AstraZeneca PLC (AZN) Earnings Call Transcript & Summary

So good morning, good afternoon, everyone, and welcome to AstraZeneca's ASCO 2021 Meet The Management Event. We're very pleased to have our oncology leadership team here. To start with, I'll hand over to Pascal to make some introductory remarks. Pascal, please ahead.

Thank you, Henry. And good morning, good afternoon, everybody. Thank you so much for your interest and for joining us today. As you will -- as you've seen at the ASCO this year, and you will hear more about it in the next few minutes, our company continues to make good progress. And in particular, the Oncology team is continuing to deliver greater results from a business viewpoint, but importantly from a pipeline viewpoint. We have some very strong data that have been presented and more to come. The first quarter was a strong quarter as you saw and we continue to make good progress across the entire portfolio of products. But today the focus of course is on Oncology. And without further ado, I'll hand over to Dave and who is going to take you through the data we have as an introduction and look forward to the discussions and your feedback in the Q&A. Thank you. Over to you, Dave.

Thank you, Pascal. I appreciate the kind introduction, and it is great to be with you all here today. Hopefully, this will be the second virtual, but last virtual for a while for ASCO. We're looking forward to getting ourselves back at least in the room with some folks. If you go to the next slide, we've got a really, I think, exciting program today. One of the things I want to start with is that, really, clearly, the ambition that we've set forth within AstraZeneca Oncology is to really lead a revolution and redefine the way that cancer is diagnosed and treated. And there are 3 key pillars to that, which is really breakthrough science and leading discovery engine, outstanding and innovative clinical strategies and clinical execution. And then, of course, changing the practice of medicine in the real-world so that it's not just within a trial setting, but they were actually delivering it within the real world. And of course, our people and our passion and our culture for innovation are core to this. And I think that you see a lot of this coming through in the work that we're presenting at ASCO. We have a leading and diversified portfolio. You see 5 new oncology medicines that we've listed out here. Of course, Koselugo is also a 6th new oncology medicine that we've had an opportunity to launch over the course of the last several years, but you can really see a couple of important things. First, that we have been committed to launching medicines across multiple scientific platforms, which shows our ability to not only lead in the discovery within these scientific platforms, but also in terms of being able to have outstanding development and commercial execution against each of those. Secondly, you can see that we are really building expertise across lung, breast, hematologic malignancies, a growing presence within GI and within GU and thirdly, you can see that not only are we obviously focused on bringing new molecular entities and medicines to market, but there's deep and robust life cycle plans that sit behind each of those that allows us to not only discover new opportunities to bring these to new patients. But obviously, the business opportunities that stem from that are sizable and important and we really think that it's been a source of strength that we've had during the last year, in particular, which has obviously had some challenges due to pandemic. And then, of course, we've got a very rich early to mid-stage pipeline which looks at not only individual agents, but combinations across those agents. I've been pleased, we've all been pleased with the progress that we've made on the pipeline over the course of the year, and we'll touch on some of that today as we see some of it at ASCO. I alluded to it previously, but we're pleased with the commercial delivery and the commercial execution that's been taking place. I think one of the most important points to note here is, obviously, we see pretty consistent and strong growth, both on a quarter-over-quarter and also on a sequential basis across all of these medicines. I think also that this is owing in large part to continued life cycle planning that I spoke to. But I think very importantly, the different colors within these bars represent regions across the globe. And I think that one of the key components of our areas of strength is a true diversified geographic footprint, where with medicines like Tagrisso, Lynparza, Imfinzi, where you can see that we've really had an opportunity to launch those across the globe that we're having good success in driving standard of care for our medicines across all of the regions in which we compete. And I think that this is a key part, not only in terms of being able to accomplish our mission and our ambition to eliminate cancers across -- death across the globe and not just in a particular region. But again, it's also a hugely important part of our diversified growth strategy within oncology. And so then that brings us to this year's ASCO. And this is the third year in a row where we have a plenary session at ASCO, and you can see the sessions that we've had with POLO, ADAURA and OlympiA. We embarked upon a strategy 3 years ago explicitly to really try to hit cancer early, to hit cancer smart and when we talk about early, it's obviously moving into adjuvant settings, neoadjuvant settings earlier than stage IV disease, where the opportunity for improving outcomes is highest and where we think society will value our medicines the most. When we talk about smarter, it's leveraging precision medicine and understanding drivers and opportunities for targeting genetic mutations in order to be able to get those better results and we think that the fact that we've now seen the third plenary session in a row is testimony to not just 1 year of interesting or great data coming out of our R&D engine, but actually consistent performance coming out of the work that's happening within R&D. And you can see, obviously, that we've got 90 abstracts, 74 presentations, and it spans all of our scientific platforms. Key highlights were Lynparza with OlympiA. I think that you'd all have to agree that the coverage that we've gotten on OlympiA has been really, truly remarkable. I think in short, the prognosis for women, harboring the BRCA mutation with early high-risk breast cancer has overnight changed. In Calquence, we see continued data to help support best-in-class profile of Calquence among BTKis. Imfinzi continuing to demonstrate that we're bending survival curves in the Stage III setting based upon PACIFIC, where we remain still the only medicine approved within this setting and continued pipeline medicines and advancements that are there, and in particular, I think we're proud of the advancements on the ADCs. So really an exciting ASCO. And if we go to my last slide, we've got a great program plan for the rest of the session today. We're going to go, and we're going to talk by tumor type first, and then we're going to have a close from Susan on what's next. Just to quickly highlight, we'll have Mohit Manrao and Greg Rossi lead our discussions on lung cancer. Mohit leads our global franchise for Tagrisso in lung cancer, Greg leads for I-O. Breast cancer will be led by Cristian Massacesi, SVP of late-stage development, Sunil Verma, who is our VP of late-stage breast cancer. Niko André and Anas Younes will lead hematology. Niko is Franchise Head for Hematology. Anas is the SVP for R&D for Heme. And then lastly, Susan Galbraith, who you all know exceptionally well will talk about what's next, and then we'll have 45 minutes for Q&A. So without further ado, let me turn it over to Mohit and Greg to talk through the lung session.

