so far because it's obviously being followed by the IDMC. And then lastly, if you move over to the right-hand side, just in order to give a sense of the relative size of the population that today is addressable from the ADAURA study, about 25% of the number of patients in the Stage Ib through IIIa are treated today as we see in the Stage IV setting. So today, in Stage IV, you see that there's about 845,000 treated patients. We believe that there are about 220,000 treated patients in the Stage Ib through IIIa in today's context. And then if you also keep in mind that the duration of therapy for patients on Tagrisso for ADAURA is per protocol up to 3 years, what you saw in the study so far is that patients are on average treated for 22 months. But keep in mind that this is an immature number because there are still a number of patients that are still on therapy and have not yet reached the 3-year point. So we would expect this number to mature as the dataset does. The last point that I'd like to make on this is that, of course, this is also based on current screening rates, which are really quite low across the globe. I think just to put into context, in the United States, there's estimates that fewer than 10% of the eligible patients just based upon smoking risk factors are being screened today in the United States. So there are probably even fewer patients that are never smokers being screened. And so there's a tremendous opportunity to grow awareness there. Next slide, if you would, please, Craig? And then just turning on to Imfinzi and within IO. Again, we are making very good progress with the Stage III unresectable non-small cell lung cancer marketplace. We continue to see growth across the globe. We have talked about the fact that, in the United States, we have really gotten to standard-of-care levels of CRT rates in Imfinzi post-CRT, and it is very good to see that China is now coming on board, that European countries are beginning to really get their stride and make good inroads. And it comes also at a time where we see expansion in our opportunities. We have approval in the United States for the CASPIAN study and have launched now in extensive-stage small-cell lung cancer in the U.S. We're looking forward to CASPIAN launches across the globe. And you can see that we have quite a bit of anticipated lung cancer news flow coming. I would just point out that we've got a series of studies in the Stage III setting with PACIFICs 2, 4, 5, all of which that are looking to build upon our first-mover advantage that we have in the Stage III setting but also between AEGEAN, BR.31, ADRIATIC, looking at a number of studies in even earlier stages of lung cancer. And then we highlighted MERMAID, which we can talk about more in the Q&A, but this is an even earlier stage of disease looking at minimal residual disease as an indicator for when early intervention with PDX therapies could make good sense for improving outcomes. I'll turn it now over to Cristian, who'll talk about other aspects of our IO portfolio.

Thank you, Dave. Can you give me the next slide, please? Thanks, Craig. So let me start the way that we believe that to really cure cancer we needed to treat earlier because this is where survivorship is possible. I think AstraZeneca realized the potential of pushing immunotherapies in earlier disease stages and now leads the space with the largest proportion of Phase III trials in early-stage cancer across all checkpoint inhibitors. So building from PACIFIC's success, we invested in all 3 of PACIFIC's trials, as Dave already mentioned, we added a neoadjuvantational setting to introduce complementary things in monotherapy in combination in Stage I and 3 non-small-cell lung cancers. Our investments in early disease extend beyond the non-small cell lung cancer is touching small cell, liver, bladder cancer, cervical cancer. We also see opportunities to disrupt in establishing new standards of care in advanced disease within [indiscernible] through novel mechanism of actions, combinations and biomarker strategies that eventually will allow us to identify patients that most likely can benefit from our treatments. We're exploring many promise in combination with Imfinzi, including, of course, tremelimumab combo but also with other agents in our portfolio pipeline as well as with chemotherapy, radiotherapy, ACE and BCG. We're also exploring a new wave of asset sets, such as our PD-1/CTLA-4 bispecific and molecules that are inhibiting the adenosine pathway. With a full range of mechanism in our toolbox from targeted therapies, ADCs, DDR agents, the next wave of radiotherapy -- oncolytic viruses, I think we can -- we hope to further add to the power of Imfinzi. In addition, we are continuing in the huge effort in innovating in terms of patient selections using multiple biomarker strategies, including the use of TMB in the blood, ctDNA, PD-L1 status and HER2 biomarkers. Give me next slide, Craig, please. We have a renewed focus on advancing treatment in liver cancer, which is the third leading cause of cancer death, and treatment options in this setting are still very limited in our view. Only 20% of patient remains alive at 5 years after diagnosis. And many patients with liver cancer are diagnosed only after the disease is advanced. So there is really an urgent need for new effective and tolerable treatments. The results that we presented during ASCO from Study 22, I think, showed the promising clinical activity and tolerability with Imfinzi plus tremelimumab, even in the context of a novel regimen for patients with advanced liver cancer. Patients were treated with a single priming dose of tremelimumab, given a high dose of 300-milligram in combination with Imfinzi [indiscernible]. And this arm, as you see in the curves presented in the slide, achieved the longest median OS along with the treatment tested almost 19 months with one of the best safety profiles. We believe that this is not a regimen of dual checkpoint located with tremelimumab, and Imfinzi may play an important role in this challenged cancer and in these patients that do not have so many treatment options. We, I think, while the PD-1/PD-L1 inhibitors have revolutionized the treatment of some cancer, still, they do not have demonstrated sufficient efficacies as monotherapy in liver cancer. However, some research is suggesting that CTLA-4 inhibition may provide more durable, longer-lasting efficacy, particular in combination with checkpoints. So Study 22 is also encouraging a sign for our Phase III studies ongoing in HIMALAYA in front-line setting that is testing this exact-same regimen in the patient population. The data with HIMALAYA is expected later this year. We also have a very robust development program across stages of liver cancer with immunotherapy approaches. The Phase III EMERALD-1, EMERALD-2 in HCC, Phase III study TOPAZ-1 in biliary tract cancer. EMERALD-1 is a combination of Imfinzi or Imfinzi plus bevacizumab and transarterial chemoembolization, TACE, in patients with locoregional HCC. EMERALD-2 is a Phase III study of Imfinzi or Imfinzi plus bevacizumab as adjuvant treatment in patients with HCC, while, of course, at high risk of recurrence after curative hepatic resection or ablation. TOPAZ-1 is a Phase III study of Imfinzi in combination with chemotherapy as a first-line treatment for patients with advanced biliary tract cancer. So HCC and liver disease, in general, is an important area of medical need. And I hope I was able to convey to you the real focus and how important this indication is for AstraZeneca. And of course, with a focus also in Asia, where this disease is, of course, mostly prevalent. With this, I conclude my presentation, and I think, Craig, back to you.

Thanks, Cristian. Thanks, Dave. Appreciate it. So now we have some time for Q&A. We need to stop on 5 past the hour. I'm not sure I need to go through all the instructions on how to ask a question because, believe it or not, we've got a huge mass of questions of people raising their hands already. So we've got some written out that I'll ask, and we've got some people raising hands. I'll try to do in the fairest way possible, but I'm pretty sure, even with short answers, we're unlikely to get to everyone. But I'll open the line first to Michael Leuchten at UBS. Michael?

I was just wondering, in the ADAURA discussion, the point was raised that 45% of patients did not receive chemotherapy. And the discussion was asking a question who those patients were. So would you able to help us with how many patients were screened to get to the 682 patients that ended up in the ADAURA study, so from screening to actually study enrollment, what was that gap?

Cristian, is that a figure that you've got on hand? Or is that some...

Yes, I think, Dave, I can take this one. So actually to enroll 682 patients, 2,447 patients have been screened. So let's say, almost 2,500. This represent approximately 28% of patients screened then actually enrolled into the trial. And the number of patients, Stage Ib enrolling the trial were about 30% of our patient population, so 212, and the number of Stage -- not Ib, so Stage II and III, were 470. This was, per protocol, capped, the number of Stage Ib patients. So 30%, that was the number of patients that we wanted to enroll in the protocol. Does it answer your question?

Yes.

Thanks, Michael. I will now move to an online question. Dave, this may be a question for you. It's from Marietta Miemietz from Primavenue. Do you expect lung cancer screening programs to be implemented? And if so, what does that do to patient numbers and characteristics in early and metastatic cancer?

So thanks for the question. I mean, I think that today, we estimate that about 15% of lung cancers are being diagnosed while still localized, about 20% regionalized. So you get about 35% that are being diagnosed at this earlier stages of disease. That means that we see still an awful lot of cancers getting diagnosed in Stage IV. We've seen improvements made on the heels of studies like NELSON and NLST within Europe in terms of screening rates with low-dose CT that are going up. We have not seen the same level of improvement, as I made comments to in the United States so far with screening. And I think many people probably know that this is something that the previous president put quite a bit of effort into. With that said, I also think that one of the important things that is happening is that new technology is coming which allows for screening to take place that doesn't require low-dose CT, and I think that these new screening technologies will likely be part of the reality and part of practice and -- in a handful of years. So I think that those can have quite a big impact in terms of what the numbers would look like once they're implemented and put into place.

We now have a raised hand from Andrew Berens at SVB Leerink. Andrew, please go ahead.

Congrats on the strong presence at ASCO this year. Maybe this is for Dave. I was wondering when we might see some more granularity on the impact of Tagrisso in brain mets as a potential site of recurrence and then also when we might see mature OS benefit to discuss and mentioned the IRESSA adjuvant data that showed convergence after the drug was stopped?

Sure. I'll start on this, and then Cristian offer to you opportunity to comment. In terms of brain mets, CNS data, in general, we are planning to both look at and present later this year. So that's the answer on that question. And in fact, what I would say on this is that we know there's a lot of interest in sub-analyses out of the ADAURA study. And so we will look forward to having an opportunity to share those inclusive of the CNS data coming up later this year. Cristian, do you want to tackle the OS question?

Sure, with pleasure. It's a very good question. Let's start with a few evidence that we have. In metastasis setting, Tagrisso showed clear superiority over IRESSA. And in the adjuvant study, despite a very good ratio for DFS that was observed in IRESSA, it was not as good as what we observed [indiscernible] Biologically, I think the activity on T790M can explain a different outcome. And as we'll have in a metastatic setting, it is also possible -- plausible that, in the early setting with tumor lacking heterogeneity seen in later stages, a more important, more selective idiopathic [indiscernible], such as Tagrisso, can significantly improve on the efficacy of the older generation drugs like gefitinib or erlotinib. I think also that we have some preclinical work showing that Tagrisso eventually can eradicate some at higher scintilla versus geographic [indiscernible] is able to eradicate some growth. So we need, of course, longer follow-up. We need to understand if Tagrisso will improve OS by increasing the cure rate or by delaying the disease relapse or maybe both. But I think we have confidence that this huge benefit observed in DFS ultimately will translate also in the benefit in OS. I hope this answers your question, even if, of course, we don't have data.

Yes. Appreciate it.

Thanks, Andrew. So now we have an online question from Peter Welford at Jefferies, which I'll read out. So after Tagrisso, the median duration of exposure is below 2 years of presence. But can you talk about the proportion of patients reaching the 3-year point who were still on therapy? In other words, what proportion completed the 3-year regimen planned in the protocol?

So again, on this, I'll invite Cristian for you to respond after I make a comment on this. It is still very early within this. We have 3 years of follow-up for only 20% of patients. So I think that it's still very limited data at this point. Cristian, anything you want to add?

We are refreshing the data because let's not forget that the data that have been presented at ASCO are coming from a cutoff date of the beginning of the year that was provided from the PMC. So we are now, of course, refreshing the data. We will have more data, especially with regards to treatment duration, the number of patients that reached the 3 years at each time point. So I would prefer to -- yes, this will be presented further. For the moment is -- but what you said there is correct. It's about 20% of patients. But again, with the new cutoff, we will have more updated figures.

Yes. I mean, I think the other thing that I guess is implied or the question behind the question in this is what do we expect the duration of therapy to be in the real world? And obviously, it's difficult to predict exactly where this will net itself out. I think the things that I would say is that, again, protocol is 3 years. I would expect that, that is what will be in our label. Though, obviously, we'll need to continue to have discussions with health authorities on that. And we know that, for the full population, there were 79% of patients at the landmark of 3 years. And so I think that, that gives some ability to begin to think about the number of patients or the percent of the population that would be at least disease-free survival by the time we get to 3 years. And I think that it's probably also always safe to assume that, in the real world, patients do miss doses along the way in terms of relative to clinical trials. So that's how I'd start to think about kind of the question from a modeling perspective from duration.

And Dave, just another thought on this because this is a figure that is quite solid. Our discontinuation rate in Tagrisso is 11% versus 4% in the placebo arm. Is not -- it is not varying according to stage. So Stage Ib, Stage II and Stage III patients stay on treatment in the same way. And it seems not to be worth saying patients that have a little bit longer treatment duration so far. So we were extremely pleased to see how well tolerated and the compliance that we observed in this trial with -- by the patients.

Great. Thanks, guys. Maybe have time for one last brief question from Matt Weston, Credit Suisse.

It's a question regarding the commercial opportunity, given as Tagrisso gets bigger, presumably as a small molecule that has an extraordinarily high gross margin, and now that we have the ADAURA potential and potentially LAURA in the future, do you feel that Astra is going to have to share some of that revenue potential with payers in order to stop this drug from becoming so dominant within the P&L? And if that is the case, how could you envisage or have you yet envisaged how to do that? Could you give away free drug? Could we imagine lowering the price? I'd be very interested, particularly given some of the reimbursement discussions now for front line are going to be done in the presence of the ADAURA data.

So we'll try to do that in less than 1 minute, Matt.

Yes. So thanks, Matt, for the question. I mean I think that as is always the case as you move into earlier lines of therapy, one of the important points that I'd like to start on is that the delivery of outcomes in early stages of disease are ones that, first of all, society really values and also are the best in terms of demonstration of value for the healthcare dollar that's being invested. And so I think that it's important to note that, obviously, as we engage in conversations with payers, the ability to be able to talk about benefit in these earlier settings of disease is something that's quite important. Now of course, again, DFS versus overall survival makes for a conversation that we'll have to navigate accordingly. But I think that we will certainly have an opportunity for payers to see these data in a positive light in that regard. Of course, that's offset by the fact that, as we expand the number of patients and expand indications, it's customary across almost all regions with the exception of the United States for there to be price reductions. And I think that you should expect that we would be seeing some degree of expected price reduction or required price reductions in order for us to be able to obtain access, but I would say that, again, one of the things that's important along this dimension is that we're talking about very, very impressive set of results. And we think that we've been able to maintain good value across the globe on Tagrisso, and I think that these -- this ADAURA study will allow us to continue to do that.

This question, if I may, is we need more data, of course, especially on the OS follow-up. But if you look at Herceptin, the [ adjuvant ] setting is the most cost-effective part of Herceptin. In fact, the cost per [ quarter ] in the U.K. calculated by [ NAS ] is incredibly low relative to what you have in metastatic setting. So the cost effectiveness increases in the adjuvant setting, we should hopefully be able to manage the price pressure. So we'll have some price pressure. We should be able to manage it.

