AstraZeneca PLC (LON:AZN)

CMD 2020

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Jun 1, 2020

Hello, everyone. It's Pascal Soriot, CEO of AstraZeneca. Welcome to the Capital Markets event from ASCO 2020 and this opportunity to meet virtually senior oncology managers here at AstraZeneca. As usual, the presentation materials are available on astrazeneca.com and we've also sent this presentation to people on our distribution list. So please turn to Slide 2. This is our usual safe harbor statement. Let's move to Slide 3. And here is our agenda for today. We've developed an event if you turn to Slide 4, sorry, we've developed an event for you today which resembled what we had planned for Chicago and it's going to be quite a first event today to do this virtually, but I'm sure it's going to go very well and we'd all enjoy the opportunity to talk virtually. Now Dave, Jose and I will spend about 25 minutes on the opening and then there will be a 10 minute break to allow you to connect to one of the 4 breakout sessions. All the necessary details are in this slide and on astrazeneca.com. So please look at the slides. And on astrazeneca.com where you can click on the breakout session you want to attend and connect directly to the Zoom webinar. After the first breakout session, there is a 10 minute changeover break again, which will allow you to connect to a second breakout session of your choice before we all end around 17:45 U. K. Time. Each breakout session has 5 slides and then all remaining time dedicated to Q and A. We hope you like this setup and the potential to interact with our oncology management at AstraZeneca. After the event, recordings will be available from each breakout session. Please turn to Slide 5. So this ASCO 2020 is a true milestone for our company and our oncology business unit and our R and D organization. We've seen an increase in abstracts that are accepted, oral presentations, poster discussions and posters. We are thrilled by the adjuvant Phase III data for Tagrisso and the difference it can make to patients with lung cancer. The ADORA trial is a real highlight of the ASCO and probably the most important adjuvant data in a solid tumor since Herceptin in 2,005. Imfinzi has shown sustained Phase III survival in small cell lung cancer, the highlight for Imfinzi at this year's meeting and an early promise in liver cancer with samilimumab, which is covered in one of the breakout sessions. Following the recent approval in the U. S. And Japan for 3rd line HER2 positive metastatic breast cancer and HER2 has several Phase 2 datasets in new tumor types including gastric cancer gastric cancer, sorry, survival, lung cancer but also colorectal cancer. In a few moments, Jose will cover these highlights in more details. Please turn to Slide 6. Over the past year, we've highlighted a number of opportunities in the pipeline that are moving forward primarily in Phase 2. Some like capivasertib have already moved into Phase III and others like the oral SERD also for breast cancer are soon following into Phase 3. It is really encouraging to see that many of the so called what's next opportunities are featured at this year's ASCO including the V1, our ATR and A2AR inhibitors and the antibody against NKJ2A, monalizumab. This increasing presence for the mid stage pipeline at the ASCO gives us confidence that we can continue to replenish the late stage pipeline with new opportunities on top of what Tagrisso, Imfinzyl, Imparza and Calquence can provide with an R2 being a whole pipeline of its own. Before I hand over to Dave, I would like to thank the oncology community in AstraZeneca for their dedication to the patients with cancer and to the company's success in this area. We're very proud of the medicines like Tagrisso and we're working very hard every day to bring new medicines forward as you can see here, which you will learn more about in the 4 breakout sessions. Over to Dave, please. Thank you, Pascal. Appreciate the introduction. I'm going to now just spend a couple of minutes with an overview on the oncology strategy and highlighting some of the growth that we've seen and reported out on in the Q1. If you can please turn to the next slide. Thank you. So I think one of the really important highlights here and we see this reinforced yet again at ASCO 20 is that we have been focused in on building a very diverse oncology and hematology portfolio. We've launched 6 major new oncology medicines, the 5 that are here, in addition to Koselugo, which was recently approved for pediatric NF1. And I think that consistently what we see across all of these medicines is best in class for each and every one of them. And really a effort being placed on ensuring that the development as well as the commercial efforts are around developing standard of care defining medicines, whether that's with Tagrisso in defining and redefining EGFR mutated disease, Imfinzi in the stage III lung cancer setting, Lynparza across multiple tumor types where we continue to build and change standard of care and establish the PARP class. In HER2, in redefining HER2 positive metastatic breast cancer treatment and standard of care and now moving this ASCO into other tumor types. And then lastly, of course, with Calquence. And I think also what's important as you take a look at what's next, you see a consistent theme around moving into earlier stages of disease where we really believe the opportunity is greatest to be able to make the biggest impact on patient outcomes. If you turn to the next slide, Slide 9, just in terms of taking a look at these medicines, you can see consistent strength in terms of the commercial business and the ability that we are demonstrating to launch and also continue to expand and drive growth across regions and across each of the medicines that we're working in. Based upon this performance, we had quarter 1 sales of just north of $2,500,000,000 which puts us on a run rate to be a $10,000,000,000 oncology organization. And I think that that is on a trajectory that puts us very squarely into one of the top tier oncology companies. And we're proud of the efforts that we're making as a company to be able to deliver that. I want to reiterate the thanks from Pascal. It's been truly unprecedented times for the last several months. And I want to thank our colleagues in Operations Development and Commercial for just ensuring that we're able to maintain a continuity of care to cancer patients across the globe. Jose, over to you. Thank you very much, Dave, and welcome, everybody, and thank you for making it possible despite the challenging times. I'd like to present some of the highlights that we have mentioned. And I'd like to start, of course, with Adora, if I could have the next slide, because Adora clearly has become one of the perhaps most expected presentations at this year ASCO. And it was, as you know, as part of a late breaking session at the planning session yesterday. The ADORA trial is our adjuvant Tagrisso study. This was in patients with Stage 1b, 2 and 3a non form cell lung cancer that had been resected successfully. This is with negative margins and these patients had confirmed EGFR receptor mutations. And these patients after surgery were allowed to receive conventional chemotherapy based on the decision of the patients and physicians. And then patients were randomized to osimertinib 80 milligrams daily versus placebo. The study primary endpoint was disease survival in patients with Stage IIIIIa disease. And very importantly, when the study was designed, the assumed cash flow ratio for DFS was 0.7. This is what the community thought was going to be meaningful. This study, as you know, was unblinded sorry, was unblinded by the ADMC 2 years ahead of scale, which is absolutely unprecedented. And at the time of the unblinding, all the patients had been fully enrolled, they have been fully enrolled, and all patients have been followed for at least 1 year. If we move to the next slide, this is the summary of the adverse events. These are the expected mild adverse events with these new generation of TKIs. And what we have today is a median duration of exposure of 22.3 months of osimertinib. This, of course, will change over time. It will mature. But this is a good exposure. Next slide, please. Sorry, and this is the primary endpoint. And I'd like to pause here for a second because there are several observations. 1st, I don't recall and if somebody has seen it, please let me know, studied that positive ever in the history of solid tumor oncology in the adjuvant setting. I was one of the lead investigators in the Herceptin adjuvant study that Pascal has referred to. We were incredibly excited. It was practice changing. This is far more dramatic in terms of the effect, a ratio of 0.17. I think this gives us all of us a lot of pause because this is clearly not only practice changing, but the results are very, very positive. The other point I'd like to make, if I may, is that let's look at the behavior of the placebo arm. These patients don't do well. And I think this is quite to me an eye opening and again another, so to speak, realization that patient with the control arm with optimal surgery and with optimal adjuvant therapy, they simply do not do well. So this is a population in much need. Let's move to the next slide. Now if we put together a secondary end point, as you will remember, in the overall population, that's including from 1b to 3a, still very positive hazard ratio of 0.21. We have a very solid theme. And then if we move to the next slide, please, you will see the forest plot in which we look at how the different subgroups perform with osimertinib and all of them, the benefit is seen all across. I know we are not used to see this kind of forest plot. So when you would look at stage 1b, you might be led into the impression that the results are not that positive, they are positive. The hazard ratio here is 0.5. So what's happening is that the performance of all the other variables and subgroups are absolutely extraordinary. So a very positive study across all subgroups in the patient population. Next slide, please. The survival data is very immature. We have a 5% maturity. It will take a long time for us to see benefit in the survival as you know. Next slide please. Can we go to the prior? So I'd like to finish with the conclusion and I'd like just to go, if I may, straight to the boxed conclusion, because I think that's the critical point here. We have seen that adjuvant or somartinib is a highly effective practice changing treatment for patients with Stage 1b, Stage 2, and Stage 3 EGFR mutant non small cell lung cancer after complete tumor resection. The overall, there was a 70 9% reduction of risk in distress occurrence. As the discussion very eloquently mentioned yesterday, Doctor. David Spiegel, this is a practice changing new therapy for patients with early lung cancer. Let's move to the next slide, please. I'd like now to give you the update on Caspian, that's our Imfinzi small cell lung cancer study. Next slide, please. And what we presented was an increase, sorry, an updated overall survival data from our study with Durva, plus chemotherapy in these patients with extended disease. What we see is a consolidation of the survival benefit. Please look not only at the median overall survival that is positive, but perhaps if you could, look at the number of patients that at the tail of the curve in the duva arm remain with this remain alive. We see a plateau with the numbers that is quite hopeful, 22.2% at 24 months remain alive. Next slide. So the summary of this study is that first line durva plus EP continue to demonstrate a sustained improvement in overall survival compared with what's a real life droplet control arm that allowed different types of chemotherapy, and also up to 6 cycles and the use of PCI. The hazard ratio is 0.75. If we go to the conclusions slide at the bottom, these results further support durvalumab plus EP as the new standard of care treatment for first line extensive small cell lung cancer, offering on top of that flexibility of the platinum choice. Next slide, please. Now, I'd like to just briefly mention a summary of the HER2 trials that were presented. We had data in 3 different tumor types on top of the data that you are well aware already in breast cancer. Let's go to the next slide. And this is the randomized Phase II study of an HER2 in third line HER2 positive gastric cancer. As you know, the data was presented at the same time with a simultaneous publication in the New England Journal of Medicine. The study is positive at multiple levels. The primary endpoint response rate, 51%, versus standard of care, 14 0.3%. But perhaps what defines to me the best way to look at this data, if I may, is please look at the waterfall plots. Look at the number of patients that had complete remissions. We're talking about 8.5 percent of patients are complete remission in third line gastric cancer. This is totally unprecedented. I never thought I was going to see this level of activity. And then also all the limited