Thank you, Dave, and welcome, everyone. Myself and Greg here would like to cover 2 things. One is holistically share with you what we are trying to drive in lung cancer. And secondly, double-click on our innovative portfolio and show and share with you the latest progress we are making across platforms and medicines. If we go to the next slide, starting at a lung cancer level, our aim and ambition is to radically transform outcomes for lung cancer patients. And actually, to Dave's point, really aim for ultimately eliminating lung cancer as a cause of death. We believe to do that as truly a leader in this space. We need to, of course, work on translating science to evidence and evidence to practice by bringing our personalized treatment and our innovative medicines into life of patients. But more importantly, also embrace the entire patient journey and work towards really helping drive screening and early detection and helping patients get a chance of curative therapies much earlier. But also work hand-in-hand with health care systems, HCPs, and other stakeholders to help improve quality of care. In terms of our approach on personalized treatment, our entire pipeline and our LCM programs are focused on answering the unmet needs in non-small cell as well as small cell through our TDR platform, IO platform, ADC platform. And actually, we already -- as you know, we have Tagrisso and Imfinzi on the market in critical indications, helping solve those needs, but also we have already showcased unprecedented data with Enhertu. And we have a gamut of medicines in our late-stage pipeline addressing those needs. We're also moving as a leader in the ctDNA based personalized intervention, all the way from identifying patients early, but also identifying their risk factors and preparing therapies for right intervention at the right time. But more importantly, also monitoring for MRD and looking at right time when the cancer starts coming back to have adaptive interventions. Again, if you look at diagnosing and treating patients early, here as a founding partner for the lung emission alliance, we are working alongside like minded partners and actually now in 50-plus countries where we are working on the ground to help drive early detection and screening for lung cancer. As you know, later diagnosis drives poor outcomes in lung cancer. And today, vast majority of the patients are detected in a late-stage where cure is no longer an option and curative-intent therapies are no longer being used. So with that in mind, we are really trying to drive a stage shift towards early detection where potentially patients would have an opportunity to be on a curative path to surgery and other options available today. But for the tomorrow, where we are actually going early with new innovative therapies to help them have radically transformed outcomes. And last pillar here is shown as improved quality of care. Here actually hand-in-hand, again, with our partners, but also through our programs, we're looking at how we can support patient care and have a right quality of care given to patients across the world. We've got clinical trials where we are looking at integrated remote care but also in clinical practice. As to COVID, in our European team, we have launched a higher program where we are really having a oncology integrated remote care platform from teleconsultation to telemonitoring to home infusions, all built around patient services within the same platform. Also we're looking at convenient dosing for our therapies and, more importantly, working hand-in-hand with health care systems on addressing health care equity and sustainability for long term. From here, we double-click into a few of our platforms and medicines and to start off with, let's start with Tagrisso on this slide. Tagrisso, no doubt, is a medicine, which is transforming and changing the course of EGFRm disease in non-small cell lung cancer. And this is, by far, the most trusted medicine for patients and physicians as an ally across the continuum for non-small cell lung cancer. And this is by no chance. Actually, this is based on the established clinical leadership that the medicine has and the bench to bedside excellence our team has shown over the years in making this a standard of care across the continuum around the world. Just looking at the clinical profile and leadership Tagrisso has, way back in 2015, you'll remember Tagrisso was the first EGFR TKI to overcome T790M resistance and showed best-in-class blood-brain penetration. On heels of that very quickly and at record speed, we brought this medicine into first-line where it continues to be the global standard of care, and the first and only EGFR TKI to have shown OS of more than 3 years. Adding to that, a best-in-class CNS risk reduction, which is very important for this group of patients, alongside an excellent tolerability profile. And last ASCO, we -- we had early unblinding of ADAURA data and which showed again an unparalleled efficacy in the DFS in early-stage curative intent population and 80% relative risk reduction. But also, again, additionally, adding to the CNS protection, we have been a CNS risk reduction, we've been seeing with Tagrisso. We saw here protection against distant mets especially CNS, again, which for this population is supercritical. And you see on the right top chart how this has -- this clinical profile has resonated quite well with both regulators and payers around the world. Today, we have 90-plus approvals in the metastatic setting in first-line and second-line and actually 67 approved reimbursements in second-line and 44 in first line, which is actually double versus where we were last year. And more importantly, in China, now we are listed on first-line NRDL as of March of this year, and this is the third year to be -- in the third line -- in the second line space on NRDL. If you see adjuvant actually already within a year's time, we have 55 approvals now, which is, again, I think, a record-breaking speed for molecule of this class. And we already have 8 reimbursements or early access even by health care systems who have already responded to the value Tagrisso brings in the early stage continuum by driving towards potentially curative intent therapies for these patients. And at the bottom, you see how this strong momentum, this clinical profile, these reimbursements and approvals have led into really patients benefiting where our teams across the world have ensured that every patient has an opportunity to get on this therapy. And as of end of quarter 1, we have more than 250,000 patients treated globally with Tagrisso. The story doesn't stop here because we continue to press ahead, working with our HCPs and clinical partners to really address the remaining unmet needs for EGFRm patients. And from what we hear and how we shape our program, we hear there are 2 unmet needs. First is early stage where, again, we have building on ADAURA, we have Neo-ADAURA and we have LAURA program in place, complementing the PACIFIC regimen. And in late stage, where the real unmet need is what comes after a resistance. And that's where we have an intensive program in form of ORCHARD, SAVANNAH and other combinations we are exploring to answer the unmet need for these patients. If we go to the next slide, looking at the ADC platform, and let me just contextualize the opportunity for ADCs in non-small cell lung cancer. Chemotherapy continues to remain an important partner for lung cancer, whether it's in combinations or in late-line monotherapy setting. And with ADCs, we have an option of delivering that chemotherapy without the side effects associated with it by targeting it through monoclonal antibodies. And we have 2 industry-leading best-in-class assets, both a HER2 directed ADC in form of Enhertu and a TROP2 directed ADC in form of Dato-DXd. The data is something you've already seen in the past at ESMO and WCLC this year, which has -- based on which we have already started a program for Enhertu in both HER2 mutant disease in the form of Phase II with DESTINY-Lung02 and in form of a first-line in Enhertu + durvalumab + chemo Phase I program in DESTINY-Lung03. On datopotamab deruxtecan, we also have initiated a vast clinical program based on the data we saw in heavily pretreated population where we already have a pivotal trial in a second third line EGFR/ALK wild type with TROPION-Lung01 as well as we are exploring in Phase I combination with immunotherapy agents plus/minus platinum chemotherapy. With that, let me hand over to Greg in terms -- and to cover IO.

Thanks, Mohit. And I think the important data here from ASCO for Imfinzi was clearly the 5-year data for our PACIFIC regimen. And you can see the slide, the panel on the left that summarizes that. Not shown there actually, I think is the most important piece of data, which is actually 3 quarters of those 43% of patients who are alive for 5 years are actually living still progression-free despite being off therapy for 4 years, that's a remarkable effect. Validates I think the concept of going early with Imfinzi, validates, I think, the value that we've been able to create in now over 70 countries across the world. If you look at the very bottom of that panel, you'll see that we're heavily invested in a series of trials in early stage lung cancer. Whether it's in the unresectable setting or in the resectable setting and I think the emerging data to the IO class really, again, supports the idea that we at AZ had a number of years ago, going early, particularly with Imfinzi, was going to be a really important therapeutic approach. And I think we're seeing the validation of that at this ASCO. In the middle. Just a reminder that in small cell, the ongoing CASPIAN launches around the world are really going very strongly, I think, particularly in Japan and in Europe with France and Germany now getting on track. We're going to see the 3-year data in the second half of this year. We're excited about that from CASPIAN regimen in extensive stage small cell. And again, I think similar to the non-small cell setting, we're very excited around the ADRIATIC study that we hope to be able to report in the coming quarters. And then lastly, I think the other story that we're really starting to see emerge, and I think you saw the program that Mohit talked about, in lung cancer is actually the combinations that we have at our disposal with the very broad portfolio we have. I show you the data here on the right-hand panel from HUDSON study. This is a study that we showed at World Lung earlier on in the year. But even here at this meeting outside of lung in melanoma, you see the combination of ceralasertib, an ATR inhibitor, along with Imfinzi, in patients who have progressed or failed checkpoint inhibitor in their front line, really showing some quite remarkable effect. And I think that breadth of program is something that we can really sort of rest on will become the next part of the evolution for AZ Oncology, not just in lung cancer, but for IO, more broadly. So the next slide just summarizes really what you've just heard from Mohit and myself, I think in the interest of time, I won't go through this in detail, other than to say, we have a very comprehensive program. We have it across all segments of lung cancer and all stages of lung cancer. And so clearly, we're here as a leader in lung cancer for a long period of time. Now let me pass to Cristian and Sunil, who will talk us through breast cancer.