Right. Thank you, Pascal. I will go to James Gordon at JPMorgan.

A question about Tagrisso. So it was 2 questions. They're both about LAURA, so I'll say it's one question. So the question was, can you talk about where you are in enrolling LAURA and when you think you could complete the enrollment? Is this a study that's way into the future? Or are you actually quite near getting enrolled? And also -- so we got help here last night. We got the ADAURA efficacy broken out by the different stages. So if we're trying to extrapolate ADAURA to LAURA, is the best way to look at the Stage IIIa population, where you have a 0.12 hazard ratio? Or is there a reason that's not the way to try to extrapolate?

Thanks, James, for the question. Cristian, I actually -- I turn both of those over to you, and I can also make some comments in terms of some thoughts around what we might see from benefit within LAURA study, but why don't I start with turning it to you.

First of all, LAURA is proceeding well. There are no safety signal. So in terms of tolerability, because this was one of the main open questions in this specific setting that we were, of course, wondering, so far, there are no major issues. We started the study, and we have a fully allocated trial in terms of sites, countries. The study is proceeding per plan. But of course, we will -- it's a study that will need additional months to complete enrollment. The -- this is, I think, where we are. The database lock for LAURA is planned around the end of 2021 or just a little bit after.

Great. And then, Cristian, in terms of James' second question with respect to anticipated potential magnitude of benefit, and obviously, we need to conduct the study to see it, but we...

We need to conduct the study. But I have to say, Dave, we are much more confident after we have seen with ADAURA. We believe that, based on what we learned in terms of PACIFIC readout, this gives us also confidence, we believe the study has a high probability of technical success.

Next, we have Tim Anderson from Wolfe Research.

Some payers in x U.S. countries require overall survival for maximum reimbursement. [ That's not ] Tagrisso here. I think we all know Tagrisso will yield a survival benefit, but you don't technically have it because the data's immature. So I guess it's more of a commercial question than anything. This will back uptake or reimbursement of pricing of this new adjuvant data in any geographies, and might they try to use this as an excuse to try to limit the product? And then just a second question. I have to imagine that ADAURA helps your argument in China as you're discussing FLAURA and whether to really might get NRDL listing. Can you confirm that, that probably shifts the odds in favor of NRDL?

Thanks, Tim. So on those 2 components, first, as we think about ADAURA, you're absolutely right that, in certain geographies, we will have a more complex value discussion and submission by having only disease-free survival as opposed to having overall survival as well. With that said, it is quite customary to include quite a lot of modeling, which we will do as part of those submissions. It is also quite customary to engage with payers in these earlier lines of disease in the absence of having fully mature overall survival. And so while that will enter into the discussion and I think will play a part in sort of the magnitude of price concession that certain countries might seek, I don't see it as being a -- as a barrier to being able to obtain reimbursement, at least at some level. I mean I think that the other piece -- and Pascal has spoken to this as has José, as a reminder, that the cost/benefit of Herceptin, as an example, was really quite high, remains quite high once moved into the adjuvant setting. And so we've got a number of analogs also that we will be able to use and draw upon as part of those conversations. On your second question, I definitely believe that ADAURA helps us in any jurisdiction where we don't yet have first-line national reimbursement in terms of being able to really solidify the clinical benefit narrative that we have.

Great. Thanks, Dave. Next question we have Mark Purcell from Morgan Stanley.

Dave, Cristian, thanks for doing the session. The first question was just in terms of sort of testing and just thinking outside the U.S. academic center. So in the U.S., I think it's pretty clear how strong these pace are, but a very large proportion of patients in the U.S are treated in a community setting, where I think EGFR testing is around about 65% at the moment. And then there's one thing going to a test and then convincing these guys to actually action treatment on the back of the test. So with those 2 components to it, can you help us understand where testing is outside the U.S.? And on the basis of receiving a positive test, what proportion of those tests are actually then action-ed in terms of treatment? And in your slides, obviously, you mentioned other things that could help you in terms of testing rates and getting patients onto treatment, including things like circulating tumor DNA. So how far away are we from potentially getting an easier route to treatment for the community oncologists? And then given, Craig, a lack of questions, just one quick follow-up. In terms of Imfinzi in the adjuvant setting ahead of BR.31 data coming out in 2021, could you help us understand, given you've got the novel trial designs in the past, how your adjuvant trials compare versus those of your competitors as we enter this sort of 24-month window of seeing more adjuvant data in lung cancer?

Great. Thanks, Mark. I'll propose -- Cristian, I'll take the testing question on, and then the Imfinzi question, I'll then turn it to you to respond on. Mark, in terms of testing, and I guess for just my own clarity on this, I'll speak about testing as being distinct from screening or early detection. In terms of testing today, both x U.S. and, frankly, even in the U.S., EGFR testing is not common, and it is not part of standard practice. I think the predominant reason for that is that you need to look no further than the guidelines to see that there's no real difference in terms of the treatment decisions and choices that are made for Ib to IIIa patients based upon their EGFR status. ADAURA changes that we believe. And I think that we certainly heard both from Dr. Herbst as well as from Dr. Siegel to discuss it in terms of the view that they had on this. And I think that they certainly have insight into how the guidelines will likely evolve. Also the fact that tissue availability for patients who are being resected is high, I think, also helps to give us greater confidence that there's going to be good uptake and adoption of testing now that there's an option here. Screening, on the other hand, is very low, and I think it's a much more difficult needle to move. And I think that low-dose CT scanning, despite all of the efforts that have been made, the needle hasn't moved very much on this except for within Europe, and this is where I do think that the new technologies that are coming out that allow for blood-based screening to take place will revolutionize the screening rates. And I think that that's going to be something that will take more time, and that's something where the real effort needs to be put in, in order for us to get more patients detected in the earlier settings so that we can really drive more towards cure. Cristian?

Yes. Dave, I apologize. I had some Internet connection issue. In the meanwhile, I hope I will not repeat what you just said. But I think that, in early setting, what we can say, Mark, is that the testing is very low. We need to be very, very pragmatic here. We know metastatic already varies according to the region between 70% and 90%. It depends on the region. Japan probably is the country where testing is the highest across stages. We learned during ADAURA conduction and with the rest of the program we're adding an early setting that, for some Stage III patients actually, testing is done in some selected centers because are part of specific programs. More air is in -- for patients in Stage I and II. So -- and then, of course, Dave already provided additional information.

Cristian, the other question that Mark had asked was around the Imfinzi adjuvant studies and whether or not -- and how we saw BR.31 stacking up relative to the other studies from a design perspective? Mark, is that a good articulation of your question?

Yes. Thanks, Dave. Thank you. It's just...

Sorry, Mark. I had one moment of breakout with Internet.

It happens. So it's basically like looking at your adjuvant designs for lung cancer through tendencies, so for example, BR.31. So how are your trial designs compared to others as we enter this sort of period of 24 months when we're going to start to see data for IO in the adjuvant setting, potentially as early as Q4 this year? So any important things we should think about in terms of how your trials are designed versus some of your competitors?

I think our trial is quite aligned with most of the other trials. Our trials, as you know, is conducted in collaboration with the BCG Group. And the time lines are quite stable, COVID permitting, of course, COVID-19 permitting because this can carry some level of risk for this specific study that, together with the group, we're trying to quantify. The studies are fully enrolled. So we are data maturing, and I think we are ready for the first interim analysis that should happen soon. We believe the study is highly competitive vis-à-vis study design and the questions that the study is supposed to answer in the specific setting.

Thanks, Mark. We don't have any more raised hands. At this stage, we don't have any more questions coming in. So I'll ask my own question and leave those coming through. So and I think a key message from the presentation today is a refreshed focus or refreshed energy and enthusiasm around immuno-oncology and AstraZeneca's presence and program in immuno-oncology. And Cristian, you talked about [ claiming ] in Study 22. You've obviously talked just now about BR.31. What's driving this refreshed enthusiasm, this refreshed focus? Do you think the market fully understands AstraZeneca's opportunity in immuno-oncology post-MYSTIC? I guess that's a question both to Dave and to Cristian.

So David, do you want me to start on this?

Yes, please.

Yes. I think, Craig, our proposition in immunotherapy space is cure more patients. Independently of the indication, we are developing our trials. I believe that what I mentioned in terms of number of clinical trials that we are running in the early space, it is the fact on the commitment that we have with our vision. Dave mentioned briefly the MERMAID study -- MERMAID-1 study that we launched. I think this is another example of how our vision wants to be executed. So we have a personalized cancer monitoring to detect minimum residual disease, MRD, in patient completely resected with Stage II and III non-small cell lung cancer, and then we want to use this MRD concept to predict their lapse and customize the treatment in a smartest way to be able to go beyond the usual lines, swimming lines -- lanes. So we want -- so this is just another example how we think immunotherapy can really make even more difference at what we have seen today. This is the -- our way to see the development, not only Imfinzi but all our next portfolio coming in immunotherapy. And this is beyond immunotherapy. Today, we don't speak anymore about immunotherapy asset, and now we speak about therapeutic approaches with the backbone of immunotherapy agents. I hope this answered partially your question, Craig?

Yes. And I think, Cristian, just to build on the comments that you have made, I think that the enthusiasm comes, as Cristian highlighted, from knowing that we've made a number of important investments into expanding the early disease presence that we have in lung cancer but also into other areas, bladder cancer, liver cancer, small cell lung cancer. All of these are areas where we've looked to expand our early presence. And I think that also, as Cristian highlights Study 22, I think, very importantly, also introduces important data around single high-dose tremelimumab. And I think that, that is about a broader IO program and begins to also revitalize not only the durvalumab-Imfinzi-PD-L1 discussion but also CTLA-4, which obviously is something that's been an important area of investment for us and look forward to seeing the HIMALAYA results.

So we got about one minute left. So the last question of the day goes back to Mark Purcell of Morgan Stanley.

So the question is, well, 2 very, very quick ones. So could you help us understand how important the ORCHARD and SAVANNAH trials are when it comes to the Tagrisso franchise? When would you get data and the potential benefit they could show in terms of prolonging therapy? And then secondly, we haven't heard much about your PD-1/CTLA-4 bispecific. So when should we get more data on that -- on that compound? How enthusiastic are you about that, given your comment today, Dave, on the Study 22?

So why don't, Cristian, I take the first question from Mark on ORCHARD and SAVANNAH, and then you can pick up on bispecific. There are 2 main thrusts of our strategy. We've talked a lot about early-stage disease being one. I think the second that we haven't talked as much about today, but your question raises -- is dealing with resistance and disease that emerges over time as these are also really underserved populations with high unmet need. I think that what's important about ORCHARD is that it looks for ways that we can either potentially address acquired resistance or just existing underlying resistance that might exist to Tagrisso. So as a targeted therapy, I think it gives an opportunity not only to have potentially options to extend also Tagrisso's use into multiple lines of therapy, which is obviously a question that we'll begin to see -- asking the question, for example, do we begin to see potential benefits of adding new combinations on to Tagrisso, even in patients who have had progression post-Tagrisso. I think that'll be an important question that will be asked. But also, we know that there are patients that will still continue to be treated in the Stage IV setting and diagnosed in the Stage IV setting. Today, 60% of lung cancer patients are diagnosed Stage IV, and so I think any and all efforts that we can make to get more responders for a longer period of time is an important thing for patients, and it's an important value driver for the company. And also, again, keeping in mind that the loss of exclusivity is after 2030 on this medicine. So we are still very much in a life cycle maximization stage. Cristian on the bispecific?

Yes. This time, Mark, I heard the question, loud and clear. So the -- I mean, at this meeting, this ASCO meeting was very important for CTLA-4 inhibition in my view, not only for our data also from some additional works that have been presented with a combination of CTLA-4 inhibitors and checkpoint inhibitors. So one of the major issues with the CTLA-4 inhibition was related to toxicity. So we believe that, first of all, our Study 22 showed a different way, a different concept, a novel concept of CTLA-4 inhibition. But we also believe that our CTLA-4/PD-1 bispecific can represent a value alternative of what currently is available and a more convenient approach because, hopefully, will be combinable also with other partners. So [indiscernible] study show a marker, we have a very aggressive and accelerated development plan with this asset. This asset is still in an early development group and running through several studies, Phase I, Phase II studies. We established the single-agent recommended dose, but the drug is tested and is proceeding quite nicely across different indications.

Okay. Thanks, Cristian. Thanks, Dave. So we've now come to the end of this session. Thanks for your time. Thanks for your interest in AstraZeneca, as always. You will receive a feedback request following the end of this session. Please take 30 seconds to comment to see how we can improve from here. That will be much appreciated. And all that remains for me to say is have a great rest of the day. And please disconnect now. Thank you.

Hello. Welcome, ladies and gentlemen, to AstraZeneca's Capital Markets Event from ASCO 2020. I'm Tom Waldron from the AstraZeneca IR team and your moderator for today. I'd like to welcome you to Virtual Breakout 2 for Enhertu and breast cancer, with the opportunity to meet the members -- with members of our company's senior oncology team. Today, I'm joined by José Baselga, who held -- who leads our oncology research and development; Mika Sovak, who is our global franchise head for Enhertu and heads up Enhertu and breast cancer; and Jon Wildin, our global product leader for Enhertu life cycle management. This session will last 30 minutes. There will be a short 5-slide presentation with the majority of the time reserved for Q&A. The presentation materials are available at astrazeneca.com/investors, and we've also sent to the people on our distribution list. Before I hand over to today's panelists, I'd like to remind you that this meeting is being recorded. By continuing to participate, you are consenting to be recorded. If you don't wish to be recorded, please disconnect now. This event is also strictly for invited sell-side analysts and institutional investors of AstraZeneca. Therefore, if you're a journalist, consultant or an employee of another pharmaceutical company, please disconnect now. [Operator Instructions] After the event, recordings will be available from each breakout session. So please turn to the next slide. Now I have to remind you the usual safe harbor statement and forward-looking statements disclaimer that you see here. And with that, I'll now hand you over to our first panelist. Please go ahead, José.