number of patients that did not derive clinical benefit, the overwhelming majority of patients did indeed have clinical benefit. Next slide, please. And then when we look at the overall survival and the progression free survival, you have here nicely displayed the Kaplan Meier curves. This study is positive in 3rd line gastric cancer, in HER2 positive disease, with a HACHS ratio of 0.6. Again, I'd like to emphasize this is 3rd line, not second line, not first line, practice changing. Next slide, please. In terms of the side effects, you have them displayed on the left. These are displayed by GRATE and by therapy type. And what you see is consistent with what we know. The GI symptoms that are associated with HER2 as well as neutropenia. And on top of that, on the DRiD, you have some additional data on drug discontinuation and those interruption. When you look at the data in this trial, we need to look at the same time in comparison with what was observed in the control arm. Because these are patients that are not in necessarily a good physical condition. And conventional therapy, as you can see also, had very substantial side effects. Next slide, please. This is the data on HER2 mutant cancer. Basically, I think it's fair to say that not a single patient progressed on this therapy, and the Orboe plot very eloquently speaks to the degree of tumor shrinkage that was seen in this population of patients with HER2 mutant non small cell lung cancer. Next slide, please. In terms of the, treatment emergent adverse events in more than 15%, What we have is what we already know. There's nothing in particularly different from what we are already becoming familiar and with what physicians are becoming incredibly confident in managing. Next slide, please. And then the last piece of data is in patients with colorectal cancer. Again, very high activity in a patient population that had received multiple lines of therapy. And one cannot escape to see the consistency of outcomes that we've seen with colorectal cancer, with gastric cancer, with non small cell lung cancer, and also with breast cancer. These were all plots, they all tell a very similar story. Next slide. And here also, we have the treatment emergent adverse events. Again, this is a heavily predicted patient population. I believe they had received a prior or 4 prior lines of therapy. So this is not your first line population. Next slide. And with this, I'd like to thank you for your attention. And I'm going to handle over to Thomas. Thank you, Jose. I just want to end now our session by saying that we are at the end of this opening session. As Pascal mentioned earlier, we've got a few minutes now to connect to the 1st breakout session. They are supposed to start at 16:35 U. K. Time. And you've got 4 different topics to choose from, and they are visible here on this slide, which is our last slide. And each session is repeating once, so you can choose 2 when the others are being recorded and will be available afterwards. In order to connect, please use the details in this slide or simply visit synegya.cominvestors where you can also click your way to the right Zoom webinar. And for convenience, I wanted to share actually how that looks like, but that means I need to change window for a few moments. So if you just allow me a little bit of time here to find the right window to share with you. So if you go to this page here, as for Seneca Investors here and you go to the front and then you can click your way through to hopefully if the webcast is running, click your way through to the event here. And then you can essentially just click whatever webinar that you want to attend. So hopefully that's working for you. Good luck with those breakout sessions. And thanks for your interest in AstraZeneca today. Thank you. 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 Christian Massichesi, 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 and A. The presentation materials are available on our website as will the 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. To ask a question in Zoom webinar, the best way is for you to raise your hand using the icon in the menu bar. I will then be very happy to open your line. If you can't do that, you can type your question into the Q and A dialog box, also located in the menu bar, and I can read the question out. If you cannot use the chat functionality, that would be great as this is reserved for technical queries only. 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 Christian 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 Jose did a very nice job of sharing the data which you all heard Doctor. 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 frontline metastatic setting across the globe as the standard of care in EGFR mutated disease. We talked about achieving sales of almost just shy of $1,000,000,000 for the quarter, which is putting Tagrisso on a run rate of being a $4,000,000,000 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 frontline. 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 frontline 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 ADORA data, which we'll do in the second half of this year and look for that 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, Jose quite nicely presented again the panel that you see on the left in terms of the ADORA 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 in 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 and 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 Meier's that were presented by stage of disease, we see very consistent benefit irrespective of stage of disease, irrespective of ethnicity and other factors that can sometimes come into play. And so I think that that is a very important characteristic of this data set. Obviously, the studies of ADORA sits in the context of a much broader program of life cycle management. We are awaiting the results in the 2021 plus timeframe from the LoRa study, which would be in the stage 3b, the nonresectable population. Certainly one of the questions that we get is do we think that Adora is a good read through for LoRa? Certainly the fact that we've got positive results from Adora and Flora suggest that the LoRa 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 ADORA study, About 25% of the number of patients in the Stage 1b through 3a are treated today as we see in the Stage 4 setting. So today in Stage 4, 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 Adora 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 data set 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, Greg. And then just turning on to Imfinzi and within IO, again, we are making very good progress with the Stage 3 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 and 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 had 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 3 setting with PACIFX II, IV, V, all of which that are looking to build upon our first mover advantage that we have in the Stage 3 setting, but also between Aegean, BR31, 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 and 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 Christian, who will talk about other aspects of our IO portfolio. Thank you, Dave. Can you give me the next slide, please? Thanks. 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 success, we invested in an all suite of PACIFIC's trials, as Dave already mentioned, with others in neo adjuvantaging setting to introduce fundamentally the affinities monotherapy in combination in stage 1 in treated small cell lung cancer. Our investments in early disease extend beyond the non small cell lung cancer, a study in small cell, liver, bladder cancer, cervical cancer. We also see opportunities to disrupt and establish new standards of care in advanced disease with Imfinzi, of course, 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 are exploring many promising combination with Impezi, including of course the combo, but also with other agents in our portfolio pipeline as well as with chemotherapy, radiotherapy, TACE and BCG. We are also exploring a new wave of assets such as our PD-one, CTLA-four 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 that 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 F2 biomarkers. We have a renewed focus on advancing treatment in liver cancer, which is the 3rd 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 present in your ASCO from Study 22, I think showed promising clinical activity and tolerability with Imfinzi plus pramedimumab, given in the context of a novel regimen for patients with advanced liver cancer. Patients were treated with a single priming dose of trimilimumab, given a high dose of 300 milligram in combination with Imfinzi monthly. And these 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 now the regimen of dual checkpoint located with emolimumab and Imfinzi may play an important role in this challenging cancer and in these patients that do not have so many treatment options. We I think while the PD-one and PD L1 inhibitors have revolutionized the treatment of lung cancer, still they do not have demonstrated the sufficient efficacy as a monotherapy in liver cancer. However, some research is suggesting that CTL-four inhibition may provide more durable, longer lasting efficacy, particularly in combination with checkpoints. So Study 22 is also encouraging a sign for our Phase III studies ongoing in malaria in frontline setting that is testing this exact same regimen in the patient population. The data with malaria are expected later this year. We also have a very robust development program across stages of liver cancer with immunotherapy approaches. The Phase III, MRL1, MRL2 in HCC, Phase III study TOPAS1 in biliary cancer. MRR1 is a combination of Imfinzi or Imfinzi plus nevacizumab and the transalteria chemobolization pace in patients with local regional HCC. MRR2 is a Phase 3 study of Imfinzi or Imfinzi plus bevacizumab as adjuvant treatment in patients with HCC, while of course a high risk of recurrence after curative hepatic resection or ablation. TOPAS 1 is a Phase 3 study of infants in combination with chemotherapy as first line treatment for patients with advanced biliary tractive 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 the focus also in Asia where these diseases are, of course, mostly prevalent. With this, I conclude my presentation. And I think, Greg, back to you. Thanks, Christian. Thanks, David. Appreciate it. So now we have some time for Q and 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 and people raising their hands already. So we 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 Lotzen at UBS. Michael, please go ahead. Yes, thanks so much. I was just wondering, in the Adoura discussion, the point was raised that 45% of patients not receive chemotherapy and the discussant 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 ADALA study? So from screening to actually study enrollment, what was that gap? Christian, is that is that a is that a figure that you've got on hand or is that some yeah. 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. These represent approximately 28% of patients screened then actually enrolled into the trial. And the number of patients at Stage 1b enrolled in the trial were about 30 percent of our patient population, so 212. And the number of stage non-1b, so stage 2 and 3 were 470. This was a per protocol capped the number of stage 1B patients. So 30% was the number of patients that we wanted to enroll in the protocol. Does the answer your question? Yes. Thank you. Thanks, Michael. I'll now move to an online question. Dave, this may be a question for you. It's from Marietta Miemetz at Prima Venues. 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 4. 