Thank you, Greg and thank you, Mohit. Let me start, go to the next slide, please. Let me introduce breast cancer telling, first of all, that it's still the leading cause of death around the world every year. We have nearly 700,000 people dying from breast cancer. AstraZeneca cancer medicines have helped breast cancer patients for more than 4 decades. Since times of Nolvadex till the most recent approvals of Lynparza and Enhertu. But importantly, I think in the last years, we had an acceleration of our portfolio of development. On top of the approved drugs, we have other foundational assets for breast cancer. For instance, our next-generation SERD Camizestrant, the AKT inhibitor capivasertib, our TROP2 ADC Dato-DXd and the PD-L1 durvalumab. So a comprehensive portfolio medicines. I think I want to link to what Dave said at the beginning. In breast cancer, our mission is very bold. We want to redefine the outcome and revolutionize the care for patients with breast cancer. Let me try to tell you briefly how we think to do this. And here, I link to what Dave introduced. We want to hit smarter. We want to redefine the treatment paradigm and enabling a more personalized approach to some specific subpopulations. So in other words, we want to break the swim lanes in breast cancer. Then we want to hit earlier. We want to offer -- we're going to try to offer more tolerable curative options. Options for those patients at high-risk of recurrence to help them to live not only longer but also better. And then finally, we want to hit harder because I think we have a foundational assets, foundational therapies across the key subtypes and through combinations, we can drive significant benefit and outcomes. Now the plenary presentation of Lynparza OlympiA trial, because this is the perfect example of our strategy to go early, hit harder and smarter. Using Lynparza in early breast cancer after surgery in high-risk HER2-negative, gBRCA1/2 mutant women reduced the risk of recurrence or death by 42% of the placebo. At 50 years, about 86% of the Lynparza patients were still alive without invasive breast cancer compared to 77% in the placebo group. Very importantly, Lynparza also showed it could reduce the risk of distant tumor recurrence or death by 43%. OS was not mature at the interim analysis with 2.5 years of median follow up. But the survival curve was trending in parts of favor with a 32% reduction in the risk of death. The study of course is ongoing, and the readout of the overall survival data will follow. So I want to put this data in the context of other readouts. Recently, for instance, the CDK4/6 inhibitor Verzenio reported a 25% reduction in the risk of cancer recurrence in adjuvant therapy for high-risk HR-positive breast cancer patients. In general, when you have a 30% reduction in the invasive disease-free survival, this is considered clinically meaningful. I want to use the word of ASCO. When they said that Lynparza is the first PARP inhibitor that may change the standard of care in adjuvant systemic therapy for patients with germline BRACA12 mutated early breast cancer. Patients with tumor BRCA12 mutation represent about 5% of all breast cancer cases. Unfortunately, these mutations predispose women to aggressive disease, and they are diagnosed at younger age. So Lynparza, in this setting, will serve a very high unmet need. With that, I will pass to Sunil. Please, Sunil.

Thank you so much, Cristian. And truly, just an impactful and practice-changing results with OlympiA. Thanks for sharing that. So I'd like to walk through our late-stage pipeline, first highlighting Enhertu, which we think has truly transformative potential for HER2+ and really redefining HER2-low breast cancer. And 3 really important points to highlight. First of all, as you all know, this has now been approved now more than a year. Dave alluded to sort of the rapid uptake and growth for this agent in HER2+. Also pleased to share is the most prescribed medicine in the third-line setting for HER2+ metastatic breast cancer and we continue to see global approvals, including in EU earlier this year. At this ASCO, we saw data for Enhertu beyond the efficacy that we have reported previously. With strong efficacy systemically and also now strong intracranial activity with CNS activity from DESTINY-Breast01 as well. Also very pleased to start to report the data that we're seeing in HER2-low breast cancer. This is from BEGONIA. With Imfinzi plus Enhertu together in combination in first-line HER2-low metastatic triple-negative breast cancer. We saw a response rate of 67%. The data is early. However, we're seeing activity both in HER2 1+ as well as 2+. So I think important to note, this is our ADC plus IO. As Cristian and Dave mentioned, we want to hit harder and this sort of solidifies our promise of using Enhertu as a foundational therapy and adding the right combination and seeing this activity in HER2 1+ and 2+ also solidifies our belief in HER2-low as an important target, including in HR negative setting. And finally, this is going to be a really exciting next few months as we anticipate data from DESTINY-Breast03, of course, head-to-head versus T-DM1, DESTINY-Breast02, post T-DM1. And of course, DESTINY-Breast04, our first randomized study from HER2-low patient population, and we have an expansive and extensive program. If you can go to the next slide, please. So this is just how we keep busy. We have this incredible program in HER2+ breast cancer. As many of you saw, there was recent data and recent release of information of our first-line treatment within HER2 and HER2 pertuzumab versus chemotherapy + Trastuzumab + pertuzumab, the DESTINY-Breast09 study. We have 2 Phase III studies, which are underway, looking at HER2-low DESTINY-Breast04 and 06. And also, we are expanding our studies in the early breast cancer in addition to DESTINY-Breast05, which is the post neoadjuvant versus trastuzumab Emtansine. And furthermore, strong interest and clinical devlopment program in multiple other tumor types, as noted here. Next slide. So we continue to have a really strong ambition and really strong commitment to breast cancer. Here's our late-stage breast cancer pipeline with some of the other assets, which we believe are foundational first of all, capivasertib an oral AKT inhibitor. We now have 3 Phase III studies in breast cancer, including also studies in prostate cancer. The ones in breast cancer are focusing on resistance in combination with fulvestrant with CAPItello-291. Our fulvestrant and CDK4/6 in CAPItello-292, and we feel this is going to address the needs of patients with endocrine resistant disease. And furthermore, we also have and continue to have a strong focus on triple-negative breast cancer. We do feel that this is an important pathway for triple-negative breast cancer with CAPItello-290, a large Phase III study underway. So we want to endocrine -- we want to address the endocrine resistance through this asset. And camizestrant, our next-generation SERD. We have shown some really promising activity at ASCO last year. Here's the data from ASCO. There was updates at San Antonio last year as well. And we have strong belief that we have a great therapy for patients that will offer us great efficacy and also great safety and as a result, we have a number of Phase III trials. You are already aware of SERENA-4, our first-line CDK4/6 combination and more to come very soon, as you'll hear about our ambition to really help patients with endocrine sensitive and also address resistance. And furthermore, our belief that we want to continue to build on our ADC platform is further highlighted with this incredible partnership we had with Daiichi Sankyo with DS-1062, a TROP2 antibody drug conjugate. We shared this data at the ESMO breast meeting just recently. We have seen response rate of 43%, including response rates, which were quite durable. And we want to make sure that we continue to build on this. We feel that this is a really promising preliminary activity in heavily pretreated patient subset. And furthermore, it confirms our belief that is a favorable profile versus current standard of care. So this is our ambition. We think that we're going to be poised to redefine breast cancer. We think we're poised to really bring foundational therapies across early and metastatic setting and we believe that we can go and redefine how we treat and manage breast cancer patients with the right combinations. And I think the wonderful data that Cristian shared at ASCO plenary shows that our strategy is coming through, and we continue to drive our ambition to help breast cancer patients around the globe and really transform the care through our 6 medicines and more to come. So with that, thank you very much, and I'll pass it on. Thanks.

Yes. Thank you. We can move to the next slide right away. Now focusing on Calquence, which is our highly selective BTK inhibitor. I will focus on CLL, which is the major indication for Calquence because here at ASCO, we show 2 very important data sets, which today, clearly give us the confidence to see Calquence as a clear standard of care in chronic lymphocytic leukemia and also with the potential for a best-in-class agent. You look here at the 2 pivotal data sets that have led to the registration in CLL relapsed/refractory and in frontline with an impressive risk reduction in PFS of 90%, respectively, 80% and for dual combination with obinutuzumab or monotherapy. On the next slide, you see that Calquence is actually a medicine that deploys its value once it's really in clinical use. And you can see this on the left side on the inflection point, when the drug was launched in the U.S. in November 2019 in the frontline CLL indication really seeing a very, very rapid clinical uptake and significant positive feedback from treating physicians. Today, we are looking at growing, rapidly growing share across all lines in CLL, larger than 40% of all new patient shares. And we were also able to maintain continuous growth throughout the pandemic in that disease. And obviously, we're focusing now on bringing Calquence as a broad treatment option also with the opportunity to reduce chemotherapy, particularly in frontline. As of today, we're approved in 60 countries for CLL, we have full reimbursement in 10 countries, and we report sales in 25 countries. And on the next slide, you can see that our launch trajectory is well on track. The first wave in the U.S. with significant uptake in clinical practice. Now we're in full swing for the rollout in Europe and the rest of the world, where we see excellent clinical feedback, in particular, from key hematology markets like the U.K., like Germany, like France and we're looking forward to the third wave with the regulatory submission in China in 2022. And I'll now pass it over to my R&D colleague, Anas, who will look at the data for Calquence we have here at ASCO and then give you an outlook on the Heme portfolio that we have at AstraZeneca.