Thank you very much, Tom. It is a pleasure to be here with all of you, although virtually. I'd like to give you an update on Enhertu. I'd like to just start with some data on our launch. The launch has been strong despite the COVID-19 challenges. We have here on the left some of the data. We are dealing with a 30% share of patients in the third-line setting with over 1,000 patients being treated to date. It has -- Enhertu has strong awareness, 45% unaided brand awareness among health-care practitioners. And we are expecting Japan approval in March 2020. At the same time, before we go into the data that has been at ASCO this year, I'd like to give you an update on ILD. We are continuing to make progress on delivering a lot of efforts in improving and decreasing ILD. We're happy to say that we have implemented now methods to monitor and to use innovative digital technologies to allow for early intervention. And also, we have an extensive program for education and awareness around management guidelines. And we will prevent -- we'll present, in due time, update on the -- introduction in the overall risk and severity for ILD in patients receiving Enhertu. We go to the next slide, please. So we are going at pace in the development of Enhertu. When we announced our collaboration with Daiichi Sankyo, our very strong partnership, we announced that we believed that this drug was not going to be only a breast cancer HER2+ agent, but rather that it would be a drug that would have capacity to transform the landscape on the HER2-low breast cancer, but also that it would allow us to look beyond breast cancer. And this is why this ASCO meeting has been so special because it is the time that we are presenting to the community what is underlying our belief that this drug is transformational beyond breast cancer. Next slide, please. So the first dataset is with gastric cancer. This is the data that was presented on our randomized Phase II study in gastric cancer. The paper, the study has also been published at the same time, as you know, in the New England Journal of Medicine. What we saw here, and I think the waterfall plot speaks by itself very clearly, an unprecedented level of clinical activity in patients in third-line HER2+ gastric cancer. If you could pay attention just for a second to the proportion of patients that achieve a complete remission. This is totally unprecedented in this patient group. And if you look at the complete clinical benefit or the disease or control rate, this is north of 85%, very -- very high clinical benefit. And then this is complemented with positive overall survival, as you can see, in the Kaplan-Meier curve on the right, showing a hazard ratio of 0.59 with a median overall survival with Enhertu of 12.5 months, again, in a third-line advanced gastric patient population. We have achieved a break-through designation and orphan drug designation in the U.S. in May. And also, we have a global regulatory submissions plan underway. Next slide, please. Now in addition to the data in gastric cancer, we have presented data on HER2+ mutant -- let me rephrase, on HER2 mutant-positive lung cancer. And this is the Kaplan-Meier curve on the left. Please notice that not a single patient had a progression of disease. As best response, the activity is seen uniformly along this dataset with a 62% objective response rate and a median PFS of 14.0. We think that this data is also going to be practice changing in patients with HER2 mutant lung cancer. And then to the right, you have the data in patients with colorectal cancer. These are patients with advanced HER2+ colorectal cancer, had received an extensive number of prior lines of therapy, including a number of them that had received prior HER2 therapies. And what we have reported is a 45.3% objective response and a median PFS of 6.9 months, also quite remarkable. Next slide, please. Now we had mentioned that we had full intention to go back into breast cancer, an area of long tradition at AstraZeneca for many, many years and you are well aware not only of our Enhertu data that applies to breast cancer and to our capivasertib program. We just enjoyed last year at ASCO some of the critical data that was presented in FAKTION. But this year, for the first time, we are presenting the clinical activity of our oral SERD AZD9833 on the shoulders of the clinical presentation at ACR just a few weeks ago. What we have seen here is that this agent in patients that had received multiple lines of prior therapy, including a large number of patients having received prior CDK4 and prior fulvestrant therapy. What we have seen is encouraging clinical activity at multiple dose levels and a dose-dependent safety profile. We have seen the class effect of bradycardia that seems to be a hallmark of these consultations. But the number of patients that had interruption due to bradycardia or to other side effects is quite low. So we're very pleased that we have been able to report that we have a 16% response rate in this patient population and a clinical benefit rate of 42%. And based on this data, we are going to be launching a number of Phase III clinical trials in ER+ breast cancer. Next slide, please. And with this, this is the end of my talk. And I guess, we are now going to go into the questions-and-answers session.

Yes, that's right. Thank you, José. [Operator Instructions]. Perhaps we'll go to the first question on the call, which comes from James Gordon.

Can you hear me, okay?

Yes, we can hear.

Thanks for taking my question. It was about Enhertu and the regulatory part in the U.S. So I heard about global filings for gastric, which makes sense. But the discussion, I think it was what came out on Friday afternoon, was noting that the study -- the patients in the study were all Asian, Japanese and South Korean. Is there any risk that, in the U.S. that they want some data which is in Caucasian people? Is that a discussion that's already had? I know there's another study that's still coming. It's got Caucasian enrollment. And also just on the regulatory, the other bit was just the lung study. It wasn't quite clear what you think you might be able to find in lung? Is there a chance you can? Or is that definitely, it's just going to be hypothesis generating and you need to get a controlled study? So I know you do have break-through therapy there.

So thank you very much. I would like to have -- ask Jon Wildin if he could answer the 2 questions regarding the regulatory path, both for the gastric and for the lung cancer studies.

Yes, of course. Thank you for the question, James. I'll be taking them in reverse order. So for launch, I just want to remind everybody that, obviously, we already have the break-through status. And therefore, you obviously know we've been in dialogue with agency over that. A little bit more work to do. For gastric, as you heard from the presentation, we'll be looking at global filings. And again, just to remind everybody, we did get break-through and also orphan drug status for gastric, again, announced quite recently. You are correct. There is another study that is ongoing. It's DESTINY-Gastric02, which is in a European and U.S. population base. The objective is to replicate responses that we've seen in the data that's been presented at ASCO this time around. We're not sure whether or not the agency would request that, but obviously, it's useful to have that study running. And if they do, we can provide that data.

Right. So our next question comes from Tim Anderson.

When you first entered into the collaboration, you laid out the -- what I think is one of the most ambitious development programs ever with a new entrant into a category where there's lots of therapies. You showed -- I don't know if it's the exact-same slide, but a similar slide today, talking about ultimately displacing things like PERJETA from front line, working your way all the way up to adjuvant and neoadjuvant. A gating factor to that early advance into earlier tumor types or earlier settings is IPF, which is a consistent signal that we see. And I'm wondering now that you have more data in hand, realistically, is the -- are your aspirations the same? So are you just as confident now that you can push into things like adjuvant? Because it seems like with breast cancer adjuvant, we're talking about women that, at baseline, are very healthy. They have single-tumor burden and to potentially expose them to permanent IPF is just a nonstarter. So I think that IPF is something that, from a risk-benefit standpoint, is very acceptable in later lines, but in early lines, isn't really that realistic.

Sorry, IPF, you mean ILD?

Sorry, yes, ILD, interstitial lung.

Okay. Yes. So thank you for the question. I'll take that one, if I may. So our plans are totally on schedule. So basically, all what we had agreed to do, we are moving at speed. So I don't foresee any delays in the initiation of the studies based on the clinical development plan that we had. We all, all along, have been aware of the ILD situation. And all along, we have manifested that we are extremely confident that we will bring down the severity and the frequency of ILD. These ILD cases were seen, again, in the early part of the program when the magnitude of the problem was not well understood and when there was not awareness nor a management plan nor an early diagnostic plan. What Daiichi Sankyo and AstraZeneca have done together is to put together this management team of ILD, and we are already -- have implemented not only the awareness campaign but also the management plan and the guidelines. And we are going to be monitoring and reporting on the outcome of the ILD in the next set of studies. I think suffice it to say is that, in the market where there already has been this awareness made extensive to everybody, we are seeing, to-date, very little ILD. So I think it's an early indication that these ILD numbers will come down.

Okay. So our next question comes from somebody on the phones with the number ending in 304. If you'd like to announce yourself and your company when you -- when I unmute you, now please?

I think this is going to be me, Jo Walton, from Credit Suisse. My question is about the SERD and the emergence of visual disturbance. We're curious to understand if you think it's of a concern. It's the only SERD data that we saw at ASCO. With this, how much of a burden would it be? Would it, for example, stop patients driving?

So thank you very much. I'll take that myself unless, Mika, would you like to take this? Or would you want me to take it?

Go ahead, José.

So this -- what was happening here is that the toxicity criteria for visual disturbances is not well defined in the classical scales that we are using. In no cases we have seen any anatomic damage to any of the patients. We have done extensive ophthalmological analysis. It's a very short-lived minimal visual disturbance that occurs when there's change in the light conditions. So for example, these patients explained that this occurs sometimes early in the morning when they wake up or sometimes at night. So there's one -- it lasts for a very short period of time. It does not interfere with any of their physical activity. So for example, a critical question that you asked, is that -- it does not interfere with driving at all. It goes away, from what we know, and it's still early days. It goes away after the first cycle, so there is a tachyphylaxis to that. And if you look at the old ER therapy geography, visual disturbances is a class effect of ER interception. So to us, it's a sign that we're hitting ER. Again, we are working quite intensively to try to find a way how to define these toxicities because the scale that we're using is not helping us. And I think, again, the last one I'd like to make is that patients are not being discontinued because of this disturbance is very minimal.

And our next question comes from Mark Purcell.

Tom, can you hear me.

Yes, I can hear you now.

Quick question. In terms of the plans that Daiichi have outlined in the slides at ASCO, obviously, a large number of trials, but can you help us understand your latest thoughts in terms of doing a tumor-agnostic study? And what could be required from the regulators as such in terms of achieving a pan-tumor opportunity. There are 2 studies noted that are Phase II studies with that objective. And when you sort of think about the responses you're seeing. With the TROP2, we saw some late responses. I just wondered if you saw some late responses also with Enhertu as you explore different tumor types, including lung and what bearing that has in terms of this sort of pan-tumor approach you may take?

So just 2 questions here. One is which is our pan-tumor approach to get approval on our indications and then the issue of the late responders. Jon, would you like to take this because this is mostly non-breast cancer? Jon?

Sorry. José, can you hear me right?

Yes, perfect.

Yes, I heard your question, Mark. So yes, in terms of the presentation that you saw from Daiichi, the approach is twofold. We're looking at both patients with mutation -- HER2 mutations, similar to the lung cancer data that you've seen and also looking at expression. The short answer is it is an unusual regulatory path. But obviously, it's something that we need to pursue. We need to pursue it because, ultimately, there are patients not in gastric, not in breast, not in other tumor sets where HER2 is classically used as treatment today, but there are HER2 expresses in multiple other tumor sets. And ultimately, we need to generate that data. So as regards to regulatory question, it's hard to comment in detail, but it's certainly an area that we're following up.

And in terms of the late respondents?

José, do you want to comment on the late responder data from your perspective?

No, no. Why don't you go ahead because, I mean, I don't have a particular view. I mean, the -- go ahead, Jon, because I don't have a particular view on this.

So in the -- in all the data that's been presented over the past few days at ASCO across the tumor sets, it depends on how you're defining late to some extent, Mark. What we have seen is that the majority of the patients, particularly in the HER2 mutant population, the response is very rapid and very deep. There are, in a population, always those patients where it just takes a little bit longer. But I wouldn't say it was a characteristic of the pharmacology that we've seen so far.

And I think our next question comes from Andrew Baum, Andrew?

Can you hear me?

Yes, we can hear you.

Great. José, could you talk to the assay and the criteria you're using for low HER2 in the ongoing Phase III trial. Are they identical to the criteria and the assay that you used in the Phase II? And then since we have you, PALLAS failed on Friday. I know from our previous conversations that, that would have been a surprise to you. I appreciate the data is not out there. But in the spirit of thinking through learnings of trial design or perhaps the dangers of cytostatics in the adjuvant setting, I'd just be curious if you want to contribute anything on the reasons perhaps why this may have failed and how similar issues might be avoided in your own trials.

Sure. Andrew, and I'm glad that you're in this session but you're not on the TDR session. Thank you for that. Although, I suspect you'll go next. So the HER2 current testing method in the Phase III studies in the low HER2 and what we are doing in the future, I'd like Mika, if she could answer this, and then I'll come back with my views on PALLAS, if I could. Mika?

Happy to answer that. So thanks, Andrew. I think the question was around, are we using the same way of identifying the patients in the HER2 low space between the Phase II and the Phase III. The answer is yes. I think we are really excited about our program in the HER2 low space and really trying to define this new treatment paradigm. I think we also appreciate the fact that the currently available diagnostics for HER2, even in breast cancer that are currently used, there is room for improvement. So we are -- have an active program, trying to figure out ways, the innovative ways using potential of digital technology, where we can really help optimize the assay. And so this is something that we are continuing to increase our understanding of to make sure that we really are identifying the optimal patients. José, back to you for PALLAS.

So PALLAS, I'm still digesting this, Andrew. It's a big surprise to have a class of agents such as CDK4/6 that are so incredibly active in the first-line setting and then they failed in the adjuvant setting. So I don't know exactly, and we need to look at the data to get an insight. But one thing it does, it disrupts in full the whole strategy in early breast cancer. I think an obvious explanation is that it is wanted to Phase II compliance. All the insights that we have received from multiple investigators, and again, all this is soft intelligence, and there was also some neoadjuvant studies that were presented here at ASCO with other CDK4/6 inhibitors support the notion that it is really hard to keep these patients in the adjuvant setting with the CDK4/6 inhibitor, and hence, there are major compliance issues. So that's point number one. Point number two that could be at play here is that, unlike triple-negative breast cancer, ER+ disease, the [ bluff ] rate is continuous over many, many years. So it's a different proposition that in a triple negative, the [ bluff ] rate is low. So it could well be that the number of events at 2 years is too limited to see benefit. And yet, there is no carryover effect after 2 years with palbo. So they are not preventing these occurrences that occur after 2 years. So I think it's a combination of both, but we really need to look at the data as soon as we can. And I am -- I was surprised to see this. And it's going to change very much the way we think about early ER+ breast cancer.

So we do have a few questions in the question-and-answer session. I think we've got time to answer those. So a question from [ Steve Hamill ]. Can you discuss the HER2 low data presented for Enhertu? Are you concerned that this is a negative signal for Enhertu in HER2 low cancers, particularly breast?

Is the data on colorectal?

No, sorry.

I think it's potentially asking if it's -- the colorectal data has any implications on breast, perhaps.

Yes. Yes. Yes. I can take that. I don't think you can make any -- truly any correlation. That's why you do the studies -- the different studies. We have robust data in low-expression HER2. And the biology of colorectal is very different than the biology of HER2+ disease. So as a matter of fact, we have far more data on low HER2 breast cancer than in any other disease type. So this does not affect at all our beliefs in HER2+ low breast cancer.

Okay. Thank you, José. And another question on the -- in the Q&A dialogue box. Can you elaborate by what you mean by global regulatory submissions underway for gastric on Slide 5? Are you filing globally on DESTINY-Gastric01?

I think Jon partially had addressed this question in the past, but maybe you want to give us a refreshment?

Yes. So -- obviously with data this good, with conversations that we're having with agency and, yes, we will be approaching on a global basis. But as one of the previous questions indicated, it's important to recognize that, that dataset is a Japan-Korea dataset, 80% of the patients from Japan, 20% from Korea. We are, as you know, running a separate study, DESTINY-Gastric02, to support that in the Western population in Europe and the U.S. But there clearly is some risk there. But yes, that's the plan.

Okay. And just finally, we did talk about AZD9833, the oral SERD, a moment ago, and some of the tolerability questions that Andrew had, but is there anything else we can say in answer to [ Danny ] with a broader question on tolerability, toxicity profile of the drug?