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 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. Thanks, Dave. We now have a raised hand from Andrew Burns at SVP Leerink. Andrew, I've unmuted your line. Please go ahead. Thanks very much for taking the questions. Congrats on the strong presence that I asked you this year. Maybe this is for Dave. I was wondering when we might see some more granularity on the impact of Tagrisso and brain mets as a potential side of recurrence. And then also when we might see mature OS benefit to discuss and mention the IRISA adjuvant data that showed convergence after the drug was stopped? Thanks. Sure. I'll start on this and then Christian 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 ADORA study. And so we will look forward to having an opportunity to share those inclusive of the CNS data coming up later this year. Christian, 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 metastatic setting, Tagrisso showed clear superiority of Erylesa. And in the adjuvant study, despite a very good as a ratio for DFS that was observed in IRESSA, This was not as good as what we observed in ARESA. Biologically, I think the activity on T790M can explain a different outcome. And as we learn in metastatic setting, it is also possible plausible that in the early setting with tumor lacking heterogeneity, seen at later stages, a more potent and more selective, a geographic AI such as Tagrisso can significantly improve on the efficacy over older generation drugs like gefitinib or verlotinib. And I think that we have some preclinical work showing that Tagrisso eventually can eradicate some higher self kill versus early GFRTKI is able to eradicate some clones. So we need, of course, longer follow-up. We needed to understand if Tagrisso will improve OS by increasing the cure rate or our delaying the disease relapse or maybe both. But I think that we have confidence that this huge benefit observed in BFS ultimately will translate also in a benefit in OS. I hope this answer your question, even if of course we don't have data. Yes, I appreciate it. Thank you. Thanks, Andy. So now we have an online question from Peter Welford at Jefferies, which I'll read out. So on 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 are still on therapy? In other words, what proportion completed the 3 year regimen planned in the protocol? So again on this, I'll invite Christian 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. Christian, anything you want to add? And 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 for the DMC. 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 and 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. It is not varying according to stage. So stage 1b, stage 2 and stage 3 patients stay on treatment in the same way. And it seems not to be worse in 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 many patients. Thanks, guys. Then we got time for one last brief question from Matt Weston, Credit Suisse. Please go ahead Matt. 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 Adora potential and potentially LoRa 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 and 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 frontline are going to be done in the presence of the ADORA data? So we'll try to do that in less than one 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 health care dollar that's being invested. And so I think that it's important to note that obviously as we engage in conversations with payers, that 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 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 are talking about very, very impressive set of results. And we think that we've been able to maintain good value across the globe onto Grosso. And I think that the SEDURA study will allow us to continue to do that. Right. Thanks for the question. And maybe Roderick, this question, if I may, is we need more data, of course, especially on the OS follow-up. But if you look at Aceptin, the adjuvant setting is the most cost effective part of Aceptin. In fact, the cost per quarter in the U. K. Calculated by NASS is incredibly low relative to what you have in the metastatic setting. So if the cost effectiveness increases in the adjuvant setting, we should hopefully be able to manage the price pressure. So we have some price pressure, we should be able to manage it. Thank you, Pascal. I will go to James Gordon at JPMorgan. James, please go ahead. Hello, thanks for taking the questions. Question about Tagrisso. So it was 2 questions 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 complete the enrollment? Is this a study that's way into the future or you actually quite near getting that enrolled? And also so we got helpfully last night, we got the ADORA efficacy broken out by the different stages. So if we're trying to extrapolate ADORA to LAURA is the best fit to look at the stage 3A population where you had 0.12 hazard ratio or is there a reason that's not the way to try and extrapolate? Thanks, James, for the question. Christian, I actually I turned 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 LoRa study. But why don't I start with turning it to you? Sure. First of all, LoRa is proceeding well. There are not safety signal. So in terms of the 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 size, countries. The study is proceeding per plan, but of course, we will is a study that will need additional months to complete the enrollment. This is, I think, where we are. The database lock for LoRa is planned around the end of 2021 or just a little bit after. And then Christian, 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. We need to talk about the study, but I have to say, Dave, we are much more confident after we have seen with ADURA. We believe that based on what we learned in terms of specific readout, this gives us also confidence. We believe the study has a high probability of technical success. Thank you. Craig? Great. Thanks, Dave. Thanks, Christian. Next, we have Tim Anderson from Wolfe Research. Tim, please go ahead. Thank you. Some payers in ex U. S. Countries require overall survival for maximum reimbursement? I'm going to ask about Tagrisso here. I think we all know Tagrisso will yield a survival benefit, but we don't technically have it because the data is immature. So I guess it's more of a commercial question than anything. Would this pullback uptake or reimbursement or pricing of the sninajuvant data in any geographies 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 ODORA helps your argument in China as you're discussing FLORA and whether you might get NRDL listing. Can you confirm that that probably shifts the odds in favor of NRDL? Thanks, Tim. So on those two components, first, as we think about Adora, 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 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 a 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 kind of 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 have Jose, 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 Adora 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. Thank you. Great. Thanks, Dave. Next question, we have Mark Purcell from Morgan Stanley. Mark, nice to see you on the call. Please go ahead. Thank you. And Dave, Christian, thanks for doing the session. First question was just in terms of sort of testing and just thinking outside the U. S. Academic center. So in the US, it's pretty clear how strong these days are, but a very large proportion of patients in the US are treated in the community setting where I think EGFRM testing is around about 65% at the moment. Then there's one thing getting a test and then convincing these guys to actually action treatment on the back of the test. So with those sort of two 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 actioned 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 easy route to treatment for the community oncologist? And then given Craig, I have a couple of questions, just one quick follow-up. In terms of Imfinzi in the adjuvant setting ahead of BR31 data coming out in 2021, Could you help us understand, given you've gone for fairly 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? Thanks very much. Great. Thanks, Mark. I'll propose Christian, 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 ex US and frankly, even in the US, eGFR testing is not common and it is not part of standard practice. I think the predominant reason for that is that you need 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 1b to 3a patients based upon their eGFR status. Adora changes that, we believe. And I think that we certainly heard both from Doctor. Herbst as well as from Doctor. Spiegel, the 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 is a much more difficult needle to move. 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. Christian? Yes. Dave, I apologize I had some Internet connection issue. In the meanwhile, I hope I will not repeat what you 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 pragmatic here. We know metastatic already varies according to the region between 70% 90% depends on the region. Japan probably is the country where testing is the highest across stages. We learn during Adura conduction and with the rest of the program we are having nearly setting that for some stage 3 patients actually testing is done in some selected centers because they're part of specific programs. More rare is in for patient in Stage 12. So and then of course, they've already provided additional information. Christian, the other question that Mark had asked was around the Imfinzi Adjuvant Studies and whether or not and how we saw BR31 stacking up relative to the other studies from a design perspective. Mark, is that a good articulation of your question? Yeah, I think so, Dave. Thank you. It's just Sorry, Mark. I had one moment of blackout with the Internet. No, no, no. It happens. So it's basically like looking at your adjuvant designs for lung cancer for Imfinzi. So for example, BR31. So how are your trial designs compared to others as we enter this sort of period of 24 months when we can 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 CCCG Group. And the timelines are quite stable. COVID permitting, of course, COVID-nineteen permitting because this can carry some level of risk for this specific study that together with the group we are trying to quantify. The study is fully enrolled. So we are data are maturing and I think we are ready for the first interim analysis that should happen soon. We believe the study is highly competitive vis a vis study design and the questions that the study is supposed to answer in this 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 when I think a key message from the presentation today is a refreshed focus, a refreshed energy and enthusiasm around immuno oncology and AstraZeneca's presence and program in immuno oncology. And Kristian, you talked about TRME in Study 22, you've obviously talked just now about BR31. What's driving this refreshed enthusiasm, this refreshed focus? And you think the market fully understands AstraZeneca's opportunity in immuno oncology post MISTI? I guess, discussion both for Dave and for Christian. So David, do you want me to start on this? Yes, please. Yes. I think, Greg, 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 aerospace is the fact on the commitment that we have with our vision. Dave mentioned briefly the Mermade study, Mermade 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 minimal residual disease, MRD, in patients completely resected with Stage 2 and 3 in small cell lung cancer. And then we want to use this MRD concept to predict the relapse and customize the treatment in a smart in a smart test way to be able to go beyond the usual lines, swimming lines, veins. So we want so this is just another example how we think immunotherapy can really make even more difference than what we have seen today. This is our way to see the development of not only Finzi, but all our next portfolio coming in immunotherapy. And this is beyond immunotherapy. Today, we don't speak anymore about immunotherapy asset. And we speak about therapeutic approaches with the backbone of immunotherapy agents. I hope this answered partially your question, Craig. Yeah. And I think Christian, just to build on the comments that you have made, I think that the enthusiasm comes, as Christian 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 Christian highlights, Study 22, I think very importantly also introduces important data around single high dose tremolimumab. 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-four, which obviously is something that's been an important area of investment for us and look forward to seeing the Himalaya results. So we've got about 1 minute left. So the last question of the day goes back to Mark Purcell of Morgan Stanley. Mark, please go ahead. Thank you. So the question is, well, there's 2 very, very quick ones. So could you help us understand how important the Orchard and SABANA trials are when it comes to the Tagrisso franchise, when we will get data and the potential benefit they can show in terms of prolonging therapy. And then secondly, we haven't heard much about your PD L1, CL4 bispecific. So when should we get more data on that and that compound? How enthusiastic are you about that given your comments there, Dave, on the Study 22? Yes. So why don't Christian, I take the first question from Mark on Orchard and Savanna, 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 1. 