Thanks, Niko. As you all know by now, we have very strong data presented at ASCO in the frontline setting and in the relapsed setting. In the front-line setting in the ELEVATE treatment naive, this is a long-term follow-up data of more than 500 patients randomized to 3 different arms comparing acalabrutinib alone, acalabrutinib with obinutuzumab versus obinutuzumab plus chlorambucil. What you can see on the top panel. It's a very impressive performance for either the single-agent acalabrutinib or in combination with obinutuzumab with very impressive PFS sustained activity with very good tolerable safety profile. In the lower panel, even in the high-risk patients that were included in this trial, these are the patients with 17p minus or mutated TP53. Again, same thing, you can see sustained clinical benefit for either with a single agent or in combination with obinutuzumab compared to chemotherapy arm. Next slide, please. And then the second trial, which is our head-to-head comparison with ibrutinib, first generation BTK inhibitor. We showed that they both have similar activities, so the non-inferiority endpoint was met. But of course, there was a significant reduction in key toxicities, confirming the notion that if you go with a more selective BTK inhibitor, you do not compromise efficacy, but you improve on the safety profile. And this is here what you see, significant reduction in afib, aflutter, a key toxicity that is observed usually with first generation BTK inhibitors. But it's not limited just to afib, there's significant reduction in multiple key toxicities, including hypertension, pneumonitis, bleeding diarrhea and arthralgias. So again, this confirms that going with more selective BTK inhibitor does not compromise the efficacy, but give you a better safety profile. Our current portfolio in the clinical testing, including 5 assets, 5 agents, 3 in what we call the cell death portfolio, and we're focusing really on targeting more than one Bcl-2 protein for a reason because there's tremendous evidence in preclinical data and in clinical data suggesting that if you target more than one Bcl-2 protein family, you have more enhanced efficacy. So if you look at our first asset, this is the AZD0466. This is dual inhibitor of Bcl-2/xL. Undergoing testing in multiple different types, which is shown on the bottom of this panel. We're testing it in AML, MDS, different types of non-Hodgkin lymphoma. And the second asset is our MCL1 selective inhibitor. This is the AZD5991. Although it's selected for MCL1, but we're focusing on combination either with Bcl-2 inhibitor venetoclax or azacitidine. And the third asset is CDK9 inhibitor, which is also a dual inhibitor for both MCL1 and BFL1 but through different mechanisms, through transcription down-regulation of these 2 targets. In the middle panel, we're moving forward with our bispecific antibody targeting TIM3 and PD-1, mainly in Hodgkin lymphoma for obvious reasons because a PD-1 targeted agent has been approved in that space. We believe that dual inhibition of TIM3 and PD-1 would give us a better activity compared to PD-1 alone. And the last panel on the right side, we're also testing our oral AKT inhibitor in the same space where PI3 kinase inhibitors approved in lymphoid malignancies. And for this reason, we're focusing initially on follicular lymphoma and Mantle cell lymphoma. And finally, this is even more forward-looking to show you where we want to be in the next few years. The maroon color, this is where acalabrutinib is approved and launched in CLL, both in frontline and relapsed setting. In Mantle cell lymphoma now, it's in the relapsed setting. Of course, we have a frontline trial that we're waiting for its readout. We have a front-line diffuse large B-cell lymphoma trial also enrolling. But the blue box is where our current assets are being tested and hoping to find an indication in any of these blue boxes based on unmet medical need spaces. But the yellow Box is where we want to be in the next few years. These are based on our undisclosed targets that are in the work right now, and we hope to share this information with you in the next few years. And with this, I'll stop, and I'll pass it to Susan.

Thank you, Anas. I'm delighted to be able to join you today from our fabulous new building in Cambridge, although part of me would love to be face-to-face with you in Chicago. So if you can just go to the next slide, what we're going to share today is just some sense of the things that are coming from our discovery and early development portfolio. So the previous speakers have talked about our overall strategy, which is very focused on going early in disease. And I think as you look into the future, the potential is to substantially increase the number of cancers that are diagnosed through screening, particularly with the technological advances of circulating tumor DNA provides that opportunity. And so I think as you see from the data we presented with PACIFIC, with ADAURA and with OlympiA now in this ASCO, we're already embedding this principle into the development of our assets. But additionally, with going into the early stages of disease and monitoring the relapse and resistance mechanisms to speculating tumor DNA, the other piece we need to have is the comprehensive portfolio in order to create the combinations that will be there for the future. And there's 2 key aspects that you got to have. One is direct killing of tumor cells. You can see this on the right-hand side of the graphic on the right, tumor drivers and resistance mechanisms, such as Tagrisso, DNA damage response that targets synthetic lethality like Lynparza, but I also think we've got a growing portfolio that will emerge into the coming years of our antibody drug conjugates, building on what we've seen with Enhertu and Dato-DXd. And we've got a very exciting portfolio coming through that you'll see shortly. We've also did a deal last year with Fusion because that gives us access to radioimmunoconjugates with alpha emitting agents that can be paired with our antibody protein engineering. And then I think epigenetic changes are key aspects that enable cancers to go through the evolutionary bottleneck that happens after typical debulking with current standard of care. So our epigenetic portfolio is also building preclinically and will come into the clinic soon. And to put that together with the activating the immune system that you see on the left-hand side of the graphic, both classic checkpoint inhibitors, that you see in the immuno-oncology space, which includes some bispecific molecules, but also ways to activate the immune system in the settings where the tumors are ignored by the immune system. So activate it in those immune deserts, and you can do that in a variety of ways. We've got some oncolytic virus therapies. We've got investments in cell therapy and also in immune cell engagers. So this is a portfolio we intend to bring forward. Today, I'm just going to focus on a few aspects of these because we don't have time to go into all of it. I'm going to give a talk about an update on the DNA damage response area. Some of our next-wave IO vaccines that are coming into the clinic and just give you a taste of some of the modalities that we're investing in the discovery space, ADCs, radioimmunoconjugates, I have already talked about, PROTACS and the functional genomic capabilities are underpinning synthetic lethality targeted. So we've already shared with you at AACR this year some of the exciting preclinical data we've seen with our PARP-1 selective inhibitor AZD5305, which entered the clinic in the fourth quarter of last year. And we're excited about the potential of this molecule because we can see preclinically a wider therapeutic index by having just PARP-1 inhibition and no PARP-2 inhibition, which drives some of the hematologic toxicity seen with potent PARP trappers, including olaparib and that means that we can combine with chemotherapy in preclinical models and maintain a therapeutic index. So that's a key principle that we're testing now in the Phase I trial, and we look forward to sharing those data with you again in the coming months and years. We are seeing progress in terms of understanding what we need to do to overcome resistance to PARP, which is going to be a growing unmet medical need as we see activity, such as the great data we've seen with OlympiA. And we have data that was presented at ASCO in an externally sponsored research study by Shannon Westin in the -- with adavosertib in the EFFORT study. EFFORT included patients dosed with WEE1 and olaparib as well as with our ATR inhibitor ceralasertib plus olaparib. And what you can see here is that there is activity post PARP through these mechanisms. Again, optimizing dosing schedule has been important in this setting. And on the right-hand side, Greg Rossi also referred to these data that were presented at the World Congress on Lung Cancer showing activity for our ATR inhibitor ceralasertib in the post checkpoint inhibitor population in non-small cell lung cancer. That's backed up by data we presented at this ASCO again in melanoma study or the VICTORY study, again an externally sponsored research study, where we saw a 30% response rate with highly durable responses and promising medium OS data. In terms of the next-wave IO, I would just flag to you that we will be having data reading out later this year from the randomized Phase II study post -- in the Stage III PACIFIC setting unresectable non-small cell lung cancer. Looking at durvalumab versus durvalumab plus oleclumab our CD73 inhibitor or durvalumab plus monalizumab our NKG2A2 inhibitor. We also have data from a neoadjuvant study, the neoCOAST study in early-stage with these same combinations I referred to the data with HUDSON and melanoma, but the melanoma data we are leaving to a Phase II study that we'll be initiating shortly called the MONETTE study in that setting. On the right-hand side, you see 2 new agents that will be entering the clinic this year. We have a bispecific PD-1/TIM3. The TIM3 element of this bispecific binds to a unique epitope, which is differentiated from other TIM3 antibodies that have been in the clinic. And we see exciting data in patients in preclinical models that are resistant to current checkpoint inhibitors. In addition, we've got an Anti-GDF15 antibody, which is also entering the clinic later this year. Again, GDF15 is expressed on the placenta and drives immune tolerance in that setting. We see activity in models such as the Lewis lung model, which is insensitive to PD-1, PD-L1, treated with both monotherapy and with combinations with GDF15 and PD-L1. So we're excited about both of those opportunities. And again, we look forward to sharing clinical data with you in the coming years. In terms of preclinical models, I think we're starting to understand the elements of the system that you need to design for antibody-drug conjugates to be clinically relevant. It's not just related to target density, but also internalization kinetics. You have to understand the lysosomal trafficking and recycling, the stability of the molecule is critical. There's going to be different sensitivities in tumor types depending on the warhead mechanism of action. And the bystander kill activity by having linker molecules that are stable in the peripheral circulation, retrievable in the tumor microenvironment, I think is key, particularly when you've got heterogeneous target expression. And that underpins, for example, the activity you've seen with Enhertu in the low HER2 settings. We think there are clinical data now emerging, underpinning the ability to actually expand the druggable space by targeting protein degradation, for example with PROTACS but not exclusively used in this mechanism. I think this is really an exciting opportunity to look at targets that have previously been considered to be almost intractable. On the right-hand side, the quality of target validation and understanding the patient populations where you have targetable vulnerability, but like targeting PARP in BRCA mutant population, I think is key with the CRISPR screens that we have been developing. We're using these extensively. We're also part of the DepMap collaboration, which helps with target identification. What this means is that we're embedding this into our early discovery space as well as understanding, which is the right patient populations to target early on that helps with diagnostic development. So what I hope we've been able to convey today is that we've got not just the exciting Phase III molecules that previous speakers have spoken about, but also a broad and comprehensive program in early development as well as in the preclinical space, which we look forward to showing developed over the coming years. This is just a summary of not only what's now on the right-hand side with agents that are in Phase III and are already approved. But also the portfolio of agents that are coming behind them. With that, I think I'll end, and we'll open this up for the Q&A session. Thank you.