No. I think that what you have noticed is that we have to define the final dose -- yet. As you have seen here, we have used multiple dose levels. And I think it's fair to say that, when you look at the level of activity that we see, it's quite consistent across multiple dose levels. And the only dose response that we see, if you wish, is in toxicity. So I think that this is the goal of this study is to show which is the best dose to go forward. And I think that we are confident that we have a dose range that we are going to be able to develop -- as a matter of fact, we're doing the study right now -- it's called SERENA-2, in which we will pick the dose that has the better tolerability and, at the same time, clinical activity. We are not concerned. We don't see any side effect here that would limit in any way, form or a shape the development of this drug, and we think we have a real chance to make this drug as best-in-class.

Okay. Thank you, José. We'll take question from Michael Leuchten.

So the question is for José on biomarkers. There was data presented at ASCO on the KATHERINE data looking at biomarkers and splitting the groups that way. And it didn't really show much difference on how T-DM1 performed in that study. So as we were thinking about how Enhertu could move into the earlier breast cancer setting, how do you read that biomarker data? Do you need biomarker to go into the earlier setting? Are you thinking head-to-head trials? What do you take from that data?

Well, the only biomarker that we are seeing here is the expression of HER2. And by the way, we have a very extensive biomarker group, and we are working at all the variables. Many of the biomarkers that have been used in the past, for example -- and I led some of these studies, for example, PI3-kinase mutations, as an indication of resistance to Herceptin and Pertuzumab with very clear data that these patients benefit the least. I don't think it -- they would apply to Enhertu. Just because, basically, the key mechanism of action in Enhertu is not to block the signaling pathway of HER2. In this case, PI3 kinase could play a role -- PI3-kinase mutations could play a role in resistance. But rather, this is an incredibly important chemotherapy payload. So we do believe that, if the drug becomes internalized, it will have an effect irrespective of the additional mutations that may be inside that particular tumor.

Thank you. Perhaps we'll take our next question from the Q&A dialogue box from Sam Fazeli. Could you please explain why you think Enhertu didn't work in HER2 low patients in gastric? Do you see potential for the adjuvant setting in gastric cancer despite the side effect profile?

Thank you. So I'm going to handle this over to Jon to comment.

And so for clarity, the data that was presented at the meeting at ASCO, we still got to do a little bit more work to present the specifics of the HER2 low cohorts. Dr. Siena did present it for the colorectal, and he made a comment that we haven't seen much activity. But I think fundamentally, they're very, very different tumor sets, and you can't read from one to the other, and it's very important. There's no doubt that there's strong interest within the organization and across the alliance to make sure that we fully explore the potential, particularly to help these patients where HER2 expression is perhaps below the traditional level. But it's early days, and I think we should be careful not to read too much into that.

Any comments on the question on adjuvant was for colon cancer or was for breast cancer?

I think it was for gastric -- adjuvant setting in gastric cancer.

You want to comment on that, Jon?

Yes. It's interesting. We've been having -- obviously, on the basis of the data that we saw a few months ago and now have been presented at ASCO and, again, to remind everyone, NEJM published a few days ago, inevitably, we started to look at this. But absolutely, we need to consider all the front-line options just as it's being considered for breast cancer. So it will be there, yes.

Our next question will come from the live call, which comes from Simon Baker.

It's kind of related to Sam's question on gastric is just then in the totality of what you presented, in terms of the response differences between IHC3+ and 2+. I was just wondering if that has any relevance to your thinking about HER2 low breast? Is it relevant? Has it changed your views on the potential there? Just wondering if you could give us some thoughts.

So I'd like Jon to comment on the gastric data, and then I'll give you my views on the HER2 low breast, if I may. So Jon, why don't you start and then I'll go on.

Yes. So as we've said, it's early days, but I'm straying into your space now, José, but I just don't think you can do a strong read across from one tumor type to the other. They're potentially very, very different. And also, as we've mentioned before, there's a significant dataset already available in HER2 low breast. We just don't have that yet in any of the other tumor sets. So from my perspective, it's early days, and we just need to continue to explore that.

Yes. Just to continue on that. Where we have -- the base dataset actually is in HER2 low breast cancer. So the dataset stays on its own, and it's very, very -- it's robust. It's there. So we are moving ahead with HER2. I think it's going to be very difficult to, as we have learned, to cross-study -- cross-disease comparisons on HER2 expression. We have learned that they are very different diseases. So we need to go disease by disease on this one.

Okay. We'll move on to the next question from [ Carl Brown ]. [ Carl ], if you'd like to unmute yourself, you'll be able to ask your question. Okay. [ Carl ], you can now ask your question. I'm sorry, about that.

Okay. Can you hear me now?

You can -- we can.

Okay. Great. I was curious, a competitive agent tucatinib spends a lot of time talking about the data that they presented in third-line breast in patients with CNS metastases. I believe in the Enhertu trial, there were patients that did have CNS metastases. And overall, the data was quite robust. Will there be more studies specifically looking at these patient populations so that you can more specifically address this question and the agents can be compared against each other? Or do you think the data you have in hand today is enough to get the message across in terms of how effective you see Enhertu is versus tucatinib?

And that's a great -- that's a great 2 set of questions. And it is indeed, we had patients with brain metastases in our DESTINY study. So I would like to hand over to Mika to respond to 2 questions. Mika, if you could.

Yes. Absolutely. So I think it's -- we've definitely been looking at HER2CLIMB data. I think any data for patients in HER2 disease, they definitely show benefit in patients who have brain mets that don't need any immediate therapy, right? And I think that, that is actually really critical to understand. When we -- you're right that we did just -- was it 10 days ago at ESMO breast present our brain metastases data that we have from the Phase II study, in which we demonstrate a median progression-free survival of patients who had stable brain metastases of 18 months. And I think if you put that in the context of what HER2CLIMB saw, obviously, a randomized study, but PFS of the same number in their patients. And I think it's important when a physician is considering the best treatment for their patient, they have to consider many factors, brain mets is definitely one of them, can often be treated with local therapy. But burden of disease, visceral disease is also, I think, a really critical factor. So when we look at our data, we're definitely interested in further investigating activity in brain mets. I will also commend tucatinib. I think they've actually gone into a disease area where patients have normally been excluded. So I do think that that's a very valuable that they've done that. We're looking forward also to the additional Enhertu data that we'll be able to see in patients to frame that.

So for our next question, we'll go to the Q&A box. Luisa Hector asked a question, which is how is Enhertu ILD awareness campaign progressing, the ILD event rate/severity varied across gastric, lung, colorectal. Why? Timing of awareness, tumor type, lung doctors detecting more efficiently. How is the ILD experience in the real-life setting as breast cancer launch proceeds?

So Luisa, I think this is the highest density of questions per unit of time I've seen in a long time. But Mika will answer them.

Yes. So in terms of the -- as we have just launched Enhertu, the amount of data that we are getting across the board is increasing every day. We've had a significant increase, obviously, in the numbers. The total number of patients that have been treated since approval in the U.S. have almost doubled what we saw. So we are starting to get more information. And all the early data really is very promising. But the key really is around education and awareness. And that -- this is what is really important in the management of ILD. I think we also presented additional data at ASCO. It's across all different tumor types, where the rates are consistent or lower than what we've seen in the breast cancer setting. So again, around the education awareness, we're very -- we have a lot of confidence that that's really the key to management.

I think you want me to have, Luisa, it may take a few -- I mean, the reason why we present the data, but it's taken a -- it will take some time for us to gather this data just because we need to provide enough follow-up time after patients have been -- implemented these changes. So it's not that you -- if you want to present data in a way that is fully interpretable, it requires to have enough follow-up. So that's what we're working on. And what we're doing is that we are looking at the outcome of these patients once we implemented the awareness and the margin guidelines. And that's what will be upcoming. And when we're ready, we're going be able to present.

Actually, I see Luisa also raised her hand for the live Q&A. So if I can go over to her to just ask if there's any follow-ups she'd like to ask.

Sorry, no. That's absolutely fine. Thank you.

And so our next question comes from Seamus Fernandez. Seamus?

My question -- just 2 things. José, can you talk a little bit about how the strategy might evolve in breast cancer in the wake of the failed PALLAS study? Any thoughts on the CDK4/6 market and kind of the ER+ patient population. I know you've got a few shots on goal there, especially as we think about the Oral SERD. And then just a quick question. Enhertu looks extremely impressive in the CPI refractory patient population, but we saw a slightly higher rate at ILD. Can you just help us understand, is it possible, in your mind, to combine the 2 in the lung cancer setting? And then just as a very quick one, wanted to just understand if there are accelerated regulatory pathways for Enhertu in all 3 of these settings. It would seem like there certainly is.

Yes, I'm sorry, I missed the question on the combination in lung cancer, what combination?

Yes, the ability to combine a PD-1, a CPI...

Okay, fantastic, fantastic.

And some of the higher rates of ILD...

Yes. Yes. Got it. Got it. I got it. So the PALLAS study in CDK4/6, it's -- we need to digest the data, and we need to see what went on. It's surprise to everybody, myself included, on how such an active therapy combination in the first-line setting [indiscernible] setting is showing this data in the early disease. I think the very obvious thing to look at would be the compliance of patients with early disease to CDK4/6 inhibitors. As you know, these therapies have side effects. We have seen in some of the early neoadjuvant studies, some of them at ASCO, showing that compliance is an issue in patients with early disease. So we need to look at the compliance. That's point number one. And then point number two, ER+ disease in adjuvant setting, recurrence rate occurs over multiple years. So it's a constant decrease in -- the events occur over multiple years, is very different to triple-negative breast cancer. And hence, it could well be that 2 years of therapy with the CDK4/6 inhibitor is not enough. Having said that, I think that it's going to be a whole new world when it comes to early ER-positive breast cancer. And as you can imagine, we are thinking very, very intensively on how to be a player there because I think we have an opportunity to help these patients further. In terms of the combination with PDX and HER2 in lung cancer, Daiichi Sankyo and ourselves, we are involved with a number of clinical studies. As we speak, we are fitting these patients, and we don't have yet -- it's too early for us to say. But this is a question that we feel it's critical, and we are enrolling patients in clinical trials on this front. And then finally, the question on the regulatory path for non-breast, I'd like to have Jon, if you could comment on it.

Yes, sure. So across the 3 datasets that you've seen today and over the weekend at ASCO, just to remind everybody that the HER2 mutant lung cancer populations already received breakthrough designation from FDA. So obviously, there's a lot of interest there. And similarly, the gastric data, which, as you saw from José's presentation, is going to be submitted globally, that's also received break-through and an orphan drug designation from FDA. The colorectal data is still some work in progress from a regulatory perspective, but you can clearly see across the program, there's a lot of interest from the authorities to continue to drive that. And José, if I may build on your point, there are 4 studies currently running with -- sorry, 3 studies currently running, 1 of that start in combination with the different PDX checkpoints.

And if we go now to Emmanuel Papadakis. And Emmanuel, if you'd like to unmute yourself when you're ready to ask your question.

So perhaps I could take a question on the theme of adjuvants follow-up, I guess. You've initiated many studies, included neoadjuvant now. And I know, José talked in the past about being optimistic for a place for Enhertu in the adjuvant setting yet to initiate that study. I think Daiichi described it on the weekend as under consideration. So perhaps you just give us your latest thoughts there.

We're not ready yet to share what are we going to do because it's still in the middle of discussion, Emmanuel. So as you can imagine, there are multiple considerations to be taken. Now by the way, the PALLAS data is not affecting Enhertu at all because it's a complete different disease, right? So it's a complete different disease, and we're talking about HER2-positive disease. Now there are many, many questions. As you know, I was one of the principal investigators of the CLEOPATRA study, which is the Herceptin-Pertuzumab study. So I think there are 2 -- I think 2 possibilities, if you wish, where Enhertu could help these patients, for sure. One would be to identify patients at high risk, patients that are in real need to receive therapies. But the other one that we need to take into consideration is the possibility of deescalating therapy for breast cancer. I mean, these patients that are receiving best of standard of care HER2 therapy, many of them are doing this at the expense of toxic systemic chemotherapy, such as AC and taxanes. So maybe there's an opportunity to explore the escalation effect. And this is something that we're still discussing. And I'm not yet ready to share what are we going to be doing at the end.

So there are no more questions polled. If anyone would like to ask another question, we do have a couple of minutes left. So please raise your hand. Emmanuel, would you like to carry on?

I'm struggling somewhat to understand the clinical development strategy. You've got a -- the only Phase III ongoing is in combination gene therapy in triple-negative breast. It seems very likely within a short space of time standard of care in that setting will be checkpoint inhibition with potentially an AKT, per your former partners in Switzerland. And you've not yet initiated any earlier studies, for example, in combination CDK4/6 and HR+ breast. So just your thoughts in terms of where the clinical development for SERD goes from here because the action data seemed to us, certainly, very good.

Yes, right. So we're going to be starting Phase III studies precisely on the FAKTION clinical trial -- at the backs of the FAKTION trial design. So we're going to be launching studies in ER+ disease. As you can imagine, we are contemplating the possibility of exploring combination with the checkpoint blockade in triple-negative breast cancer. We're going to have also a strategy in patients that are receiving CDK4/6 inhibitors. So it's not just restricted to the triple negative, but rather, we're going to have a number of studies in ER+ disease on the shoulders of the FAKTION data. In addition, I'm sorry, to the prostate cancer programs as well.

And are we likely to see that going to Phase III?

Yes.

And then we do have a couple more questions in the written Q&A dialogue. One, a follow-up on -- perhaps on ILD. I think we covered this mostly last time -- in the last answer, but Steve Scala was asking when serious adverse events occurred with Enhertu relative to the institution of AZ prescribing procedures. Is there anything further we can say on that?

We've not had the data yet. Mika?

No. So I'm not complete -- if the question is around the impact of recent guidelines, I think you're right, José, we still -- they've been implemented, but, because it does take several months before we see the event and the number of patients, we don't have any updated information as of the yet, but we do continue to follow.

Thank you, Mika. So -- and I think the last question for this afternoon's session will be from [ Trung Han, ] who has asked in the Q&A chat on the Phase III SERD program, you mentioned multiple Phase III studies. What combos or approaches are you looking at?

Well, I would qualify multiple. We're going to have a number of Phase III studies. We're not yet in a position to announce them. We'll -- as soon as we are ready to do, we'll do so.

Okay. Thank you. I think that brings us to the end of this second breakout session. Details are available -- of the presentation and the event recordings will be available on astrazeneca.com/investors. You'll receive a request for feedback following this session, and we'd be very grateful if you'd take the opportunity to comment. And finally, I'd like to say thank you to our panelists, to José, to Mika to Jon, and to all of you for your interest in AstraZeneca. You may disconnect now.