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 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 4 setting and diagnosed in the stage 4 setting. Today, 60% of lung cancer patients are diagnosed stage 4. And so I think any and all efforts that we can make to get more responders and 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 2,030 on this medicine. So we are still very much in a life cycle maximization stage. Christian, on the bispecific? Yes. This time, Mark, I heard the question loud and clear. So the I mean, this meeting, this ASCO meeting was very important for CTL4 inhibition in my view, not only for our data and also from some additional works that have been presented with a combination of CTL4 inhibitors and checkpoint inhibitors. So one of the major issues with the CTL-four 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 a CTL-four inhibition. But we also believe that our CTL-four PD-one bispecific can represent a valid alternative of what current is available and a more convenient approach because hopefully it will be combinable also with other partners. So, capital and story short, Mark, 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. That's great. Thanks, Christian. Thanks, Dave. So we 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 would be much appreciated. And all it 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 InHER2 in breast cancer, with the opportunity to meet the members with members of our company's senior oncology team. Today, I'm joined by Jose Bezelga, who leads our oncology research and development Mika Sowak, who is our global franchise head for Inherto and heads up Inherto in breast cancer and John Weldon, our global product leader for Inherto Lifecycle Management. This session will last 30 minutes. There will be a short 5 slide presentation with the majority of the time reserved for Q and A. The presentation materials are available at astrazeneca.com/investors, and we've also sent it 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 employee of another pharmaceutical company, please disconnect now. To ask a question on the Zoom webinar, please raise your hand using the icon in the menu bar. During Q and A, I'll open your line so that you can ask your question. Alternatively, you can type your question into the Q and A dialog box, which is also located in the menu bar at the bottom of your screen. Please do not use the chat functionality for Q and A as this is reserved for technical queries only. If you've joined the Zoom webinar using the telephone numbers provided, please press star 9 to raise your hand. That's star 9 to ask a question. And would you also please only ask one question? Thanks in advance for that. After the event, recordings will be available from each breakout session. So please turn to the next slide. Now I have to remind you of 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, Jose. Thank you very much, Tom. It is a pleasure to be here with all of you all virtually. I'd like to give you an update on and her too. I'd like to just start with some data on our on our launch. The launch has been strong despite the COVID-nineteen 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 and HER2 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 and 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 present in due time update on the introduction in the overall risk and severity for ILD in patients receiving nHER2. If we go to the next slide, please. So we are going at pace in the development of ERN HER2. 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 positive 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 data set is with gastric cancer. This is the data that was presented on our randomized Phase 2 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 positive 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, it's north of 85%, 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 an HER2 of 12.5 months, again in the 3rd line advanced gastric patient population. We have achieved a breakthrough designation, an Orphan's 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 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 data set 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 positive colorectal cancer, had received an extensive number of prior lines of therapy, including a number of them that had received the prior therapies and what we have reported is a 45.3% objective response and a median PFS of 6.1 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're well aware not only of our HER2 data that applies to breast cancer and to our Capiva Serti program, we just enjoyed last year at ASCO, some of the critical data that was presented in fact, but this year, for the first time, we are presenting the clinical activity of our oral SERD, AZD9833, on the shoulders of the preclinical presentation at AACR 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 CDK 4 and prior full spectrum 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 this class of agents, but the number of patients that had interruption due to bradycardia or to other side effects is quite low. So we are 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 positive 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 answer session. Thank you. Yes, that's all right. Thank you, Jose. And we're now going to Q and A. And please limit yourself to one question. Perhaps we'll go to the first question on the call, which comes from James Gordon. I'll just unmute James. It was about in HER2 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 Friday afternoon, was noting that the study that 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 called Caucasian enrollment. And also just on the regulatory, the other bit was just the lung study, it wasn't quite clear whether you think you might be able to find a 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 breakthrough therapy there. So thank you very much. I would like to have asked John Willdan if he could answer the two questions regarding the regulatory path both for the gastric and for the lung cancer studies? Yes, of course. Thank you for the question, James. We'll take them in reverse order. So for Lal, I just want to remind everybody that obviously we already have the breakthrough status and therefore you obviously, you 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, did get breakthrough and also orphan drug status for gastric, again announced quite recently. You are correct, there is another study that is ongoing. It's DESTINY Gastrico 2, which is in a European and US 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 agency would request that, but obviously it's useful to have that study running. And if they do, we can provide that data. Thank you, John. Right. So our next question comes from 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 frontline, working your way all the way up to adjuvant and neo adjuvant. 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, you know, is the develop are your aspirations the same? So are you just as confident now that you've been pushing the things like adjuvant? Because it seems like with breast cancer adjuvant, you're talking about women that at baseline are very healthy, that have single tumor burden and to potentially expose them to permanent IPF is just a non starter. So I think that IPF is something that from a risk benefit standpoint is very acceptable in later lines, but in early lines, is it really that realistic? Sorry, IPF, you mean ILD? Sorry, yeah, ILD, interstitial lung. Okay. Yeah. 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. And we all, all along, have been aware of the ALD 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 Daiki 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. Thank you. Okay. So our next question comes from somebody on the phones with a number ending in 3.04. 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. Hi, Jo. Go ahead. It is you. My question is about the 3rd and the emergence of visual disturbance. We're curious to understand if you think it's of a concern. It's the only third 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. So I'll take that myself unless, Mika, would you like to take this or would you like me to take it? Go ahead, Jose. Yeah. So, what's 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 this change in the life condition. So for example, these patients explain that this occurs sometimes early in the morning when they wake up or sometimes at night. So this one it lasts for a very short period of time. It does not interfere with any of their physical activities. So for example, a critical question that you ask is that it does not interfere with driving at all. It goes away from what we know in this still early days. It goes away after the first cycle, so there is a tachyphylaxis to that. And if you look at the at the old ER therapy bibliography, visual disturbances is a class effect of ER interception. So to us, it's a sign that we are 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 point I'd like to make is that patients have not been discontinued because of this disturbance. It's very minimal. Thank you. And our next question comes from Mark Purcell. I will just unmute you, Mark. Hey, Tom, can you hear me? Yes, can you hear you now, sorry. Fantastic. Thanks very much. Jose, thanks for taking the session. Quick question, in terms of the plans that Daiichi have outlined in their 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 2 studies with that objective. And when you sort of think about the responses you're seeing, with the TROP-two, we saw some late responses. I just wondered if you saw some late responses also within HER2 as you explore different tumor types, including lung, and what bearing that has in terms of this sort of pan tumor approach she may take? Thank you so much. So just to be 2 questions here. 1 is which is our pan tumor approach to get approval in our indications and then the issue of the late responders. John, would you like to take this because this is mostly non breast cancer? John? Sorry, Jose, can you hear me all right? Yeah, perfect. Yeah, I heard your question, Mark. Thank you. 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 a 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 responders? Jose, do you want to comment on the late responder data from your perspective? No, no. You go ahead because I mean I don't have a particular view. I mean the go ahead John 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 responses 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. Thank you. And I think our next question comes from Andrew Baum. Andrew? Can you hear me? Yes, we can hear you. Perfect. Jose, could you talk to the assay and the criteria you're using for Loha2 in the ongoing Phase 3 trial? Are they identical to the criteria and the assay that you used in the Phase 2? And then since we have you, Palace 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 spirits of thinking through learnings of trial design or perhaps the dangers of cytoplasmics 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. Thank you, Andrew. 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 3 studies in the LOCKH2 and what we are doing in the future. I'd like, Mika, if you could answer this. And then I'll come back with my views on PALAS, if I could. Micha? Yes. 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 2 and the Phase 3, 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 have an active program trying to figure out ways, you know, are there innovative ways using potential 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. Patients. Jose, back to you for Pallas. Thank you. So Pallas, I'm still digesting these, Andrew. It's a big surprise to have a class of agents such as CDK4six that are so incredibly active in the first line setting, and then they felt 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 does it disrupts in full the whole strategy in early breast cancer. I think an obvious explanation is that is one that the Phase 2 compliance. All the insights that we have received from multiple investigators and again all this is soft intelligence and there was also some neo adjuvant studies that were presented here at ASCO with other CD4 inhibitors support the notion that it is really hard to keep these patients in the adjuvant setting with a CDK4six inhibitor and hence their major compliance issues. So that's point number 1. Point number 2 that could be at play here is that unlikely positive breast cancer, ER positive disease, the relapse rate is continuous over many, many years. So it's a different proposition that in triple negative, the lapse 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 Paolo. So they are not preventing these recurrences 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 positive breast cancer. Many thanks. Okay. So we do have a few questions in the question and answer session, We've got time to answer those. So a question from Steve Hamill. Can you discuss the HER2 low data presented for HER2? Are you concerned that this is a negative signal for in HER2 in the HER2 low cancers, particularly breast? Is this the data on colorectal? No, sorry. I think it's potentially asking if it's the colorectal data has any implications on breast, perhaps. Yeah. Yeah. Yeah. I can take that. I don't think you can make any truly any correlation. That's why you do the studies in different studies. We have robust data in studies. We have robust data in low expressing HER2. And the biology of colorectal is very different than the biology of HER2 positive 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 positive low breast cancer. Okay. Thank you, Jose. And another question on the in the Q and A dialog box. Can you elaborate by what you mean by global regulatory submissions underway for gastric on Slide 5? Are you filing globally on Destiny Gastric 1? I think John 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 data set is a Japan Korea data set, 80% of the patients from Japan, 20% from Korea. We are, as you know, running a separate study, Destiny Gastric O2, to support that in the Western population in Europe and the U. S, but there clearly is some 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 and 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 slide right now. It's called SIRENA2, 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 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, Jose. We'll take question from Michael Lupton. Thanks very much, Tom. So the question is for Jose on biomarkers. There was data presented at ASCO on the Catherine data looking at biomarkers and splitting the groups that way. And it didn't really show much difference on how TDM-one performed in that study. So as we are thinking about how in HER2 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? Thank you. 