Thank you, Susan. I appreciate that, and thanks to all of our presenters for what I think were some really good insights into the various aspects of our program. So Henry, can I ask you to give instructions for Q&A before we turn it over to participants to join for that.

Yes, sure. So thanks very much all. So as a reminder, we're on a Zoom, so you can raise your hand. You can ask questions in the chat. You can e-mail IR team at astrazeneca.com or you can dial starline if on the phone to raise your hand as well. So our first question in is from Sachin Jain. I will allow you to talk.

Hi, can you hear me?

Yes.

A couple of questions, if I may. So firstly, for Dave. You talked on the 1Q call around the Hansoh competition. That was, I think, predata and that you've seen the data, had some time to reflect and discuss with KOLs. Any updated perspective as to how you think [indiscernible] may compete in both the U.S. and China? And then secondly, I guess, for Susan, in your IOs combo what's next. I think got some combination that is ongoing as well with DS-1062 in the lung space. So when could we expect that data? I know those studies start at the end of last year and is that data set a gating factor for a first-line lung study with DS-1062, noting you've already got second line study ongoing?

Sachin, thanks for the question. So maybe I will take the first of those and then maybe, Cristian, you can comment on the 1062 study and see if we want to build from there. So first, on -- Sachin, on the Hansoh drug, we certainly got good insight into progression-free survival, hazard ratios and medians. I think the areas where there remain some questions just given the maturity of the data are on response rate, although, I guess, maturity doesn't affect that. And then also on overall survival. Obviously, those are 2 areas where Tagrisso has been able to demonstrate, I think, some meaningful opportunities there. I think also it's worth and important to note here that as we talk to our investigators, the feedback that we're hearing, Sachin, is that there isn't a high unmet need in metastatic frontline eGFR lung cancer, which is not to say that there isn't an opportunity for somebody to come in and make an impact. But I don't think that we're seeing right now, data that suggests to us that there's an unmet need that's being satisfied. And I think that, that's actually kind of the most key takeaway from that, that we've taken. In terms of the China piece, Mohit, do you want to comment on the China aspect of how we see the data relative to China?

Yes. Thanks, Dave. So Sachin, thanks for the question. What we see from a China data, if you look at the Flora China population, a journal publication that came out earlier this year in targeted oncology. You would see that the side effect profile is not very different. And as Dave alluded to, the ORRs seem to be flat versus ERISA and the AMO data which wasn't the case for Flora. But also more importantly, the OS, at this point in time, when we had released Flora was less mature, but the stat significant value or the p-value was much -- sorry, HR ratio was much, much stronger. With that in mind, in China, actually, we are far ahead versus competition. We already have first-line NRDL as of this year and the earliest possible case for -- to make and NRDL would be in 2023. So we will have 2 years of data user impact as usage of Tagrisso. We already have a good formulary listing, a good team presence. And actually, as you know, we have already got an adjuvant approval. So we are moving one step ahead in terms of bringing this therapy across the continuum for nonsmall cell lung cancer.

Super. Thanks, Mohit. Cristian, do you want to comment on opportunity for combinations with IO, including next wave IO agents and 1062.

And thank you, Dave, and thank you for the question. You know specifically focused on 1062 Dato-DXd, the TROP2 ADC, there are currently 2 ongoing trials in which we are combining this ADC with pembrolizumab and durvalumab in small-cell lung cancer. Both studies are ongoing. And actually, as you imagine, this is a Phase I study in which we can plug-in additional agents like some cytotoxics like platinum asset compounds or pemetrexed. And this is dose escalation with some expansion. This can lead very rapidly to a first-line IO 1062 combo in either in as a combo or checkpoint plus Dato-DXd or a more complex regimen with a third agent. So I -- of course, the study are ongoing. Can you give you a precise date, but anytime soon, we will be able to disclose what will be the designs of the first wave of registrational trials with this specific combos. I don't know, Susan, if you want to maybe comment more on the -- some of the earlier assets and some of the combo that we are...

I think you covered it. Thanks Cristian,

Thanks, Susan and Cristian. So the next question is from Michael Leuchten at UBS, and I'm reading it out now. So -- and this is following on the Tagrisso question earlier. There have been questions about J&J's amivantamab combination with lazertinib in non-small cell lung cancer. In terms of timing, you mentioned ORCHARD, how do you think about the potential threat of this combination? And how do you think about timing for your own combinations?