Hello. Welcome, ladies and gentlemen, to AstraZeneca's capital markets event from ASCO 2020. I'm Nick Stone, your moderator today and a member of the AstraZeneca IR team. I'd like to welcome you to the Virtual Breakout 3 session for Lynparza and the opportunity to meet with members of the company's senior oncology team. Today, I'm joined by Susan Galbraith, Senior Vice President Early Oncology; and Greg Rossi, Vice President, Oncology and Global Franchise Head for IO, formerly Vice President Oncology and Global Franchise Head for DNA Damage Response. This session will last around 30 minutes. There'll be a short 5-minute presentation with the majority of time dedicated to Q&A. I hope you like the virtual setup and the potential to interact with Susan and Greg. The presentation materials are available on astrazeneca.com/investors, and we have also sent it out to the people on our distribution list. Before I hand you over to today's panelists, I'd like to remind you that this meeting is being recorded. By continuing to participate, you're consenting to being recorded. If you do not wish to be recorded, please disconnect now. In addition, this event is strictly for invited sell-side analysts and institutional investors of AstraZeneca. Therefore, if you're a journalist, consultant or employee of another pharmaceutical company, please, can you disconnect now. [Operator Instructions] After the event, recordings will be available from each of the breakout sessions. This is the usual safe-harbor statement, and I will now turn the presentation over to Susan Galbraith. Please go ahead, Susan.

Thanks, Nick. And welcome, everybody. I appreciate your interest in Lynparza. So across this year, ASCO built upon the impressive datasets we've already delivered for Lynparza across 4 different tumor types now, breast, prostate, pancreatic and, of course, ovarian. I'm showing you some of the Kaplan-Meier curves this -- here. I think I'd just point out that Study 19 and the long-term follow-up actually showed a hazard ratio for OS of 0.62. In all of these settings, we're seeing impressive tails on the curves. And we're now extending with the PAOLA-1 data, of course, into the HRD+ group. At this ASCO, we've also solidified this dataset with now OS data for SOLO-2 but also multiple other trials have read out. Opinion is that in non-germline BRCA platinum-sensitive relapse in a maintenance setting and actually showed a median PFS overall of 9 months, including activity in somatic BRCA mutations as well as those with HRD-negative disease with a PFS of 7.3 months. And in the LIGHT study, which is actually a treatment setting in platinum-sensitive relapsed ovarian cancer with 1 or 2 prior chemo regimens looking at patients with gBRCA, somatic BRCA, HRD+ and negative, we saw impressive response rates in the BRCA group's 69% and 64%, respectively. And in HRD+ at 29%, but interestingly, also 10% response rate in HRD negative with a PFS of 5.4 months. So you can see across both of these trials that we do have activity across all the groups in ovarian cancer just most activity, of course, in the BRCA-mutant and HRD+ group. GY004 group study from the NRG presented by Joyce Liu looked at olaparib versus double platinum chemotherapy cediranib plus olaparib combination in the platinum-sensitive relapsed setting second-line and third-line patients. And although the overall study wasn't positive, actually, there was a really good response rate, both in the overall group and particularly in the germline BRCA group, olaparib and olaparib plus cediranib. Both have response rates of about 90%. And then improvement trend in PFS at 12.7 in the olaparib group months versus 10.5 in the chemo group and 18 months in the olaparib plus cediranib arm. So I think you would agree that the totality of these data just show the impressive activity that we have with olaparib in ovarian cancer. Can you go to the next slide, please? So what this slide shows, first of all, is the updated PFS data. On the left-hand side, now at 63% maturity, again, reminder of a hazard ratio of 0.3 there, but also the tail on the curve being significant long-term improvements in the time to first and subsequent lines of therapy. And that's translating through now to a median OS, OS improvement estimate of around 12.9 months in the overall population. And when you account for the patients who crossed over onto a subsequent PARP inhibitor, actually, that increment is around 16 months with a hazard ratio of 0.56. And I think very importantly from a patient perspective, 28% of the patients at 5 years were alive and not had received subsequent therapy. This is really impressive from the patients' perspective. Next slide, please. So I just wanted to remind you briefly about the PAOLA-1 study and the design of that. This is in patients, those who have complete response, partial response or no evidence of disease following first-line chemotherapy. And so it's a real-world representation of patients with advanced ovarian cancer and not restricting a selection by surgical outcome or BRCA mutation status. For patients randomized 2:1 to Lynparza plus bevacizumab or placebo with bevacizumab for a 2-year duration, the primary endpoint being progression-free survival. And around half of those patients overall were HRD+ as you can see on the right-hand side. And what you can see from the Kaplan-Meier curves is that actually that half of patients that were HRD+ had more than 3 years of progression-free survival in that group, which is a really impressive number. Next slide. So what we've done with PAOLA-1 is we've done an analysis as we promised. And when we presented the PAOLA-1 data at the ESMO last year to take this population and do careful population-adjusted indirect treatment comparison with the PRIMA study because, of course, the PRIMA study excluded patients that were at the lower risk, those that have no evidence of disease. So if we do that with the PAOLA population and look at these hazard ratios and a couple of micos here, what you can see is that our [indiscernible], now again, you've got that 36-month impressive medium PFS. Niraparib alone has around a 22-month median PFS in a similar patient population. And placebo plus bevacizumab has around 17.6 months, which is the green line. And the placebo alone is 10.5 months. So the benefit overall in a very similar patient population compared to the PRIMA population is -- reinforces that, if you are eligible for bevacizumab treatment, this has been by far the most robust median PFS that you can hope for. And then on the right-hand side, we've also looked at the data in the HRD-negative group. And again, what you can see here is that there's little added benefit to olaparib to bevacizumab. Both have around a 15- to 16-month median PFS. That's the blue line and the green line that you can see on the right-hand side. Actually, placebo has around 5 months' median PFS and Niraparib 8.1. So when you adjust for the patient population, again, the benefit in the HRD negative is best for either one of the bevacizumab-containing regimens, either bevacizumab alone or the Lynparza plus bevacizumab. So again, if you are eligible for bevacizumab, this looks like the treatment that will give you the best region progression-free survival in this set. So now I'm going to hand over to Greg, who will talk a little bit about the commercial performance for Lynparza.

Thanks, Susan. And I think you can agree that, whilst the highlight from this year ASCO from an AstraZeneca point of view, in fact, largely from -- I think the entire community point of view was the ADAURA trial. There's important new data here for Lynparza. There have been questions around the relative comparisons, albeit indirect that Susan's just walked through. There have been questions around activity in non-BRCA-mutated patients. I think the data that we have here at this ASCO provide really some compelling data that we are the best PARP inhibitor from a clinical as well as, I think, a commercial point of view. What we can see here on this slide is the sales performance from quarter 1, so just under $400 million of quarter 1 sales, representing 69% growth over the relevant quarter from last year, round about half of that now coming from outside of the United States. And that's important because as we think about the growth drivers for this brand, there are a number. So first and foremost, I think it's really expanding access across the globe in ovarian cancer. We now have very broad access in the PSR setting. And you can see that on the right-hand side from the top line of the chart, we are expanding access very considerably with SOLO-1. It's clearly been approved in Europe, U.S., Japan, and now China. And we're starting to see, I think, reasonably rapid and good access for SOLO-1 because of the unprecedented value that it provides in that biomarker-directed population. And obviously with PAOLA-1, broadening that population by 2 to represent the HRD+ population and be able to still achieve a greater than 37 months median PFS is a very attractive proposition for patients, and we believe that markets will value that and provide access rapidly for that. We continue to drive our breast cancer indication, OlympiAD. That's now got approval in 3 of the major territories, and we're seeing access starting to pull through there. Pancreatic, you will have noted this morning that we have got a positive CHMP opinion around that. So we should see access for PAOLA in Europe before the summer is out. And for prostate, this one, I think, is really important. We saw in May, approval in the U.S. for the PROfound trial. You saw us provide a press release to say that we have overall survival data now, and that was including the U.S. label. And we hope that, that is going to also drive rapid decision-making in the rest of the world and access in the rest of the world, so we can bring this important medicine to a fourth tumor type of biomarker-directed therapies, the first one in prostate cancer. And I think that, in each of these cases, the health economic value, the benefit we're seeing that come through with the access that we're achieving, but I think, as we focus on the patients that really both have unmet need but also are most likely to benefit, we're seeing that, that value proposition is significantly attractive and -- both to patients, to physicians and to health systems. So we think that there's a lot of additional growth that's going to come out of these indications as we broaden the scope of our geographic reach. Go to the next slide. The -- it's not just these indications. You see here on the left-hand side, the overall survival data from PROfound that I spoke to. This is the first data with a PARP inhibitor demonstrate formally overall survival. I think you'll also agree that the SOLO-2 data from this ASCO is a very compelling survival benefit that was observed in that particular trial. And we think that this is really important for a couple of reasons, obviously, for the patients in these particular disease areas but also the validation of the PFS benefits we've got to be able to articulate that they are likely to result in ultimately an overall survival. In this case, this was with considerable crossover allowed after progression on trial. So we think that this is going to be important value. We see additional work that we're doing in prostate cancer. We hope to report the results of the PROpel trial in the next coming period where we're adding to abiraterone in a newly diagnosed metastatic prostate cancer setting. And that's an unselected population, so we'll be able to see whether or not the addition of abiraterone is sufficient, has a different biology to allow us to go beyond the biomarker-directed. But remember that about 1/4 of patients with prostate cancer have got this HRRm mutation phenotype. And it's, I think, very notable and impressive that we have the full HRRm mutation label in the U.S. for the PROfound trial. Another area to look out for is moving Lynparza into the adjuvant breast cancer setting. So the OlympiAD data were impressive. They were head to head versus active chemotherapy. We demonstrated significant benefit on PFS and on response rate in that particular setting. And we believe that, that augers well for our OlympiA trial, which should read out in the next period as well, and that would be a very important new additional indication for Lynparza. And lastly, we are now prosecuting a number of different combinations. One that I think is being highlighted previously is our durvalumab combination in ovarian cancer. We announced at ASCO another Phase III trial in progress in endometrial cancer -- in front-line endometrial cancer. And we continue to prosecute trials to understand where the combinations with our portfolio and this particular agent can derive clinical benefit and commercial value. So I'll stop there and hand back to Nick.

Thanks, Greg. So we'll now move to Q&A. [Operator Instructions] So as it presently stands, we do not have anybody polling for questions. So I will selfishly take the first opportunity. And maybe, Susan, Greg, we could just continue to expand upon the potential of PAOLA-1 opportunity in HRD because I think it's obviously a very compelling opportunity. I think you highlighted, obviously, within the slides the 50% opportunity. I think maybe if we could just think a little bit more about HRD and the opportunity for Astra and Lynparza specifically?

From my perspective, from a medical standpoint, I think it just changes the landscape completely. We've never had an option before that would have a 3-year time period between one treatment and the potential of the disease coming back. So I think it fundamentally changes the nature and actually even the -- to some degree, the definition of platinum-sensitive relapse is going to change because of the degree of activity that we've seen in HRD+. Greg, any comments from you?

Yes. I think there may be a couple of different thoughts I have on that, Nick. So firstly, I agree with Susan that a greater than 37-month median PFS is really important for patients to sort of get that offering. I think the combination therapy clearly has been demonstrated to be the most active in that particular segment. I think importantly, there's 2 aspects to it. I think importantly, we're seeing that plateauing of the curve, which I think we've seen in other settings. So whether we're talking about SOLO-2 or whether we're talking about SOLO-1, which had longer-term duration. So that's becoming a characteristic of these olaparib trials in ovarian cancer, which I think is very encouraging. The second is that the PFS surrogacy is now being validated, I think, in the PSR setting that, if you've got a large PFS effect as we have here, where it's greater than 2 years' benefit over on top of the standard of care, that is going to translate, I think, with all likelihood into a survival benefit. We can't claim that right now. But I think the indicators are very good looking at SOLO-2, and so I think that's important. And what we've seen in this marketplace is that patients are willing and physicians are willing to test patients. So we know now that, in the vast majority of centers across the world, they're testing for BRCA, they're testing for tumor BRCA, not just germline, which is important. You get additional sort of 25%, 30% of BRCA patients when you test for tumor. What that means is they've got tissue and they're willing to basically look at it for treatment decision-making, not for familial risk assessment. And so it should be able to translate that into a broader biomarker to be able to actually identify these patients. And when you do, you've got some real treatment decisions to make. I think the bevacizumab outcomes that we saw are significant. I think it validates what we've seen in other trials, GOG 218 and others. And I think now we're starting to see that HRD negative patients that bevacizumab-containing regimens are really a must. And I think that an olaparib-containing regimen with bevacizumab for an HRD+ is clearly something that is going to provide a very, I think, supportive value proposition to physicians and the patients.

[Operator Instructions] So I'll give a little bit of a moment more. And if not, I will tip another one. So maybe the next question is, given that we shared, obviously, the recent approval for PROfound and, obviously, specifically, the overall survival data, I mean maybe, Susan, Greg, how important do we think that is? I mean, it's obviously pretty compelling the first PARP. So I'd love to again hear your thoughts around that.

I think the PROfound study is groundbreaking in many ways. It's groundbreaking before -- because actually, the complexity, if you like, in some ways of the diagnostic testing that was done and the technical feasibility to do that was actually pretty impressive. And what we've seen is activity not just on our PFS but on OS across the panel of genes that we looked at that were involved in the homologous recombination repair process. I think the other thing that is a trend that you've seen across different tumor types now for olaparib is that the impressive and progression-free survival data does translate through into the later time points. You are seeing a consistent tail on those curves as I pointed out, not just in ovarian cancer, but it's also being seen in the prostate cancer setting. And so the hazard ratio for survival benefit that we saw in PROfound I think is a very exciting announcement if you consider that these were heavily pretreated patient population. And again, I think the other thing that I would say is it's really nice that the PROfound data is -- the circulating tumor DNA testing link, I think it's something that we're working on as well but that we've seen another trial is actually in the CD8 dataset that we could double the number of patients that were identifiable as having an HRRG mutation by looking in plasma and circulating tumor DNA, not just in the tumor tissue. And that's very important in prostate cancer because a lot of patients obviously have [ brain ] metastases, and it's harder to extract an adequate amount of tumor tissue. So I think that's really important in terms of delivering that impressive finding through to broader access for patients.

Any comments from you at all, Greg?