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 on all the variables. Many of the biomarkers that have been used in the past, for example, and I led some of these studies, example, PIS3 kinase mutations as an indication of resistance to Herceptin and birtuzumab with very clear data that these patients benefit the less. I don't think they would apply to an HER2 just because basically the key mechanism of action of HER2 is not to block the signaling pathway of HER2. In this case, PIF kinase could play a role PIF kinase mutations could play a role in persistence, But rather, this is an incredibly potent 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 and A dialog box from Sam Fazeli. Could you please explain why you're thinking HER2 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 John to comment. 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. Doctor. Sienna did present it for the colorectal and he made the 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. It's very important. There's no doubt that there's a 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. Thank you, Sam. Any comments on the question on adjuvant was for colon cancer or was for breast cancer? I think it was for gastric, adjuvant setting and gastric cancer. Yes. You want to comment on that, John? 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, any GM published a few days ago. Inevitably, we started to look at this. Absolutely, we need to consider all the frontline options just as it's being considered for breast cancer. So it will be there, yes. Okay. Thank you. Our next question will come from the live call, which comes from Simon Baker. Thanks so much for taking the question. It's kind of related to Sam's question on gastric. I was just thinking in the totality of what you presented in terms of the response differences between IHC 3+2+2. I was just wondering if that has any relevance to your thinking about her 2 low breast. Is it relevant? Has it changed your views on the potential there? I just wonder if you could give us some thoughts. Thank you. So I'd like John comment on the gastric data and then I'll give you my views on the HER2 low breast, if I may. So John, why don't you start and then I'll go on. Yeah. So as we've said, it's early days, but I'm straying into your space now, Jose, 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, you know, as we've mentioned before, there's a significant data set 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. Yes, we'll continue on that. Where we have the base dataset actually is in is in her to 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 suppression. We have learned that they are very different diseases. So we need to go disease by disease on this one. Okay. Somebody said that's okay. We'll move on to the next question from Carl Brown. Carl, have I unmuted you? Sorry, we can't. Karl, if you'd like to unmute yourself, you'd be able to ask a question. No? Okay. Karl, you can now ask your question. I'm sorry about that. Okay. Can you hear me now? You can. We can. Yes. Okay. Good. I was just curious, a competitive agent Tucatinib spends a lot of time talking about the data that they presented in 3rd line breast in patients with CNS metastases. I believe in the HER2 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 in HER2 is versus Tucatinib? Thanks. Thank you. And that's a great 2 sort of questions. And it is indeed we've had patients with brain metastases in our DESTENIC study. So I would like to hand over to Mika to respond to questions. Mika, if you could. Yeah, absolutely. So I think it's, we've definitely been looking at the HER2CLIMB data. I think any data for patients in HER2 disease, they've definitely showed 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 2 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 they were randomized study, but PFS of the same number in their patients. I think it's important when a physician is considering the best treatment for their patient, they have to consider many factors. Brain mets 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 the ducatinib. I think they've actually gone into a disease area where patients have normally been excluded. So I do see that that's very valuable data they've done that. We're looking forward also to the additional NF2 data that we'll be able to see in patients with brain nets. So for our next question, we'll go to the Q and A box. Luisa Hector asked a question, which is how is in HER2 ILD awareness campaign progressing? The ILD event rates severity varied across gastric, lung, colorectal. Why? Timing of awareness, tumor type, lung doctors detecting more efficiently? How is the IRD 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. Yeah. So in terms of the as we have just launched nHER2, 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, almost doubled what we saw. So we are starting to get more information. And all the early data really is very promising that the key really is around education and awareness and that this is what is really important in the management of ILD. Think we also presented additional data at ASCO 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. Okay. Thank you. I think if I may to have, Luisa, it might take a few I mean, the reason why we present the data, but it's taking a it will take some time for us to gather these 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 acquires 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 to be able to present. Actually, I see Louise had also raised her hand for the live Q and A. So I can go over to her to just ask if there's any follow ups you'd like to ask. Sorry. No, that's absolutely fine. Thank you. Brilliant. Thank you. And so our next question comes from Seamus Fernandez. Seamus? There we go. I just unmuted. My question, just two things. Jose, 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 CDK4six market and kind of the ER positive patient population? I know you've got a few shots on goal there, especially as we think about the oral surgeon. And then just a quick question. And HER2 looks extremely impressive in the CPI refractory patient population, but we saw a slightly higher rate of ILD. Can you just help us understand, is it possible in your minds 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 HER2 in all three of these settings, it would seem like there certainly is. Yeah, I'm sorry, I missed the question on the combination in lung cancer recombination. The ability to combine a PD-one, a CPI test. Okay. Fantastic. Fantastic. Good. And some of the higher rate of ILB. Yeah. Yes. Got it. Got it. I got it. So, the PALAS study in CDK4six, it's we need to digest the data and we need to see what went on. It's a surprise to everybody, myself included, on how such an active therapy combination in the first line setting, in the aesthetic 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 CDK4six inhibitors. As you know, these therapies have side effects. And 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 1. And then point number 2, ER positive disease in the juvenile setting, the current rate occurs over multiple years. So it's a constant decrease in when the events occur over multiple years, it's very different to triple negative breast cancer And hence, it could well be that 2 years of therapy with a CDK4six inhibitor is not enough. Having said that, I think that is going to be a whole new world when it comes to early year 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, the Nikky Sankyo and ourselves, we are involved in a number of clinical studies as we speak. We are fitting these patients and we don't have yet it's too early to 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 John, if you could comment on it. Yeah, sure. So across the 3 datasets that you've seen today and over the weekend for ASCO, Just to remind everybody that the HER2 mutant lung cancer population has already received a breakthrough designation from FDA. So obviously there's a lot of interest there. And similarly the gastric data, which as you saw from Jose's presentation is going to be submitted globally. That's also received breakthrough 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 Jose, if I may build on your point, there are 4 studies currently running with, so 3 studies currently running, one about STAR in combination with a different, PDFs checkpoint. Thank you. Okay. 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. Thanks very much, Tom. So perhaps I could take a question on the theme of adjuvant follow-up, I guess. You've initiated many studies, including neoadjuvant now. I know, Jose talked in the past about being optimistic for a place for an HER2 in the adjuvant setting yet to initiate that study. I think Daichi described it on the weekend as under consideration. So perhaps you could just give us your latest thoughts there. Thanks very much. We are not ready yet to share what are we going to do because it's still the middle of discussion, Emmanuel. So as you can imagine, there are multiple countries to be taken. Now by the way, the PALIS data is not affecting HER2 at all because it's a complete different disease, right? So it's a complete different disease scenario. 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 CLIA pathway, which is the Herceptin pertussumab study. So I think there are 2 possibilities, if you wish, and HER2 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 would need to take into consideration is the possibility of de escalating 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 not yet ready to share what we're going to be doing at the end. Very helpful. Thank you. Okay. 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? Sorry, if there's no one else, I'll carry on. I'm struggling somewhat to understand the clinical development strategy. You've got a the only Phase III ongoing is in combination with chemotherapy 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 with CDK4six and HR positive breast. So just your thoughts in terms of where the clinical development for COPILASertib goes from here because the FACTION data seemed to us certainly very good. Yes, right. So we're going to be starting Phase III studies precisely on the function clinical trial at the backs of the function clinical trial design. So we're going to be launching studies in ear positive disease. As you can imagine, we are contemplating the possibility of exploring a combination with a checkpoint blockade in triple negative breast cancer. We're going to have also on a strategy in patients that are receiving CDK4six inhibitors. So it's not just restricted to the triple negative, but rather we're going to have a number of studies in ER positive disease on the shoulders of the function data. In addition, I'm sorry, in addition, I'm sorry, to the prostate cancer programs as well. And are we likely to see that go into Phase 3? Yes. Okay. Thank you. And then we do have a couple more questions in the written Q and A dialogue. One, a follow-up 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 within HER2 relative to the institution of AZED's prescribing procedures. Is there anything further we can say on that? We don't have the data yet, Mika. No. Sorry, I'm not complete if the question is around the impact of recent guidelines, I think you're right, Jose, we still they've been implemented, but because it does take several months before you see the event and the number of patients, we don't have any updated information as of 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 Hun, who has asked in the Q and A chat on the Phase III SIRD program. You mentioned multiple Phase III studies. What combos or approaches are you looking at? Yes. Well, I would qualify multiple. We're going to have a number of Phase III studies. We are not yet in a position to announce them. 