Why don't I give a quick comment and then I'll turn it over to you. I was just going to suggest, I think that would be actually quite helpful. So I mean, I think that in terms of just taking a look at the landscape. I think that it's important to keep in mind that, obviously, we think that met is something that is relevant as a follow-on to Tagrisso therapy. Mohit outlined this. We've got not only the ORCHARD studies, which Michael, you mentioned, but the SAVANNAH study as well. And I do think that part of the key question that's going to come out of this is where is the role for met? Is the role for met as a second-line therapy following Tagrisso? Is it something that can be brought into the front line? And I think the percent of patients who are susceptible to that kind of treatment is going to be a key question. And I don't know that we've necessarily got insight yet into the answer to that question based on the data that we've seen so far. But I do think that our program is asking those questions in a fairly comprehensive manner through the series of studies that we've got. Cristian, anything you want to add?

Yes. I want to just mention the data, at least the data that we have seen at this ASCO. Overall, this combination, the J&J combination showed a response rate of 36% with the durational response of a little bit more than 9 months and a PFS of less than 5 months, 4.9 months. In patient with met there is resistance, there were very few patients only 17, and the response rate was higher, the initial response was higher. PFS is still around 6 months. In patients without met alteration, the response rate was less than 30%, the durational response 8 months and PFS 4 months. So we release already data with our combination with savolitinib, our met inhibitor plus Tagrisso and they are comparing quite favorable to what we are observing here. And as Dave mentioned, we have SAVANNAH that is a Phase II study ongoing that hopefully, we'll provide anytime soon some additional data that eventually can unlock a Phase III opportunity.

So the next question is from Emmanuel Papadakis. I will allow you to talk.

Maybe question on HER2, I don't really understand the registrational strategy in lung and colorectal. You had a breakthrough designation in lung a while back, doesn't seem to have accelerated anything. You've had great Phase I data in both settings. You've now started single-arm Phase II studies looking at 2 doses. So if you could just outline what's the strategy here, time lines? What is the purpose of doing those 2 studies rather than moving straight into pivotal Phase III? And then just one on datopotamab. You mentioned the ESMO breast data in triple negative breast. I think when we discussed it last year ahead of that data, you were guiding us to expect efficacy somewhat better than to delve look pretty similar, perhaps on efficacy, but certainly better on safety on hematologic safety anyway. So just your perspective in light of us having now seen the data from a competitive standpoint would be helpful. And if you could add in how you plan to position that triple negative breast relative, for example, to the Enhertu and Imfinzi combination [indiscernible] would be helpful as well.

Super. So Cristian, can I suggest on the first question that Emmanuel is asking about Enhertu and specifically how we're thinking about the strategy within lung cancer. And certainly, we can have -- Mohit also speak to this, but maybe start with you in terms of kind of thought processes there and how we're approaching Enhertu outside of breast cancer and lung.

Got it. Thank you for the question. So as you know, Enhertu mutant -- Enhertu has been already included in NCCN guidelines. And we have OTT and breakthrough designation in U.S. for this specific setting. And of course, we are in discussion with the authorities with that data set. This is a setting where represent 2% non-small cell lung cancer. And the -- our aim is to go into frontline and eventually [indiscernible] standard of care for this specific patient population is a new segment where no other anti-2 agents are approved, and we believe the level of activity we observed in later line with more than 60% response rate with very durable responses and progression-free survival will allow us to compare well with standard of care treatment in frontline. So that is the mutant strategy. HER2 expressing nonsmall cell lung cancer, we presented data last world conference lung cancer showing that we have very relevant activity in HER2 expressing. This is a particular segment that can reach 10%, 20% nonsmall cell lung cancer without approved options there. So here, probably the -- we needed to assess the combinatorial strategy to move ahead. And I think the current trials that we are running in combination with durvalumab and some cytotoxic in D-L03, DESTINY-Lung03 will inform that strategy in HER2-overexpressing. Colorectal cancer is a promising indication. It is about 5% of all colorectal cancer, are expressing HER2. We have a response rate of more than 45% with minimum PFS reaching 7 months. Of course, in HER2-low the data are less compelling, but let's not forget that the setting where we started in HER2 is in pretreated setting so most of the patients were already been exposed to topo I inhibitors like irinotecan. So we expect activity in colorectal cancer, like we already showed in other indications. And the further development will be in -- try to bring the combination area. We are generating some combo data in GI through gastric cancer setting with cytotoxic agents like capecitabine, like fluoropyrimidines. And based on this data, that will inform the registrational strategy in earlier line, second and potentially first-line for colorectal cancer.

Thank you, Cristian. Appreciate that. And Sunil, if we can address the question on 1062 efficacy and how we're seeing that relative to Trodelvy and also how we're thinking about positioning within triple-negative. And if we can keep our answers shorter, we'll make sure that we get to everybody that's got questions in the queue.

Great. Thanks, Dave, and thank you, Emmanuel, for the question. So I would highlight sort of 3 important points as to how we see the efficacy for 1062. So one is the overall response rate, we're mid 40%. The data that was with Trodelvy in a similar patient population is in the mid 30%. But I think probably more importantly, it's really the duration of effect and response that we have seen with this warhead previously. That gives us the confidence that we are going to see potentially a more prolonged duration of response. Of course, the data is so preliminary, and we haven't seen that data, but I think that gives us some confidence. And the third thing, Emmanuel, that you highlighted, quite clearly is the tox profile. We don't have the GI toxicity. We don't have the neutropenia at the same level. And I think we have sort of a more patient-centered approach with q -- day 1, every 3 weeks versus a day 1-8 schedule. So I think all those sort of bode really favorably. With respect to where we're interested, as you can imagine, we are very interested in monotherapy in moving it in earlier lines, in early stage, and we are very interested in combination. So more to come on that strategy in the next few months. Thank you.

Thanks for the answer, Sunil. So the next question is from Sam Fazeli at Bloomberg. I'm just reading out the question. It was received by e-mail. I'm sure others will ask and maybe covered in the presentation, but can you talk us through how you expect the OlympiA indications to evolve [indiscernible] of course. There seems to be quite a spread in views as to the potential IM at the bullish end. But in terms of market testing, duration of therapy, which, of course, was only 12 months, but I assume you will study longer. So Dave, that's the next one.

Yes. Thank you, Thomas. So let me -- and I think this also gets to some questions that Douglas Perkins had asked and also Andrew Barrons on the Q&A. So I think that we can maybe cover a few on OlympiA all at once. In terms of the indication, I certainly think that pretty consistent with what we studied. We are talking about women who harbor the BRCA mutation for high-risk early breast cancer. And I think that that's the most likely patient population that we'll be speaking to. That is about 5% of all breast cancers. And I think that, that will be the focus of where our regulatory conversations take place. I do think that as you heard from the discussion, there's questions and interest in somatic mutations. There's questions and interest in other HRD. I think those will be areas that we're certainly going to want to make sure that we're understanding from an evidence generation perspective and opportunity to gather. But I think that in terms of the OlympiA study itself, that's probably where it speaks to. Now in terms of some of the forecast drivers that we take a look at, I think what's important to note is that today BRCA testing globally is done fairly regularly in the early settings for triple-negative breast cancer, but it is not something that is routine and part of reflex testing for hormone receptor positive patients. And I think that the comments that we heard around the need for universal testing for BRCA is something that's going to actually be not only the greatest opportunity here to really transform care for these women, but also represents one of the biggest areas that we're going to need to make sure that we're doing our educational market-shaping and commercial launch work. So only 20% to 30% of women with hormone-receptor positive breast cancer are being tested. This is the area that needs to grow. I do think that, that's going to take a little bit of time, but I do think that we're going to start seeing that as of today, based upon the OlympiA data that you're going to see a push for that to be happening across the globe. I think Thomas that, that's probably well covered off on, on the OlympiA piece. We can go to the next question.