Yes. Maybe a couple. So firstly, again, I think there was some great data at this ASCO. If you haven't seen it around the quality of life and pain management in this setting, which I think, over and above the PFS and the OS benefits, are really important for patients of this disease. And you could see actually that the PFS benefits retrack very much with delay in pain progression and improvement in the number of domains of quality of life. And I think, albeit that this was an open-label trial, I think, that they're really important data for physicians of the patients. And this is against an active control. This was not against placebo. This was against an active control. So I think they're impressive data. I think from my point of view, I think, reiterate Susan's point that I think this broad HRRm panel, which I think may be a first for FDA to label a drug with a panel of this magnitude and this breadth, based on the biology, based on the data that we've been able to generate is really quite exciting. But I also think that if we can move this into the first line, and all the indications are that you've got, really, I think, important activity here against this target, at least in this population. And if you can use it earlier, which we've seen SOLO-1, and we're seeing it with OlympiAD when you look at the first line versus the [ subplot, ] you seem to see even better outcomes. And so getting this drug into the first-line patient population in prostate I think is a very exciting proposition. So I'm really looking forward to that PROpel trial.

Thanks, Greg. So I just want to say thanks to Steve [ Slosser ] for breaking the duck and giving us a Q&A on Zoom. So Steve's from [ Money Life ], and the question is, could you please comment on the ongoing reimbursement negotiations for pancreatic indication and the expectations for EU reimbursement following the recent EU approval?

Yes, sure. Well, obviously, at the moment, there are no active negotiations because we've only just received the CHMP opinion that's positive. So normally, there will be something around about a 60-day period between when we get a CHM+, CHMP opinion and when we get a European commission license. There are a couple of markets where you can start to have some early dialogue around access. I think the important thing for PAOLA was, this is not a huge commercial opportunity. This is a pretty small population for pancreatic patients. It represents about 5% to 7% of pancreatic patients. It's used as maintenance. It's a really valuable clinical profile that we saw in this particular trial. And we are going to be working very hard because it's a small, so therefore, low-budget impact, high-risk population that really has no major alternatives. So we think we've got a very good value proposition, but we're going to be working flexibly with the agencies to try and ensure that we get as rapid access as possible.

[Operator Instructions] In the meantime, maybe just one last question from me. I guess the question is, as you know, we saw on the last slide a little bit around the life cycle management program for Lynparza. So I guess, maybe a few more comments around that. And then in particular, what is the strategy moving forwards in terms of ovarian cancer, given obviously, the BRCA indications and the HRD+ indications. I mean, I think people are just obviously keen to understand maybe what are the next set of catalysts around that life cycle management?

Let me start, if I might, and then Greg can go on because we obviously already indicated that you've got the durvalumab combinations. But one of the combinations that we're looking at from an early oncology perspective is to address the growing need now of PARP resistance, which -- with every success that we have with olaparib, and that was early in July in the lines of therapy is then what we do when those patients that haven't got to the 5 years without requiring prior treatment, what do we do for those people. And I mean I'm quite excited about the fact that we're understanding more about the PARP resistance mechanisms, and the majority of patients become resistant of PARP inhibitor and do so because of some form of restoration of the ability to repair DNA by the homologous recombination pathway. And we know that, if you look at combinations of an appropriate drugs like our ATI inhibitor, we can overcome some of that resistance. And so we've seen some principal data, both preclinically and clinically. And we have 2 trials that I'll be interested to see readouts, and one's the VLF study in triple-negative breast cancer in combination with [ AR PARP ]. And the second is the DUET study in PARP-resistant ovarian cancer. And again, in both of those studies, we're collecting tissue for -- at entry to the study, so we'll have a much better understanding of all of the different mechanisms of resistance and work out which patient populations can be addressed through the ATR combination. So that is one that I'm looking forward to seeing. Greg?

Yes. No, I think that summarized, I think we certainly -- we're pushing forward, I think, very much in the disease areas where we know that there's likely PARP sensitivity. So we've talked about OlympiA. We've talked about PROpel. We've got this very broad ovarian program that we're prosecuting, both looking at can we get into the early stages of disease, where we can really basically drive that curative potential we're intrigued by and looking forward to what are we -- what is that long-term survival look like for PAOLA-1 and SOLO-1. And can we add to it with the durvalumab combination with [indiscernible] I think that if we go beyond what José himself might call the canonical tumors, so prostate, breast and ovarian. Are there other places where there is part sensitivity? We think endometrial is one. And so the study that we just announced around endometrial, I think, is an important one. I think it's more speculative as we go beyond that. And I think things like non-small cell lung cancer, which do have a fairly large number of HRM mutations but are the driver mutations, is a question that we're looking at in Phase II so will hopefully report fairly soon. The same is true in bladder cancer, which will report very soon. And we note from this meeting again that the TAPUR trial hasn't reported out. This is a study from ASCO that is a tumor-agnostic study and has accelerated a number of different tumors because it met the bar for expansion. And we're working with our partners, Merck, obviously, with a broader study around tumor-agnostic to really understand can we broaden the potential of olaparib into HRM or HRD populations, independent of tumor status. We don't know what the outcomes of that trial are, but that's going to be very, very interesting to, I think, really understand and review.

Thanks, Greg. And perhaps we can now turn our question over to Andrew Baum at Citi.

A question for Greg. Just on the immediate opportunity in front-line non-gBRCA breast -- ovarian cancer, your competitors have quite a powerful dialogue with clinicians and patients, particularly in the current context of COVID-19. They also -- they've had the same breadth of commercial opportunities perhaps as you do. And they also derive 100% of operating profit from the asset, again, unlike you do. So how are you thinking about your ability in order to capture market share given the selling points which COVID gives them as an organization, which is going to be singularly focused on maximizing the value of that asset and that indication?

Yes. So I think -- so firstly, remember that all of these drugs are used as maintenance therapy. And I think the most important thing in the COVID-19 situation that we're finding out actually across our brands is the access to surgery and chemotherapy is a far more important aspect than any potential sort of testing. Clearly, these are all therapies. The bevacizumab is, I think, well understood and well characterized. I think that the value proposition of 37 months median PFS, makes it as sort of, if you like, a clinical imperative. And I think that the conversations we've had, at least in the U.S., have resonated very much in terms of the clinical value proposition. And I think that, whilst COVID-19 is a critical issue for cancer patients, the need to manage around that to ensure that patients get the best possible care and how they manage the chemotherapy and surgery becomes probably the most critical question that these women are facing. Susan, I don't know whether you want to comment.

So our experience in terms of U.S. and Europe from a clinical trial perspective is that we've been able to maintain accrual in our clinical trials for the most important indications where there's a clear benefit/risk. And as Greg has already said, and we've already demonstrated, I think the benefit/risk in the setting is substantial. So even during the peak of the crisis for the most important areas, we didn't see a dropoff in the activity there. So I think, again, Greg's points about access to the surgery and access to the chemotherapy, the most important ones first off, and then we'll build it from there, but 37 months is not to be stiffed at in terms of the opportunity.

Thank you, Andrew. We also now have a question from Matt Weston at Credit Suisse.

Susan, I know there was some data around -- it's a broad question around DNA damage repair, and I guess, the next steps and what we've learned in the last year since probably we focused on the broader portfolio, so there was data on WEE1, ATR and some of the others in the portfolio. Could you just give us a quick roundup as to when you see the opportunity for next generation beyond PARP monotherapy moving towards? And what are the exciting things in Astra's portfolio?

Yes. Thanks, Matt. And I'm sorry, we can't see you in person. So the first thing is that, again, Joyce Liu and her team have presented some data looking at monotherapy WEE1 in a subgroup of endometrial cancer called uterine serous carcinoma. And I think what's interesting about that, first of all, is the level of monotherapy activity around a 30% durable response rate in this group of patients that are heavily pretreated and don't have many options. But when you look at the genetics of the tumors, if it was elegantly gone through both by the presenter and then the discussion on what you see is you've got a setup of a high level of replication stress. So you've got a high level of P53 mutation, relieving one checkpoint, and you've got a high level of oncogenic drive together with other changes that really set these tumors up for being the most sensitive to WEE1 inhibition. In that patient population, whilst you do still see GI side effects, which we've seen with WEE1, these were tolerable, and patients were able to maintain on therapy, which again, is shown by the ability to maintain the responses that we're seeing. So I think that's an exciting opportunity that we'll be looking at further. From a combination with olaparib perspective, I think the key question really is, how do we overcome PARP resistance. So with every trial where we have success with Lynparza, we have a question then about what happens for those patients that don't have a long-term benefit and who do progress. So we're trying to understand PARP resistance. And what we're finding is that, in almost all cases, you've got restoration of homologous recombination capacity, either through BRCA reversion mutations or through other changes. You can have loss of BRCA1. You can have a variety of other mechanisms. But they all basically end up with homologous recombination proficiency being restored. But it isn't restored fully, and what you still get to treatment with olaparib is you still trapping PARP on DNA, which further increases replication stress. So we've seen data previously that, with our ATR inhibitor, we can overcome this, and we're getting emerging clinical data as well as the preclinical data confirming that we do see activity in the PARP resistance setting with the combination of ATR and olaparib. We've got 2 ongoing Phase II studies, the VIOLETTE study in triple-negative breast cancer and the DUET study in PARP-resistant ovarian cancer, which I think both are going to be very important and should be starting to read out some indications from the -- in the next 12 months. So I'm optimistic about both of those. Earlier in the portfolio, we've got a new entry into the DNA damage response category, which is our DNA PK inhibitor, which, again, preclinically shows spectacular activity actually in combination with olaparib in the ATM null tumors. And of course, with the profound data we've seen that you do have activity with olaparib in the ATM group, particularly in the prostate cancer group. But as we're seeing, it wasn't as high a level of activity as you see in the BRCA-mutant group. So I think it shows that there's potential there, but there's room for improvement as well. So I think I'm very interested in the DNA-PK combination with olaparib in that particular group of patients, especially. And we also have an ATM inhibitor, which is being used in combination with radiation therapy for glioblastoma. This is an inhibitor that crosses the blood-brain barrier. I think it's potentially quite exciting. And not just in that setting. You're starting to see actually in the lung cancer settings, the increasing use of SBRT to treat oligometastatic disease and actually having survival benefit. That's another place where I think there's real interest for combination with a modality that causes double-strand DNA breaks. So I think across the portfolio, whilst you've chided me before about the speed with which we're bringing these things forward, I think these are novel areas of biology, and we're doing the right studies to answer the questions carefully about the combinability and the places where these drugs will be used best.

[Operator Instructions] In the meantime, maybe while people have a little bit of a think about it, again, just coming back, Susan, Greg, to the HRD opportunity for PAOLA-1, maybe worthwhile just explaining how excited I think we are as an organization, a little bit more about the fact that, obviously, the sort of 50% of the opportunity available to us and most compelling Kaplan-Meier curves, maybe just a couple more comments, if you may?

I can -- I think I'll just say that the data is unprecedented in terms of level of activity that has been seen and the idea that you can, for these women, offer something that means that they -- you don't have to go back on to chemotherapy for more than 3 years I think gives real hope that, that will be translated through long term into survival benefits and creates an opportunity to think about how you might further change the paradigm of how we treat patients with ovarian cancer. Greg?

Yes. I think maybe 2 additional points. I think, clearly, the data is spectacular, and the exciting concept of PFS surrogacy gives us real hope that we're going to see some survival benefits from the plateau in curves that we're observing. And obviously, it will take us a number of years to be able to read that out with mature data, but it certainly gives us great excitement. I think the key thing for me is that we're already seeing adoption of tumor testing with our SOLO-1. So we know there's a willingness to test for a biomarker-directed therapy when you've got this type of magnitude of change. We think that the HRD+ group, which obviously doubles the potential in terms of the number of patients that can get this type of outcome, is important. We think that the testing regimes, when you've got this type of clinical value proposition, will be developed in the market. They're already fairly mature in the U.S. They're developing in other markets. We have established testing and supported testing globally in the past, where there's a clinical need to do so. So we think there are patients that are going to get access, will need to get access, will have the systems to get access to this regimen. And we know that the clinical profile of a 37-month median PFS is substantial. Remember, this is for patients where they get treated to reach 24 months, and they stop. So if you think about that, a lot of these patients are actually off therapy, a very substantial part, about half of the time that we're sort of talking about is off therapy. And so that value proposition of an intensive treatment -- a more intensive treatment after cessation of chemotherapy, but then a long treatment-free interval with the potential of a lack of relapse in this for 3-, 4-, 5-year time frame that we're seeing, whether it's SOLO-1 or whether it's PAOLA-1, it's a very important clinical signal, and we think that the market is already adopting that.

Thank you both. We're just coming up to time. So perhaps one last opportunity for our attendees today to ask a question in Zoom Webinar. [Operator Instructions]

Nick, there's a question in the Q&A.

Perfect. Thank you very much. Okay. Yes. So from Mike, are there prospects for combination of Lynparza or another DNA damage repair inhibitor with radiotherapy in prostate cancer? How early do you think Lynparza could be moved in the treatment paradigm?

So the opportunity for combination with radiation therapy is one of my favorite questions that I often get asked, so thanks for asking that. I think there's substantial opportunity for combination with radiation therapy, again, as I've referred to as well, I think there's some new paradigms. One of the challenges for radiation combination development has been that there's actually chemoradiotherapies established across a number of different indications. But I think with SBRT, there's an opportunity to enhance that as that is being used further. So within prostate cancer, of course, radiation therapy is used as one option in the -- with curative intent early in the disease, and again, associated also with the use of BRCA therapy in that setting. I do think there's an opportunity to further enhance local control by looking at radiation sensitizer. And -- but it's not the only place. I also think that the introduction of more radioisotopes, you saw some data actually on a PSMA tank radioisotope at this ASCO session. I think that provides another opportunity for a combination with some of our DNA damage repair areas. And I think we're going to see a trend of that increasing across different indications. So one of the things that's always fascinated me is if you actually go to the ASCO meeting, and you go to the exhibition hall, you'll see there's a dearth of pharmaceutical companies, and it's all occupied by people that make machines. My personal view is that we've optimized the anatomical perfection of targeting radiotherapy, and it's now time for biology to have a play. So I think there's lots of opportunity there, thanks.

Thanks, Susan, and thanks to Mike for the question. Given we're now at time, I just want to thank our panelists, Susan and Greg. And obviously, to all of our attendees for your interest in AstraZeneca. And at the end of this webinar, you will receive a request for feedback, so please do take the opportunities to complete it. We'd obviously welcome your comments. And with that, I would suggest we all disconnect. And again, thank you very much for your time and interest in AstraZeneca.