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 Jose, to Mika, to John 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 will be a short 5 minute presentation with the majority of time dedicated to Q and A. I hope you like the virtual setup and the potential to interact with Susan and Greg. The presentation materials are available on astrosanecar.com/investors. 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 are 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. To ask a question in Zoom webinar, please raise your hand using the icon in the menu bar. I will then open your lines so that we can ask your question. Alternatively, you can type your question into the Q and A dialog box also located in the menu bar. Please do not use the chat functionality as this is reserved for technical queries only. If you have joined the Zoom webinar using the telephone numbers provided, please press star 9 to register. We ask you to please ask one question only and we thank you in advance. After the event, recordings will be available from each 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. Welcome everybody. Appreciate your interest in Lynparza. So across this year's ASCO builds upon the impressive data sets, 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 myeloids from this here. I think I just point out that CD19 and the long term follow-up actually showed a hazard ratio for OS of 0.62. And in all of these settings, we're seeing impressive tails on the curves. And we're now extending with APALO-one data, of course, into the HRD positive group. At this ASCO, we've also solidified these data set with now OS data for SOLO-two but also multiple other trials have read it out. OPINION is in non germline BRCA platinum sensitive relapsed in a maintenance setting and actually showed a median PFS overall of 9 months, including activity in somatic BRCA patients 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 gbreca, somaticbreca, HRD positive and negative, we saw impressive response rates in the BRCA groups, 69% 64% respectively, And in HRD positive, it was 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 positive group. GY004 group study from the NRG presented by Joyce Lu looked at olaparib versus doublet platinum chemotherapy and to doing a 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 brachycard group, olaparib and olaparapaciderinib both have response rates of about 90% and an improvement trend in PFS of 12.7 in the olaparib group at months versus 10.5 in the chemo group and 18 months in the olaparib plus adeuverinib arm. So I would think you would agree that the totality of these data just show the impressive activity that we have with olaparib and ovarian cancer. You want to the next slide, please. So what this slide shows is, first of all, is the updated PFS data on the left hand side with 63% maturity, again reminder of hazard ratio of 0.3 there, but also the tail on the curve leading to significant long term improvements in the time to first and subsequent lines of therapy. And that's translating through now to a median 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 patients at 5 years were alive and not have received subsequent therapy. This is really impressive from a patient's perspective. Next slide, please. So I just want to remind you briefly about the PALO-one study and the design of that. This is in patients that had 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 selection by surgical outcome or BRCA mutation status. And patients randomized 2 to 1 to LYNPARZA plus bevacizumab or placebo plus bevacizumab for 2 year duration, the primary endpoint being progression free survival. And around half of those patients overall were HRD positive, as you can see on the right hand side. And what you can see from the, the, the, the, Kaplan Meier curves is that actually that half of patients were HRD positive had more than 3 years progression free survival in that group which is a really impressive number. Next slide. So what we've done with PALO1 is we've done an analysis, as we promised, and when we presented the PALO1 data at 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 had no evidence of disease. So if we do that with the Paula population and look at these hazard ratios and Kaplan Meier curves here, what you can see is that alapriplofenesis map, again, you've got 36 month impressive medium PFS. Niraparib alone has around a 22 months medium 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 premium population is it, you know, reinforces that if you are eligible for vervacizumab treatment, this has been by far the most robust medium 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 of olaparib 2 bevacizumab both have around a 15 to 16 month medium PFS that's the blue line and the green line that you can see on the right hand side. Actually a placebo has around 5 months median PFS and the raprip 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 lymphasa 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 setting. 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 ADORA 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 400,000,000 of quarter 1 sales representing 69% growth over the relevant quarter from last year. Around 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 1st 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 SoloOne. 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 Solar One because of the unprecedented value that it provides in that biomarker directed population. And obviously, with parallel 1, broadening that population by 2, to represent the HRD positive 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 sort of 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 polo 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 press release to say that we have overall survival data now, and that was included in the U. S. Label. And we hope that that is going to also try rapid decision making in the rest of the world and access in the rest of the world. So we can bring these important medicine to a 4th tumor type of biomarker directed therapies, the first one in prostate cancer. And I think that in each of these cases that 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. It's not just these indications. You see here on the left hand side, the overall survival data from PROFAN 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 SOMO2 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. And 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 directive. But remember that about a quarter of patients with prostate cancer have got this HRM mutation phenotype. And it's I think very notable and impressive that we have the full HRM mutation label in the U. S. For the PROFAGON 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 augurs well for our Olympiad 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 divalumab combination in ovarian cancer. We announced this ASCO, another Phase 3 trial in progress in endometrial cancer, in frontline endometrial cancer. And we continue to prosecute trials to understand where the combinations with our portfolio and this particular agent can drive clinical benefit and commercial value. So I'll stop there and hand back to Nick. Thanks, Greg. So we'll now move to Q and A. And as a reminder, we'd really appreciate it if you could just ask one question. So please raise your hand using the icon in the menu bar. What I'll then do is open your line and introduce you so that you can ask your question. Alternatively, you can also ask a question in the Q and A dialog box, which is located in the menu bar. And then, just a reminder not to use the chat functionality because that's for technical queries only. And if you did join the Zoom webinar using the telephone numbers provided, then please do use star 9 to register the fact that you would like a question. Perhaps now we will take a look and see if there are any questions. 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 Paolo 1 opportunity in HRD because I think it's obviously a very compelling opportunity. I think you highlighted obviously within the slides the 50% opportunities. 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 we 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, you know, to some degree, the definition of, you know, platinum sensitive relapse is going to change because of the degree of activity that we've seen in HRD positive. Craig, any comments from you? Yeah. I think there's maybe 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-two or whether we're talking about SOLO-one, which have 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 that 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-two. 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 the 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-two eighteen and others. And I think now we're starting to see that HRD negative patients, the bevacizumab containing regimens are really a must. And I think that an olaparib containing regimen with bevacizumab for an HRD positive is clearly something that is going to provide a very, I think, supportive value proposition to physicians and patients. Thanks, Greg. Again, just a reminder to ask a question in Zoom webinar, please raise your hand using the icon in the menu bar. I'll then open your line and you can ask your question to Susan or Greg. Alternatively, if you are feeling a little shy today, you can obviously ask your question in the Q and A dialog box and I'm more than happy to ask that on your behalf. Obviously, please don't use the chat functionality. So I'll give it a little bit of a moment more. And if not, I will tee up 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 part. So I'd love to again hear your thoughts around that. Well, 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 was was actually pretty impressive. And what we've seen is activity, not just on RPFS, but on OS across the panel of genes, that that 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 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 event in the prostate cancer setting. And so the hazard ratio for survival benefit that we saw in PROfound, I think is a very exciting event when you consider that these were heavily pretreated patient population. And again, I think the other thing that I would say is really nice from the PReFOUND data is that the circulating tumor DNA testing link, I think, is something that we're working on as well, but that we've seen on other trials actually in the Study 8 dataset that we could double the number of patients that were identifiable as having an HRRG mutation by looking in plasma circulating tumor DNA, not just in the tumor tissue. And that's very important in prostate cancer because a lot of patients obviously have bony 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? Yeah, 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, you know, over and above the PFS and the OS benefits are really important for patients with this disease. And we could see actually that the PFS benefits really track 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 and the patients. And this is against an active control. This was not against placebo. This is against an active control. So I think that 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 Solar 1 and we're seeing it with Olympiad when you look at the first line versus the subside, you seem to see even better outcomes. And so getting this drug into the first line patient population in PROSPI, 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 Slaughter for breaking my duck and giving us a Q and A on Zoom. So Steve 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 is positive. So normally, there'll be something around about a 60 day period between when we get a CHMP positive 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 polo is 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 a 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. Thanks, Craig. So again, just as a reminder, to ask a question in Zoom webinar, please raise your hand using the icon in the menu bar and I'll then unmute you and you can ask your question. Alternatively, you can obviously type your question into the Q and A dialog box and then we will obviously answer your question from there. In the meantime, maybe just one last question from me. I guess the question is, we saw on the last slide a little bit around the lifecycle management program for Lynparza. So I guess, you know, 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 Bracker indications and the HRD positive indications? I mean, I think people just obviously keen to understand maybe what are the next set of catalysts around that lifecycle management? So let me start if I might and then I can go on because we obviously it's already indicated that you've got the tivolumab 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 as it moves early into early lines of therapy, then what do we do when those patients that haven't got to the 5 years without requiring a 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 have become resistant to PARP inhibitor and do so because of some form of restoration of the ability to repair DNA via the homologous recombination pathway. And we know that if you look at combinations of elaparib with drugs like our ATI inhibitor, we can overcome some of that resistance. So we've seen some proof of principle data, both preclinically and clinically, and we have 2 trials that I'll be interested to see readouts in. One is the Violett study in triple negative breast cancer in combination with the Alaparib, and the second is the DUET study in part resistant ovarian cancer. And again, in both of those studies, we're collecting tissue for, you know, 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? Yeah, and I think that summarizing. I think we're certainly pushing forward, I think, very much in the disease areas where we know that there's likely PARP sensitivity. So we've talked about Olympiad, 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 earlier 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 the ParaOne and SolarOne? And can we add to it with the tivadumab combination with Duo. I think that if we go beyond what Jose Baselga might call the canonical tumors, So prostate, pank, breast and ovarian. Are there other places where there is PARP sensitivity? We think endometrial as well. And so the study that we've 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 other driving mutations? You know, is a question that we're looking at in Phase IIs that we'll hopefully report fairly soon. The same is true in bladder cancer, which we'll report fairly soon. And we note from this meeting again that the TAPER trial has reported out some data. 