Great. So the next question is a live question from Tim Anderson.

Great. Can you hear me?

Yes.

I have a question -- a couple of questions. On the Lynparza, not on the OlympiA data set, but on the PROpel data set in prostate, Phase III data, I think, scheduled to come up in 2021, potentially the biggest indication for the drive kind of no mention of it today in the slide deck or presentations. And I thought given us some potential importance, we would have maybe heard about it. So can you just talk about your confidence in hitting results in this large indication? And then going back to the Astellas Pharma competitor on erlotinib, sometimes drug companies can characterize competitor molecules and evaluate them preclinically and that sort of thing. Is there any reason to think that this won't -- that their drug won't cross the blood-brain barrier. In the past, you've suggested that might be a shortcoming, I think, with their product. But what's your latest thinking?

So why don't I touch quickly on the PROpel question. And then, Susan, if I could ask you to maybe comment on the second question with respect to any preclinical work on competitive landscape and anything else you want to add around what we know there. So Tim, the only reason that we didn't speak to PROpel is that we organized today's conversation around lung, breast and hematologic malignancies. And I think that within that context, there wasn't sort of an obvious spot for it to fit. The PROpel study reads out in the second half of this year. We completely agree that this is a tremendous opportunity for Lynparza to move beyond the profound population into not only an earlier setting, but into an all-comer setting, depending upon how those data look and how they come about. So I think that the opportunity to be able to move PARP inhibition into a broader patient population than the HRRm or BRCA1-2 ATM population is one that we're really looking forward to. And it's an important opportunity for not only the molecule, but it also probably does, to your point, represent one of the more significant growth drivers for the company if we can unwind the risk out of that Phase III. Susan, do you want to speak to the -- any preclinical insights that we've got on Astellas medicine?

Yes. Sure. So if you look at the structure of the Astellas molecule and you compare it to osimertinib, one of the key differences between it is actually the modification that they've made that makes it more lipophilic. That might potentially be linked to the higher rate of the enzyme elevations that you see with the molecule. But you would expect it to be able to cross the blood-brain barrier, I think, is the expectation from the structural analysis.

Thank you, Susan. So the next question is a question that we have from Richard Parkes.

Firstly, just on the -- your SERD program. At the moment, it's very difficult to tease apart the data from the current crop of orals as to whether they'll have simply comparable or superior efficacy to fulvestrant. So I just wondered if you could talk about the PK/PD, in vitro, in vivo, clinical data that you have that supports that or do you think that simply being oral is sufficient for the class. And then second question on the DDR platform. You've obviously presented some interesting data on the WEE1 inhibitor in PARP-resistant ovarian cancer. But I think -- look back to last year, and you talked about that molecule being Phase III-ready and -- but still hasn't progressed into Phase III. So I just wondered if you could discuss the sort of gating factors to one of the WEE1 or ATR maybe programs moving into Phase III. And then if I can just add a very quick final one. Just -- Susan sort of mentioned some similarities between osimertinib and erlotinib in terms of chemical structure, and they look remarkably similar. So I just wondered what your thoughts were on potential impact to your IP and whether a decision has been made as to whether you would look to protect that if EQRx sort approvals outside the U.S.

Great. So can I propose that Cristian and Sunil, you speak about SERD differentiation, specifically can address the PK question and maybe talk a second about how we're thinking about life cycle management and moving the program from there. Then Susan, turn it over to you to comment on WEE1, ATR, DDR program. And I guess we can probably relatively quickly address the IP question, which is that we really don't discuss too much how we're thinking about IP strategy within these context. But obviously, we stay diligent and vigilant in terms of making sure that we're protecting our IP, where we think that it makes sense to do so. With that, Cristian, to you on SERD.

Yes. Richard, thank you for the question. We are receiving, can you imagine, often this question. It is a race within the SERD. And first of all, your question was, it is different than fulvestrant. I think based on the data that we have generated so far as a monotherapy the profile seems to be different. The drug is more active in heavily pretreated patients. The drug is working after a patient that has been exposed to fulvestrant. And the ESR -- in patient with tumor with ESR1 mutations, the activity is definitely superior than what we would expect with fulvestrant. As you know, we have an ongoing trial. It's a Phase II randomized study in which we test multiple doses against fulvestrant, SERENA-2 that will inform us also clinically on this potential superiority. Overall, what I can say to sum up very rapidly, I think our profile as with camizestrant is of a drug that showed a clinical benefit rate of 53% with a median PFS exceeding 11 months in patients heavily pretreated. So this is something that you would not expect with a monotherapy endocrine agent. Even more importantly, in the context of the differentiation is the combinability. This will be a critical aspect when you move the drug, specifically, for instance, in frontline in combination with CDK4/6 inhibitors. We released this data specifically in combination with palbociclib at San Antonio -- last San Antonio. We have a very good safety profile. And importantly, we do not observe any drug-drug interaction, so no decrease of exposure of palbociclib or camizestrant in this combination. So this is a program that we are expanding at very, very fast pace. We have currently, I mentioned, of course, the Phase I. We have a window of opportunity study. I mentioned the combination [indiscernible] against fulvestrant, and we have announced our Phase III frontline study exactly in combination with palbociclib that started. In few days, we will announce a second Phase III study in the metastatic setting. Maybe Sunil, you want to pick a little bit what are the plans in adjuvant, because even if it's not pertinent on the question, but I think it's very important to explain what are our plans there.

I will keep it really short. There continues to be a really big need for patients with adjuvant with about 20% of those patients relapsing. We are working really hard to identify who those patients are, where does the SERD best help address those needs of the patients. And we're committed to bringing this to patients with early breast cancer in the right patient population that will address ongoing risk and the risk of relapse and recurrence. Thanks, Cristian.

Thanks, Sunil. Susan, on WEE1, ATR, rest of the DTR portfolio.

So at last year's ASCO, WEE1 data in uterine serous carcinoma was presented by Joyce Lou. And we have started a Phase II study in the uterine serous carcinoma at setting in Q4 of last year. In the setting of a relatively small patient population and high unmet need, the Phase II study has the potential upside from registration. And similarly with ATR, I just indicated in the post-checkpoint-inhibitor-treated melanoma population. Data that we saw from VICTORY study, we are starting a Phase II study in a similar setting. So the data in lung cancer, I think we need to look at the maturity of the survival data with the patients that we've added to the study since then.

Next we have Seamus Fernandez.

Can you guys hear me?

Yes.

Great. So my question is actually on 1062. Just hoping you could help us understand your thoughts around the size of the PD-1 refractory market and where you feel 1062 could fit into that setting. It's our view that this is probably one of the more underappreciated opportunities in the Astrazeneca portfolio. So Dave, just really interested to hear you comment on your thoughts around that market opportunity specifically. And then separately, just wanted to follow-up a little bit on the Calquence opportunity. When I looked at the, I guess, some of the incremental specifics around the Grade 3/4 tolerability or toxicity issues, it didn't appear to be -- appear that there was much separation even on the Afib differentiation. So can you just talk a little bit more about the importance of hypertension avoidance as well as the avoidance of Grade 1/2 atrial fibrillation in the context of the RR data.