Hello there, all. Good afternoon, and welcome to AstraZeneca's Capital Markets event from ASCO 2020. I'm Henry Wheeler, and I'm your moderator for today. I'm a member of the AstraZeneca Investor Relations team. I'd like to welcome you to the Virtual breakout 4: Calquence and hematology and the opportunity to meet with some of the company's senior oncology team. Today, I'm joined by Michelle Werner, who looks after Calquence; and Andrew Mortlock, who looks after oncology combinations. This session will last about 30 minutes, and there'll be a short 5-slide presentation with majority of the time reserved for Q&A. I hope you like the virtual setup and the potential to interact with Michelle and Andrew. I believe we're also joined by Thomas as a panelist as well from the IR team. The presentation materials are available on astrazeneca.com/investors, and we've also sent them to the people on the distribution lists. Just very quickly before I hand over to today's panelists, I would like to remind you that this meeting is being recorded. So by continuing to participate, you are consenting to be recorded. If you do not wish to be recorded, please disconnect now. And also, as a kind reminder, this event is strictly for the invited sell-side analysts and institutional investors of AstraZeneca. So therefore, if you are a journalist, a consultant or an employee of another pharmaceutical company, pleased do disconnect now. [Operator Instructions] So with that, I will turn over to Michelle to start presenting the slides. Firstly, we've got the forward-looking disclaimer. And then I'll hand over to Michelle now. So go ahead, Michelle. Thank you.

Thank you, Henry, and good afternoon, everyone. It's a pleasure to be here with you, presenting at this breakout session. We're here to give you an update on terms of Calquence, which I'll start with, and then a bit of our pipeline from an overview perspective. So just to remind everybody, Calquence was first launched in the United States about 2.5 years ago in relapsed/refractory mantle cell lymphoma. And what we've seen is a really strong foundation in this initial launch. And when you look at the data from the first quarter of 2020, what we've seen is that Calquence was the #1 prescribed BTK inhibitor in the relapsed/refractory mantle cell lymphoma, which has provided a really excellent foundation for the CLL launch, which is underway right now. And CLL was first approved in the United States in late fourth quarter of last year. And you can see a real inflection point in the first quarter of this year because the launch feedback has been very, very encouraging. The data that has comprised the launch for CLL, the ELEVATE-TN as well as the ASCEND data have been very encouraging data and are resonating well with our physician community. 60% of all new starts in CLL are actually coming from new Calquence prescribers, which really shows the breadth of the prescribing base, which is really important for us as we're continuing to build upon the launch that we've seen in the early weeks, and that's carrying through this year. About 1 out of every 3 hematologists now have prescribed Calquence, and about 1 out of every 4 new CLL patients is starting on Calquence now. So all of these data points are very encouraging for us that Calquence has the potential to be the best-in-class BTK inhibitor. Now if we look towards the back half of 2020, we're anticipating broadening our reach across the world with worldwide launches coming later this year and then throughout 2020 as well. When we look at the overall data that was presented for Calquence at ASCO this year, multiple datasets have been presented with 7 abstracts submitted and accepted. We've had 2 molecules presented with 2 mechanisms of actions and 3 different heme malignancies, but the Calquence data is very encouraging because all of these datasets show that both in the relapsed/refractory setting as well as in treatment-naive patients that we're really continuing to demonstrate that the long-term efficacy and safety profile for Calquence remains very compelling. And that's particularly meaningful in this elderly patient population, which is notable for this particular chronic hematological malignancy. Next slide, please. Now of course, Calquence is just the start for us in hematology. And we really have an ambition to build an industry-leading hematology franchise with the launch of Calquence as really the beachhead for this strategy. And what you can see here, it's about launching Calquence, changing the practice of medicine and really transforming overall the lives of patients with multiple hematological malignancies, the first step of which is really about the introduction of Calquence worldwide. Right now, we have 13 countries that have approved Calquence in mantle cell lymphoma and 6 countries that have approved Calquence in CLL. And as I mentioned, we're continuing those launches around the world as we speak. The second step is really about maximizing the life cycle management plan for Calquence and really driving towards leadership in first-line CLL and expanding to other B-cell malignancies. And we see that through the life cycle plan that we have already underway with the Calquence program to-date. And then finally, the third part of our strategy is really accelerating the very exciting profile that we have in hematology, some of which you will be able to share some data with you today, but it's expanding our reach across lymphoma into AML as well as myeloma and really seeing through some of those opportunities that we have in our early development space. And to talk us through that a bit more, I'm going to hand off to my colleague, Andrew Mortlock.

Thank you, Michelle. So if we go to the next slide, what I want to do is just to take you through some of the molecules that will do exactly what Michelle says. This will enable us to broaden out our Hemes franchise from being focused on CLL and mantle cell into other lymphoid disease, into myeloid disease, into melanoma. So I'll give you some examples of the compounds that we're doing that'll help us kind of drive that. So on the first slide on compounds, which are really in Phase II at the moment, so this is the next wave of compounds. The MCL1 inhibitor, 5991, is being taken forward, both as a monotherapy and in combination, particularly in AML but also in MDS and has a broader potential, including solid tumor disease. Again, what I'm showing you here is some preclinical data that we shared a while ago. You can see in this particular example, we're showing in combination with Velcade. And again, you can see that, whilst the agent is impressive in its own right, essentially when we start looking in combination, we really see full regressions and an ability to drive a very deep level of tumor cell kill, which again, we think is going to translate into something very interesting in the clinic in terms of targeting deeper responses. And obviously, that will lead to much better outcome results. 2811 in the middle is a selective Aurora B kinase inhibitor. I think this is a compound which we took into AML a few years ago on a continuous dosing regimen, demonstrated a strong monotherapy proof of concept. We've reformulated it. So we can now give it twice a month. And we're seeing, again, some encouraging data in AML and indeed in solid tumor disease. And over on the right-hand side, we have a CDK9 inhibitor. Again, we've talked about this one publicly before. Again, this is being profiled, perhaps more particularly in lymphoid disease. So our lead indication here is DLBCL. Again, we've seen some very deep monotherapy responses, but again, I think we see the real benefit here is potentially in combination. You can see the preclinical data here is with acalabrutinib, but we're also very interested in the combinations with Venetoclax, Pertuzumab and will fit that into the treatment paradigm. If I go to the next slide, some agents, which are perhaps more in Phase I. And again, these will be -- some of these will be familiar, others less. So on the left-hand side is 0466. This is a dendrimer presentation of a Bcl2/xL inhibitor. This is the third in our family of cell death inhibitors that goes to CDK9 MCL1, again, showing you here some preclinical data in combination with acalabrutinib in a DLBCL model, which again shows that compound is what has monotherapy activity. The combination activity is really quite startling. And you can see in this model, we were able to -- the mice were completely tumor-free nearly 6 weeks after we finished the dosing. In the middle is an ADC which has come forward. This is -- has a PBD warhead. It's completing dose escalation. We're doing combination dose escalation at the moment with dexamethasone with either Velcade or with lenalidomide. Again, that's progressing well. We have some early monotherapy efficacy data, which we think is certainly competitive with the data that's been published by others. And we think the safety profile may be better as well. I'm not going to share the explicit data today. But again, that data is maturing and will be presented in due course. And over on the right-hand side, capivasertib is a compound which we announced last year. We were going to take into Phase III in breast cancer, triple-negative and in prostate cancer, also bidding a lot of work looking at how to being asserted can be used in hematological disease. And here, again, is some combination data showing it dosed with acalabrutinib in an ADC DLBCL model. Again, that's a combination which we're very interested in exploring in the near term, not again in a registrational study, but we want to understand which patients might respond best to that combination. If I go to the final slide, this is really looking to the sort of longer-term future. So this is really talking more about what we're doing in the late discovery stage at the moment. And where is our next group of candidate drugs going to come from? And again, we think that this is going to be really quite a different future from the drugs that we have currently in Phase I and Phase II. So it won't be as strongly based on small molecules as we perhaps are at the moment. So we do have a capability in ADCs and ProTACS, and that does include hemes targets as well as targets in solid tumors. They will be coming through the next period. Over on the right-hand side, we have worked in epigenetics for a number of years. We have a BRD4 inhibitor in the clinic at the moment, which is being trialed in AML. But we see epigenetics picking a build area for us. And certainly, we're interested again in how we would look at those being used in combination with current agents to target resistance. And then in the middle, cell-based therapy is clearly an area where others have demonstrated the utility that was sort of first-generation CAR Ts. Clearly, I think that area is now prime for others to come in. We'll be part of that wave coming in to look at those and see how we can take that technology forward. And that, again, is a significant growth area for us. So again, we'll be building on small-molecule approaches, building on where we are in CLL and mantle cell. And you can see a much broader ambition here to both broaden out the diseases we target and most particularly the methods in which we seek to find agents to target them. So very happy to take questions about our longer-term future as well as the near-term opportunities we've highlighted.

Thank you very much, Andrew and Michelle. So we'll now move over to Q&A. [Operator Instructions] I can't see any questions right now, but maybe while people are thinking, maybe one for Michelle. Would you be able to perhaps summarize the Calquence data that we've seen to date, especially in CLL? We've seen some front-line and relapsed recurrent data last year, and there's a bit of an update at ASCO here. So maybe summarize the dataset that we have with the update and how you think we're differentiated in BTK [ at last ] today.

Absolutely. Thanks, Henry. So yes, just as a reminder, our CLL indication is built off of the data that we received in the ELEVATE-TN in the front-line setting as well as ASCEND in the relapsed/refractory setting. And the ELEVATE-TN data showed us a really unprecedented PFS data. So 90% relative risk reduction in disease progression with Calquence plus Gazyva versus G chlorambucil, which is really exciting data. And then the 2-year, 24-month PFS for Calquence-Gazyva was also 93% so really encouraging data seen within that trial. In addition to the efficacy data, the safety and tolerability data also very encouraging for us, in particular, very low rates of cardiotoxicity, including afib, hypertension and no ventricular tachycardia that was seen within that study so really encouraging data. In the ASCEND data, we see similar efficacy and safety results with the profile that we see with Calquence. So a 69% reduction in disease progression or death of Calquence versus the comparator arm and the relapsed/refractory setting. With the data, as I mentioned that we showed here at ASCO, again, we're looking at really long-term follow-up data so patients who have been on therapy for over 4 years, and so even when you look at patients who are maintaining on Calquence therapy for extended period of time, their efficacy data is staying stable. So they're able to continue and maintain their progression-free survival while on Calquence. And as I mentioned that even with the long-term treatment, we're still seeing very compelling safety and tolerability data. And again, just putting that into context with this patient population that often is diagnosed at 70, 75 years old. When you're looking at these data sets with that in mind, this patient population, who can be elderly and might not have other comorbidities, both efficacy as well as the safety and tolerability profile is very important for this patient population.

[Operator Instructions] So maybe I can go with one that we've had through email here from UBS. So wondering if you could clarify the comments made at Q1 on Calquence and new therapeutic starts for BTK inhibitors. So Calquence now accounts for 25% of MDS for BTKs. Can you give any color on how this number has changed since Q4? And perhaps also qualitatively, can you give some color on how the launch is going from AEs?

Absolutely. So just a reminder, remember, the original CLL indication in the U.S. came in at the very last few days of November of last year so really late into the fourth quarter. So the first starts that we saw in the fourth quarter were, of course, some patients in the front-line setting, but also a good number of patients in the second- and third-line setting. So when we look at these data in terms of the performance in the first quarter of this year, this is really, I think, showing a shift in the launch trajectory that's coming with the experience that clinicians are having with Calquence. And now we have about 50% of our patients are being treated in the front-line setting and about 50% being treated in the relapsed/refractory setting, so we're really encouraged to see the shift towards that front-line patient population. And what we're hearing from the treatment community is actually quite encouraging as well, in particular that, when we know that clinicians try Calquence in at least 2 of their CLL patients, they themselves are noticing a difference in their patient experience, which is actually allowing them to convert to be more loyalist to Calquence, really encouraged by the profile and using it more and more in their patients. And so that's giving us a lot of encouragement that we really do have the potential to be the best-in-class BTK inhibitor in this setting.

Okay. Yes. So we're actually getting some questions in our e-mail now. So Jo from Credit Suisse. Can you summarize the combination studies, including with Calquence? And which do you think has the greatest potential? So I don't know whether that's, Andrew, your combinations, or Michelle, do you want to take that?

And I can maybe start off, and then Michelle can comment on the ones which are sort of running at the moment. I mean I think what we see with Calquence of the cell death agencies, we see a degree in which Calquence can prime cells for cell death as Tony [indiscernible] would describe it. So treatment with Calquence really sensitizes a number of cell types towards program cell death, which can be delivered with one of the cell-death agents picked basis -- on the basis of mechanism. So I think that those strategies are just going to play out in the clinic, probably in the next 12 months. So I think we'll better get feedback on those very quickly. But clearly, what I wanted to show you was that the preclinical data certainly looks very impressive. Now I realize that many of us have cured mice of cancers over many years. But I think that the reality is that the combination looks more exciting than I think we've typically seen in animals to date. In terms of what we've done in the clinic, I mean, Michelle may want to comment. We're certainly in CLL and DLBCL. I think we see the combinations really as a way to much deeper responses. And I think that, again, is a direct [indiscernible]. So Michelle, maybe I can hand that to you now.

Yes, absolutely. And again, just a reminder about one of our clinical trials that's ongoing. It's the 311 study, which is the Calquence plus Venetoclax finite treatment in CLL. And this, I think, is a really encouraging study for us to look to see how Calquence can play within this particular setting. And what we know for some of the early data -- combination data with Venetoclax that was presented at ASH last year from a safety and tolerability perspective that the data actually look quite good. And so we're hoping to be able to see good efficacy data come out of the study as well.

And I'm sure we had another one, just on multiple myeloma, and the ADC is quite a competitive area. Why do you think this is a best-in-class product?

Well, I think -- I mean, obviously, we have not shared clinical data to-date. But I mean, I think that what we've seen early on is encouraging in terms of the response rate that we're seeing. I mean, we know that the GSK, Seattle Genetics compound has had a single-agent response rate around 32%. So we have a sort of benchmark that we're aiming for. We're also familiar with the toxicities that are going to be differentiating around corneal toxicity. So I guess, at the moment, we're doing the dose escalation of that in combination. But what we've seen so far, I think, is encouraging, but we're not yet ready to share the numbers on that.

Okay. So I guess a follow-up question on the pipeline. So what areas are you most excited about at the moment, and where are our next investments going to be headed on the pipeline?

So maybe I could pick 3 things that I'm excited about. And obviously, I get excited about different things. I think capivasertib is a huge opportunity for us, particularly in lymphoma. And we've seen PI3 kinase, a AKT pathway, be really important in other areas. We understand, particularly in DLBCL, the patients, where there is an addiction to that pathway, so I think rational combinations with capivasertib, whether with Venetoclax, whether with PAOLA, whether with acala, all provide huge opportunities for us. So I think that's a very much here-and-now opportunity. I think the second one, I'd call out would be the cell death portfolio. Because it really targets one of the key issues in hematology, which is targeting the persister cell population. So we all know in first-line treatment, you can kill 90%, 95%, maybe even 99% of tumor cells. It's the last 1% that is a real issue. So whether we can use the cell death agents to target that population, the small residual population, if we can, that's obviously going to have huge benefits. And beyond that, I think the excitement is in the new approaches. I mean, clearly, cell-based therapy is a huge interest. We're still trying to understand how that performs in real-world populations. I think a combination of ProTACS, ADCs and cell-based therapies can offer us huge opportunity for us longer term. So we're going to make very focused investments in those areas going forward. And again, that'll enable us to target broader patient populations. We are, at the moment, again, moving away from diseases like CLL and really going into disease where there really is much higher unmet medical need currently, such as AML, for example.