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. Thank you. Question for Greg. Just on the immediate opportunity in frontline non gbraca breast cancer ovarian cancer. Your competitors have quite a powerful dialogue with clinicians and patients, particularly in the current context of COVID-nineteen. They also don't have the same breadth of commercial opportunities as perhaps as you do. And they also derive 100 percent 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 that the most important thing in the COVID-nineteen situation that we're finding out 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 a sort of a, if you like, a clinical imperative. And I think that the conversations we've had, at least in the US, have resonated very much in terms of the clinical value proposition. And I think that whilst COVID-nineteen 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 US 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's already said and we've already demonstrated that the benefit risk in this setting is substantial. So even during the peak of the crisis for the most important areas, we didn't see a drop off 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 you know first off and then you know we'll build it from there but 37 months is not to be stiffed up in terms of the opportunity. Thank you, Andrew. We also now have a question from Matt Weston at Credit Suisse. Matt, please go ahead. Thank you. Thanks for taking the question. 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 V1, ATR and some of the others in the portfolio. Could you just give us a quick round up 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, we won in a subgroup of endometrial cancer called uterine serous carcinoma. And I think that'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, this was elegantly, gone through both by the presenter and then the discussion, 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 V1 inhibition. In that patient population, whilst you do still see GI side effects, which we've seen with V1, these were tolerable and patients were able to maintain on therapy, which again is shown by the ability to maintain the responses that were seen. So I think that's an exciting opportunity that we'll be looking at further. From a combination with a LAPA 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 you know 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 follicles recombination capacity either through BRCA reversion mutations or through other changes. You can have loss of BRCA 1, 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're 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 resistant setting with a combination of ATR and olaparib. We've got 2 ongoing phase 2 studies, the VIALET study in triple negative breast cancer and the DUET study in part resistant ovarian cancer which I think are both going to be very important and should be starting to read out some indications from that 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 was seen it wasn't as you know high a level of activity as you see in the bracon 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 and that's another place where I think there's real interest for combination with a modality that causes double strand DNA breaks. So you know 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 combinability and the places where these drugs will be used best. Thanks, Susan, for the answer and thanks, Matt, for the question. We're just coming up to time. So perhaps one last opportunity for our attendees today to ask a question in Zoom webinar. So please raise your hand using the icon in the menu bar. Nick, there's a question in the Q and 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. I don't 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 chemo radiotherapies 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, you know radiation therapy is used as one option in the with curative intent early in the in the disease and again associated also with the use of brachytherapy in that setting. I do think there's an opportunity to further enhance local control by looking at a radiation sensitizer And you know, but it's not the only place. I also think that the introduction of more radioisotopes, you saw some data actually on PSMA tagged 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 ASTRO 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 the 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, Lee. 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. At the end of this webinar, you will receive a request for feedback, so please do take the opportunity 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, everyone. Good afternoon. Welcome to AstraZeneca's Capital Markets event from ASCO 2020. I'm Henry Wheeler, and I'm your moderator for today, a member of the AstraZeneca Investor Relations team. I'd like to welcome you to the virtual breakout for 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 the majority of the time reserved for Q and A. I hope you like the virtual setup and the potential to interact with Michelle and Andrew. And 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 people on the distribution list. Just very quickly before I hand over to today's panelists, I'd like to remind you that this meeting is being recorded. So, by continuing to participate, you are consenting to be recorded. If you don't wish to be recorded, please disconnect now. And also, as a kind of 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, please do disconnect now. So, to ask a Zoom question on webinar, please just raise your hand using the icon in the menu, and I can open the line, so that you can ask the question or you can type your questions to the Q and A dialog box, please not on the chat because this is for technical queries only. And also, you can do star 9 if you're dialed in or you can just email me as well. 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 two and a half 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 Q1 of 2020, what we've seen is that Calquence was the number one 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 Q4 of last year. And you can see a real inflection point in the Q1 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 are continuing to build upon the launch that we've seen in the early weeks and that's carrying through this year. About one out of every 3 hematologists, now have prescribed Calquence, and about one 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 twenty twenty, we're anticipating broadening our reach across the world with worldwide launches coming later this year and then throughout 2020 as well. And 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 data sets 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 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 CalPens 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 we'll 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 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 heme franchise from being focused on CLL and mantle cell into other lymphoid disease, into myeloid disease, into melanoma. I'll give you some examples of the compounds that we're doing that help us kind of drive that. So on the first slide, some compounds which are really in Phase 2 at the moment. So this is the next wave of compounds. The Mcl-one inhibitor 5,991 is being taken forward, but there's a monotherapy and in combination, particularly in AML, but also in MDS and has broader potential, including solid tumor disease. Again, what I'm showing you here is some preclinical data that was shared a while ago. You can see in this particular example, we're showing combination with ZELCADE. Again, you can see that whilst the agent is impressive in its own right, it's actually where we start looking in combination that we really see full regressions and ability to drive a very deep level of tumor cell kill, which again we think is going to translate into something you know, 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 regime. It 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 potential in combination. You can see the preclinical data here is with acalabrutinib, but we're also very interested in, the combinations with venetoclax, polytusumibut, etcetera. So we'll fit that into the treatment paradigm. If I go to the next slide, some agents which are perhaps more in Phase 1. And again, these will be, some of these will be familiar, others less so. So on the left hand side is 0466. This is a dendrogram presentation of a BCL-two XL inhibitor. This is the 3rd in our family of cell death inhibitors that goes to CDK9 and MCL-one. 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. You can see in this model, we were able to, the mice were completely tumor free nearly 6 weeks after we'd finished the dosing. In the middle is, an ADC, which has come forward. This is, as a PPD warhead. It's a 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. Not going to share this 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 3 in breast cancer, triple negative and in prostate cancer. Also been doing a lot of work looking at how cabivosertib can be used in hematological disease. And here again is some combination data showing it does with acalabrutinib in an ABCD or BCL 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. So 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 1 and Phase 2. 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 HEAM's targets as well as targets in solid tumors. They will be coming through in the next period. Over on the right hand side, we have worked in epigenetics for a number of years. We a PRD4 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 the middle cell based therapy is clearly an area where others have demonstrated the utility that was sort of 1st generation CAR Ts. Clearly, I think that area is now prime for others to come in. We will 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, but 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 that longer term future as well as the near term opportunities we've highlighted. So back to you, Henry. Thank you very much, Andrew and Michel. So we'll now move over to Q and A. So as a reminder, you can just raise your hand if you want to ask a question through the Zoom icon or type a question in the Q and A box or send me an email, henry.bruelaastrozenica.com. 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 frontline and relapsed recurrent data last year and there's a bit of an update at ASCO here. So maybe summarize the data set that we have with the update and how you think we differentiated BTK class today? [SPEAKER DOCTOR. HELEN COLLINS:] Helen Collins:] 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 frontline setting as well as ASCEND in the relapsed refractory setting. And the ELEVATE TN data showed us that a really unprecedented PFS data. So 90% relative risk reduction in disease progression with Calquence plus SCYVA versus G chlorambucil, which is really exciting data. And then the 2 year, 24 months PFS for Calquence cassiva 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 cardiac toxicity, 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 CalClense. 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 CALPONCE. And as I mentioned that even with the long term treatment, we're still seeing very compelling safety and tolerability data. And 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 have other comorbidities, both efficacy as well as the safety and tolerability profile is very important for this patient population. Thank you very much, Michelle. So just a reminder, if everyone has any questions, just don't be shy. 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 on Q1 on Calquence and new therapeutic starts for BTK inhibitors. So Calquence now counts for 25% of NCS 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 KEs? 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 Q4. So the first starts that we saw in the 4th quarter were, of course, some patients in the frontline 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 Q1 of this year, this is really, I think, showing the shift in the launch trajectory that's coming with the experience that clinicians are having with CalPENs. And now we have about 50 percent of our patients are being treated in the frontline setting and about 50% being treated in the relapsed refractory setting. So we're really encouraged to see the shift towards that frontline patient population. And what we're hearing from the treatment community is 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 loyalists to CalPence, 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. Thank you very much. Yes, we're actually getting some questions in at Remo now. So, Chung from Croats Twist. Can you summarize the combination studies, including with Cowplent's? And which do you think has the Croix's potential? So I don't know whether that's Andrew, your combinations or Michel, you want to take that? And I can maybe start off and then Michel can comment on the ones which are sort of running at the moment. I mean, I think what we see with Calquence, the cell death agencies, we see a degree in which Calquence can prime cells for cell death, as Tony Letai would describe it. So treatment with Calquence really sensitizes a number of cell types towards programmed cell death, which can be delivered with 1 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, but 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 direction of trouble. So Michelle, maybe I could hand that to you now. Yes, absolutely. And again, just a reminder about one of our clinical trials that's ongoing. It's the 3:11 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 looked quite good. And so we're hoping to be able to see good efficacy data come out of the study as well. Okay. Thanks very much. And Trung had another one, just on multiple myeloma and the ADC. It's quite a competitive area. Why do you think this is a best in class product? Well, I think I mean, obviously, we haven't 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 of 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're seeing so far, I think, is encouraging, but not yet ready to share the numbers on that. Okay. Thank you very much. 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 in the pipeline. So maybe I could pick 3 things that I'm excited about and obviously, I think people might get excited about different things. I think bevacertib is a huge opportunity for us, particularly in lymphoma. And we've seen PI3 kinase AKT pathway be really important in other areas. We understand in particularly in DLBCL, you know, the patients where there is an addiction to that pathway. So I think rational combinations with cabivosertib, whether with venetoclax, whether with polar, 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 pull 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 percent 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 of huge interest. We're still trying to understand how that performs in real world populations. I think the 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. Cool. Thank you very much. So we've probably got about 7 minutes left. Just a reminder if anyone wants to ask a question. So maybe one for you, Michelle, final one for me. What about, so Calquence and sort of the life cycle management plans? Maybe you could articulate what you're most excited about and 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's had been it has been rolling 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 in dl bcl as well, as well as in frontline mantle cell lymphoma. So these are, the main pillars of our strategy for calclients, 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 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 in over email from Suny Zhang. So over the weekend, BeiGene presented their Phase 3 ASCEND trial compared with their BTK versus emprisonid in Waldenstroms. So could you maybe elaborate on the opinion of their safety profile? Any thoughts on 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 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 with Calquence, I think it reiterates the, the fact that, Calquence is a next generation BTK inhibitor, as compared to others that have come before us. Okay. Thank you very much. I'll take a question that I've received over email from James Quigley at Morgan Stanley. So, Michelle, maybe this one's for you. So, talking about the first line launch of Calquence, where have you seen the most success with the launch of first line CLL? KOLs at ASH weren't exactly banging on the table on Calquence versus Zimbriuca from the Alabate TN presentation. So what aspects of your marketing messaging or the data have 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 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 calquins plus cassiva seems to be unprecedented data and ones that are quite compelling. Also, the 24 month progression free survival data, 93% for Calquence plus Gozyba, 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 experience of those patients who are on Calquence versus those, 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 Calquence as a result of that experience. Okay. Thank you very much. So, I see we've got a hand raised. So I will unmute. I can't see the name. It's just a phone line, but I will allow you to I'll unmute you. So if you can announce yourself please, and then go ahead and ask your question. Hello. It's Jo Walton from Credit Suisse. And it's a follow on question fits nicely here. You say that a third of hematologists have tried the product then I mean presumably 2 thirds 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 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 Q1 into the Q2 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. Thank you very much, Jack. So, we've got a question online here from Sarita Kapila, JP Morgan, I believe. So she's asking, how are you viewing the competition from Biogenes 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 Waldenstrom's definitely, goes to show that not all BTK inhibitors are created equal and certainly gives us the, you know, continues to reinforce the belief that we already have that CalPEN's being a next generation BTK inhibitor. There's opportunity to improve upon, the 1st 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 and 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. Thank you very much. Maybe I'll keep going with some of James Quigley's questions. If anyone else has any questions, please do raise your hand or send them in via the Q and A or the chat. So James has a question about the future risks of first line CLL. The data from INRUBICO 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 could 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 frontline 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 addition to that, we're also looking at, as part of our life cycle management, in addition to that, we're also looking at, as part of our life cycle management plan, a program in in DLBCL as well, which I think will further demonstrate the potential for Calquence to be used in multiple settings. Yeah. I mean, I don't think I've necessarily 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. 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. Thanks very much. 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 get a situation where we're going to say who sort of partners are, but obviously, there are a number of people who are very 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's 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, based 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 drop off 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 say so much on that 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 solids 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 at the moment. So it's very much a long term play for us, I should say. Thank you very much. And maybe just a quick follow on from Anish Kapoor at Woodline. So you mentioned the others' prime cell based therapy. What do you think are the biggest unmet needs in this space? Do you think internal or external efforts will help you take the next step? And just a follow on, when do you think we will see the first stage on the Phase II assets 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 with Tron going 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 anyway to share data on that. And clearly, I think all of our efforts here are going to be reviewed with Anders Yunus, who's coming in as Head of Hematology. He really brings a lot of expertise. We've spent the last period making sure that Anders 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. Thank you very much. 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 Q4 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 frontline setting as well as relapsedrefractory. And then that real inflection point in the Q1 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 1st few weeks of the launch, we definitely saw a few more patients in the relapsed refractory setting than we did in the frontline. And in the Q1 and then through present time, we're really seeing a shift now to be about fifty-fifty frontline as well as relapsedrefractory, which is really exciting to see that happening so quickly in the launch. Thank you, Michelle. 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 can start off that, Michel 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 magrolumab, 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 we that was an asset we felt high quality. I think within our own portfolio, we have a number of agents. I mean I've highlighted, we've asserted this being particularly interesting, I think, but I think the sell death agents will also have high utility there with Acala and without. I mean, we're not particularly Michelle is wedded to Acala. I'm not. And I must admit, I'm happy to take anything in the 2nd line DLBCL setting. I think Ocala makes a lot of sense for combinations, but we have some combinations which don't involve Ocala that we'll pursue. But yes, external opportunities will be looked at if we provide 1 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 want to comment? I don't know. No, I completely agree with you, Andrew. I mean, yes, I'm wedded to Calquence, of course, but I also am excited about our 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, you know, at 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, as a 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 a patient presents with is clearly a way forward. So we're very excited about that and we see the opportunity to bring our skills in translational medicine, next generation sequencing, etcetera, into our hematology strategy. Thank you. Maybe one final question then. We'll take James Quigley again on e mail. So maybe we talk question about the BCL-two XL inhibitor and how it's differentiated compared to the SFLAX based on the early data preclinical data we've seen to date. And also on the Mcl-one, 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, the benefit of inhibiting XL through a very short target engagement followed by a 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 inadequate allowing, I think, our agent will become incredibly important to both in a relapse setting, but also potentially preventing resistance in the first place. In terms of Mcl-one, we 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 could 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 to have combinations. We could be looking at different doses in different settings as we go forward. But the lead indication at the moment in the 1st place where we're likely to get a published data will be in AML. Perfect. Well, thanks very much, Andrew and Michel, 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 unusual post ASCO beer. All the details will be available at astrazeneca.com/investors. All the recordings for each breakout session maybe missed one. We will also be sending out a feedback form following this session. So please do send any feedback as we're always learning in this virtual world. So, yeah, thank you very much again, Michelle and Andrew, for your time, and thank you all for your interest in AstraZeneca.

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