So we've probably got about 7 minutes left. [Operator Instructions] So maybe one for you, Michelle, final one from me. What about Calquence and sort of the life cycle management plans? Maybe you could articulate what you're most excited about in the combination with Venetoclax. How is that going as well?

Well, that trial is underway right now. So it'll be some time before we're able to present data from that study, but it had been -- it has been enrolling quickly, and so we're looking forward to seeing those results in due course. And again, as we've mentioned, there's also a trial ongoing in DLBCL as well, as well as in front-line mantle cell lymphoma. So these are the main pillars of our strategy for Calquence. And all those data will be moving forward in due course. And then, of course, I'd be remiss not to also mention the head-to-head study that we have ongoing as well versus ibrutinib. And we're also looking forward to seeing the results from this particular trial, although we already see the differentiation within the clinic today. But this study would also be a good opportunity to present that position as well.

Okay. Yes, we've actually just had another question on our e-mail from [ Cindy Zane ]. So over the weekend, BeiGene presented their Phase III ASPEN trial compared with their BTK versus ibrutinib in [indiscernible]. So could you maybe elaborate on the opinion of their safety profile? Any thoughts and read-through on this?

So maybe I'll go ahead and get started. I mean, I absolutely think that these data really demonstrate that not all BTK inhibitors are created equal and that there very much is an opportunity to improve on the profile of the current market leader in this space, especially when it comes to safety and tolerability. And this is what we believe is true for Calquence as well. And what we've seen in the clinic and with the launch so far with Calquence, I think it reiterates the fact that Calquence is a next-generation BTK inhibitor as compared to others that have come before us.

Okay. I'll take a question that I've received over email from [ James Quigley ] at Morgan Stanley. So Michelle, maybe this one is for you. So talking about the first-line launch of Calquence. Where have you seen the most success for the launch of first-line CLL? KOLs at ASH weren't exactly bang on the table on Calquence versus [ Invertica ] from the ELEVATE-TN presentation. So what are the aspects of your marketing messaging, all the data and resonated with the wider prescription community to explain the strong initial uptake in first-line CLL.

Sure. Thanks, Henry. Happy to address that. Yes. So what we're hearing from KOLs and the treating community is very much a totality of the data is quite compelling. So certainly, the 90% risk reduction in disease progression with Calquence plus Gazyva seems to be unprecedented data and ones that are quite compelling. Also the 24-month progression-free survival data, 93% for Calquence plus Gazyva, also very compelling. But then when you also look at the safety and tolerability data, in particular, the low rates of cardiac toxicity, this really rounds out the overall profile that is really creating a bit of a difference. And in particular, one of the things that I'd like to call out, what we're hearing from the clinician community is that, generally, once a clinician tries Calquence in just 2 of their patients, they are actually also seeing the differences in the patient's experience of those patients who are on Calquence versus other patients that they have on other BTK inhibitors. And that's enough for them to really recognize that this is a great drug, and then they're converting many of their new patients to on Calquence as a result of that experience.

So I see we've got a hand raised. So I will -- I can't see the name. It's just a phone line, but I will allow you -- I'll unmute you. So if you could announce yourself, please, and then go ahead and ask your question.

It's Jo Walton from Credit Suisse. And it's a follow-on question, fits nicely here. You say that 1/3 of hematologists have tried the products, then I mean presumably 2/3 have not. I wonder if you could just tell us how you're managing to go through this launch in a COVID situation. And how easy it is to engage with new hematologists?

Well, I think everyone -- like everyone, we've really shifted our focus to the digital communications regarding Calquence at this time. And in particular, we're being quite successful in reaching many hematologists through peer-to-peer forums that we are sponsoring. And this is really what's helping to continue on the launch trajectory that we've seen from the first quarter into the second quarter this year. So overall, we're still pleased with how things are proceeding with Calquence, and the uptake continues to be strong. And so we're looking forward to seeing the continued good performance as we progress throughout the year.

Great. So we've got a question online here from Sarita Kapila, JPMorgan, I believe. So she's asking, how are you doing the competition from BeiGene's BTK in CLL? I guess this is after the data presentation at ASCO this year as well.

Sure. And I think that the data that we saw in ASCO this weekend showing the zanubrutinib data in Waldenstroms definitely goes to show that not all BTK inhibitors are created equal. And certainly, it gives us the -- continues to reinforce the belief that we already have that Calquence being a next-generation BTK inhibitor. There's opportunity to improve upon the first generation, especially as it comes to safety and tolerability data. And that's what we're seeing as well within our -- already the launch trajectory for Calquence in CLL. Now again, we're ahead of BeiGene in CLL. And for us, it's really about maintaining our focus on the launch that we have with Calquence to-date and making sure that we can reinforce the potential benefits of Calquence for these patients at this moment in time.

Okay. Maybe I'll keep going with some of James Quigley's questions. [Operator Instructions] So James has a question about the future risks of first-line CLL. The data from IMBRUVICA in combination with Venetoclax are quite impressive. Are there any other additional combinations or opportunities for Calquence to counteract these risks? So maybe Michelle or Andrew, actually, if you want to talk about combinations after you can take this?

Sure. Well, maybe I'll get started. And then Andrew, you can build upon. So first of all, I mean, yes, I mean, what we're seeing is a very dynamic field right now in CLL, especially in the front-line setting. And we also have a trial underway that is looking at Calquence in combination with Venetoclax. So this will also be an opportunity for us to demonstrate the merits of using Calquence in this particular setting, which could be important, depending on how the treatment landscape continues to develop over time. In addition to that, we -- just on that point, we already have demonstrated some data in combination with Venetoclax. That was presented at ASH last year. And in particular, the safety and tolerability data look very encouraging. So we're optimistic that we will continue to see a good profile for Calquence even in combination with other agents as well. And in addition to that, we're also looking at, as part of our life cycle management plan, a program in DLBCL as well, which I think will further demonstrate the potential for Calquence to be used in multiple settings.

Yes. Well, I don't think I actually have got a lot to add to that, Michelle, but I mean, I think, clearly, the opportunity in lymphoid disease to combine Calquence with other agents in targeted patient populations is very attractive in the second-line setting. We're obviously been pursuing that in a number of indications. And I think we know that, in putting any combination together, tolerability is a critical factor. So anything where we believe we can get -- we can combine more easily with standard of care agents or indeed with other novels will be to our advantage. So that's certainly something where we hope the clean selectivity profile of Calquence is going to come through and help us.

So we've got one from [ Richard Wagner ] on the chat. Can you explain -- expand on nascent efforts in cell-based therapies? Who are your partners? And what is the differentiation?

So I don't think we had a situation where we're going to say who our sort of partners are, but obviously, there are a number of people who -- obvious, people to look at in terms of partnering and certainly also looking at a significant internal build, both in terms of sort of talent and capability that is ongoing at the moment. I mean, I think that the first generation of compounds clearly demonstrated the proof of concept. But I think their full utility is still, to my view, a little bit unclear. I mean we've certainly seen studies, for example, both in the United Kingdom, where I'm based, where if you go into broader patient population, some of the very high initial response rates haven't perhaps been manifested. And where we're seeing some relatively rapid dropoff, in effect, patient population, certainly, that effect, not necessarily going on much beyond 12 months in some cases. So I think there are a number of approaches, which we are looking at. I'm not really in a position where I can say so much or not yet. I think there will be probably an update around the time of ASH on how we're going to look at that. But our cell-based therapy approach is solid. And hematological diseases, clearly, we're very aware that, in hemes, there's opportunity both with T-cells, with armored T-cells, with NK cells, with other approaches as well, more novel approaches, which we think are going to be important to them. So it's very much a long-term play for us, I should say.

And maybe just a quick follow-on from Aneesh Kapur at Woodline. So you mentioned the other cell -- the other prime cell-based therapy. What do you think are the biggest unmet needs in the space? Do you think internal or external efforts will help you take the next step? And just as a follow-on, when do you think we will see the first stage on the Phase II Actavis highlighted? Do you think we'll see any at ASH this year, or will we have to wait until 2021?

I mean I think you could well see something at ASH. I mean I think we've obviously got trials which are ongoing there. We -- obviously, those trials, some of them have been a little bit delayed through COVID. So I think exactly what's presented at ASH or what we choose to present next year at AACR and ASCO is probably a little bit up in the air at the moment, but I don't think we'll be waiting till ASH 2021 any way to share data on that. I mean, clearly, I think all of our efforts here are going to be reviewed with Anas Younes coming. As the head of hematology, he brings a lot of expertise. We've spent the last period making sure that Anas is up to speed with the portfolio. And I think there are certainly things in that portfolio that he's very excited about. And I think the next update you'll see from us, I'm sure he'll be on the call, and he'll be able to give you a perspective of exactly which of those opportunities he's most excited about based on sort of his broader experience outside.

Okay. And maybe another one for Michelle. So Andrew Frost from UBS here. Can you provide any more color on the new patient starts figure around 25%? Are you able to give any color on how the figures changed from Q4 as you discussed in Q1? Does there continue to be an upward inflection with new starts?

Sure. Absolutely. So yes, as a reminder, when we received the FDA approval in the U.S. for CLL, it was really at the very end of the fourth quarter of last year. So we only had a few weeks' worth of that quarter to actually start executing and implementing the launch. So you can imagine that we only saw fewer patients who were receiving Calquence at that time in both the front-line setting as well as relapsed/refractory. And then that real inflection point in the first quarter is really because of the uptick in that launch trajectory that we've seen over the course of the early weeks of that rollout. And yes, so what we're seeing is very much because of that launch curve. And again, as I mentioned, the experience -- the initial experience with Calquence being very positive really lending -- continuing to foster the sense that this is a next-generation BTK inhibitor. And in the first few weeks of the launch, we definitely saw a few more patients in the relapsed/refractory setting than we did in the front line. And in the first quarter and then through present time, we're really seeing a shift now to be about 50/50 front line as well as relapsed/refractory, which is really exciting to see that happening so quickly in the launch.

I'll go back to the phones now. I think Jo may have another question. I'll just unmute your line.

I did. I was just -- you made a comment about DLBCL and potentially more broadly B-cell malignancies. Just interested in your views on combinations there, particularly bispecifics, anything that you have internal? Or would you be interested in the speed advantage of external partnering, if you think that would be an interesting combination?

Yes. Maybe I could start off that, and Michelle can come in. We've been extremely open to both internal and external compounds in our DLBCL strategy. So you'll be familiar, I'm sure, that we did a deal with 47 to access their CD47 antibodies in magrolimab, I think its name is, which is in our PRISM study combined with acalabrutinib. So we've always been extremely open to high-quality assets coming in, and that was an asset we felt high quality. I think within our own portfolio, we have a number of agents. And I have highlighted capivasertib as being particularly interesting, I think, but I think that cell death agents will also have here high utility there with acala and without. I mean we're not particularly -- Michelle is wedded to acala. I'm not. I must admit, I'm happy to take anything in the second-line DLBCL setting. I think acala makes a lot of sense for combinations, but we have some combinations which don't involve acala that we'll pursue. But yes, external opportunities will be looked at if we provide one of the partner agents. There's nothing sacred about both drugs having to be AZ. We'll go with the best that we can find. And Michelle, you may you want to comment. I don't know.

I completely agree with you, Andrew. I mean, yes, I'm wedded to Calquence, of course, but I also am excited about the other agents in our early portfolio, too. And so I think you highlight that quite nicely about the opportunities that we have to combine potentially with already commercially available medicines as well as those that are already in development and then, thirdly, also in partnership with external agents. And so I think that gives us lots of different opportunities to pull this forward.

I think the only other thing to add is that I think we have -- this company had a strong history in stratified medicine evidenced by what we've done, particularly in lung cancer. And again, we see that very much as a sort of future in later-line lymphoma, where, clearly, genotyping patients and coming forward with combinations that are targeted towards the particular molecular operations the patient presents where there's clearly a way forward. So we're very excited about that, and we see the opportunity to bring our skills in translational meds and next-generation sequencing, et cetera, into our hematology strategy.

Maybe one final question then. We'll take James Quigley again on e-mail. So maybe we talked -- a question about the Bcl2/xL inhibitor and how it's differentiated with competitor, Venetoclax, based on the early data and preclinical data we've seen to date. And also on the NCL1, which indications are we planning to develop?

Yes. So in terms of the Bcl2/xL, I mean, clearly, it's distinguished by the fact that it has 2 mechanisms of action. It obviously targets Bcl2 but xL as well. So in many ways, it has a similar pharmacology to Navitoclax rather than Venetoclax, which was the first of the AbbVie compounds. And clearly, what AbbVie found with Navitoclax was that, on chronic dosing, there was a lack of tolerability because of its effect on platelets. So Navitoclax was stopped for that effect. What we found with our compound is that we're actually able to achieve a [indiscernible] inhibiting xL through a very short target engagement followed by a kind of dose holiday. So we've gone with intravenous approach to that, a short infusion. And we believe that gets around the toxicity that was seen with Navitoclax. So in terms of where we'll be using it, we'll obviously be using it in patients who've developed a reliance on xL as a survival mechanism. So that is one of the more widely documented resistance mechanisms to Venetoclax itself. Potentially, we could also use it in patients where we have a strong suspicion that XL is going to be the resistance mechanism. So I think as we start to plot resistance mechanisms of Venetoclax, I think our agent will become incredibly important to in a relapse setting but also potentially preventing resistance in the first place. In terms of MCL1, we've particularly focused that at the moment on AML and MDS. We do have preclinical data that says we could go into lymphoma. And I think we also can potentially go into solid tumors. I think the real issue there is that I think, in some of the solid tumor indications, we're certainly going to need tough combinations. And we could be looking at different doses in different settings as we go forward. But the lead indication at the moment in the first place we're likely to get a published data will be in AML.

Perfect. Well, thanks very much, Andrew and Michelle, for your time today. And thank you very much to all of you for joining. I'm sorry, we won't be able to join you for our usual post-ASCO beer. All the details will be available at astrazeneca.com/investors, all the recordings for each breakout session if you missed one. We will also be sending out a feedback form following the session, so please do send any feedback as we're always learning in this virtual world. So yes, thank you very much, again, Michelle and Andrew, for your time. And thank you all for your interest in AstraZeneca.