Great. Thanks, Seamus. Maybe, as you suggest, I'll start first with offering a commentary on 1062 and then ask Niko to comment on what we're hearing from advisers and how we ourselves are looking at the ELEVATE-RR data and some of the takeaways that we're hearing as we talk through that. On 1062, I mean, I think, Seamus, you quite rightly point out that if we take a look at the treatment of nondriver mutation lung cancer in the metastatic setting, the lion's share of lung cancer patients are being treated with chemo -- excuse me, with checkpoint inhibitors or checkpoint inhibitors with chemo. And so the size of the patient population, particularly those that are being treated with PD-1 plus chemo that ultimately are refractory is substantial. And so I do think that within that context that's the reason why we very much see 1062 as being a really important strategy in this second, third line population. Not only is chemotherapy the standard of care for these patients, but also the previous exposure to IO, and we've begun to see some data that suggests that within that patient population some of the earlier data suggests that we've got an ADC that's demonstrating the results. I think that this is a very sizable and important lung cancer opportunity, and that's why we've prioritized that as high as we have within the 1062 portfolio. I also think that TROP2 is overexpressed fairly significantly within lung cancer, which is not to suggest that biomarker work won't be useful in order to be able to take it into other tumor types. But certainly within lung and triple-negative breast cancer, we think that an all-comers approach is one that should prove to be meaningful in terms of benefit to patients, irrespective of whether or not there's a biomarker or not. Niko, do you want to comment on Calquence and really some of the things we're hearing about the data itself? We've had opportunity, obviously, to talk to our advisers on that to provide some color there.

Yes. Thank you. So first of all, it's important to really understand that there's been a safety trial, meaning that there's been significant focus on really measuring all these safety events very specifically. Meaning that the readers are fairly intense. I think I really love the part and the question that says, what's the differentiation between Grade 1, Grade 2, Grade 3 atrial fibrillation. So having treated atrial fibrillation for years in clinic myself, you don't want to see this, whether it's Grade 1, Grade 2 or grade 3. Because it automatically means the patient will be on continued monitoring. At some point, they will all require treatment. Meaning that whatever you can do to bring down the overall number is clinically extremely meaningful. An additional point with regards to [indiscernible] and grading is that grading atrial fibrillation also in the safety trials is somewhat tricky. Still, I think the overall grade difference that we see in the ELEVATE-RR trial between 9.4% and 16% is clinically very, very meaningful. And that's certainly also the feedback that we received from all the clinical colleagues that we've exposed to these data upfront in our advisory boards.

Thank you, Niko. So the next question is from Simon Baker, Redburn.

One on Lynparza, 1 on Calquence. Let's see on Lynparza. I wonder if you could give us your expectations for the increase in BRCA testing post-OlympiA. One of the discussion said the debate now is when we shouldn't rather than when one should screen. And how you expect that to evolve? And what you could do to influence that? And related to that, the discussion also talked about the potential for PARP inhibition in cancer prevention. Do you have any plans to pursue that? Or is that more a potential area for 5305? And then on Calquence, I wonder if you've got any data on the age profile of patients currently on therapy in light of 1 of the comments made at the conference that this was definitely an option for older patients, over 65, but it was a bit more nuanced in younger patients. Any data on that would be very helpful.

Thanks, Simon. So Simon, maybe I'll just quickly cover off on the increase in BRCA testing and then invite Sunil, if you want to comment on the prevention dimension. And I think that, Simon, quite rightly also signals that there's lessons that can be learned from this that can apply to 5305 as well. And then Niko, I'll turn to you on Calquence. Simon, I commented on this briefly in response to 1 of the questions that we had, had earlier on BRCA testing. I do think that the discussion in particular, who talked about exactly, as you said, universal BRCA testing being the question and that there's an opportunity here to really just ask the question who shouldn't be tested as opposed to who should be tested does represent a paradigm shift in the way that BRCA testing, I think, is going to be considered as of this morning across the breast cancer community. I think that what's positive here is that we know that BRCA testing across most of the globe has been established in the metastatic setting, and so the infrastructure exists. And so I think that, if you will, kind of the supply side of testing for BRCA is in place and is there the demand side, I think, will have been absolutely influenced by the presentations of this weekend. And there's work that's going to need to be done here. As I alluded to before, relatively low BRCA testing in the early settings for HR-positive patients. But we expect that to be an area that we'll be working on, but I do think it's going to take some time for uptake there. Sunil, do you want to comment on the prevention aspect that also was mentioned by the...

Yes. Thank you, Dave. And just going to the BRCA testing and somebody who's been in practice for more than 15 years, seeing these results, this is going to change practice immediately given the magnitude of treatment-related benefit that we are seeing for these patients. And I think that's going to drive it. The issue about sort of prevention, I think, is a really important one that we've been discussing it. And as you outlined, this impacts both olaparib and 5305 as well. One of the key determinants is, of course, safety and tolerability. And I think what we saw with OlympiA is that patients were able to tolerate this. The discontinuation rate was less than 10%. There were low rates for AML and MDS, and that gives us an opportunity to sort of set a new paradigm with the next wave of studies. So we certainly will be evaluating that potential for olaparib as well as 5305. I think it just changed a new paradigm in thinking previous attempts at chemoprevention, which marks up and haven't been as successful, but in a defined patient population I think if the benefit is right it can change practice. So we'll be evaluating that opportunity moving forward.

Niko?

Yes. So the median age of the RR trial, CLL trial also via relapsed/refractory is all between 65 and 67 years. Very important is that we're putting significant effort also to look into older populations and additional data sets that we're running as we speak. We have the frail trial with a population that is in a much older age simply because we really want to ensure that we have the full holistic data scale. What we know from clinical practice, obviously, is that many CLL patients are elderly, hence the safety and tolerability profile is absolutely essential. This is why ELEVATE-RR really gives us a lot of confidence. Important to note, and you will see the data later today. These are data in relapsed/refractory CLL in high-risk patients, which puts an additional level of the bar higher on safety events. So the data from our perspective, therefore, are considered to be very strong.

Okay. Thank you, Niko. Next up, we have Andrew Baum.

A couple of questions, both on eGFR. I just want to make sure that we're not underestimating the commercial damage almonertinib may do to you. Given that the sponsor company is likely to come in at a 50% to 60% discount potentially, European governments are not exactly rolling in, in capital given the impact of the pandemic. In the U.S., you've got closed formularies like Geisinger and Intermountain Health, and that's even before you think about potential reform changes on drug pricing in the U.S. could open up Medicare to catastrophic coverage. So I wonder whether, Dave, you could talk through putting aside what they don't have in terms of science, just the needs must, particularly in Europe, where a heavy discount could either force significant market share loss or price discounting from you in order to maintain share. And then second, also on eGFR, thinking about the resistance mechanisms of which MET is only a minority. It strikes me that you may need a big hammer to hit or rather than a whack them all strategy to addressing each escape mechanism. Your partner, Daiichi, has HER3 ADC, which could have utility in that segment. So I'm just interested in whether you could express any interest in adding that asset to your existing collaboration.

Thanks, Andrew. So on the first question, I think you quite rightly point out that certainly we are very aware of the risk that almonertinib represents. And I think that the question that I think is most important that you're asking, there's sort of multiple levels of this. The first level is, is the efficacy and tolerability and clinical profile sufficient to be able to kind of make a judgment relative to Tagrisso. The second is, is it sufficient to get approval? And then the third starts to get into pricing strategy. I do think at this point that the pricing strategy is in many respects still speculation, I must say. I think that we're going to have to see exactly how that evolves. But the way that I look at this and how I'm thinking through it, if I start first with the U.S., I mean I think that within this context you are right that there are certain closed systems where I think that there's an opportunity to be able to come in and have conversations around preferred status. And we've gotten experience with that. This is not the first time that these kinds of conversations are taking place. We do find that the clinical profile of the medicines, the unmet need that exists within the marketplace are really key and are really important elements here. I do think that continuing to reinforce and being aware of the fact that Tagrisso is going to have to be, I think, an essential part of any formulary because of the fact that it's got the ADAURA data. And we're the only medicine that's got 3 indications with positive Phase IIIs across second line, frontline and also within the adjuvant setting. So I think within that context, exclusion isn't the real risk, Andrew. And I think that, that's kind of one of the key pieces here. Now that doesn't mean that there isn't pressure that can be placed from a contracting perspective. And obviously, we'll cross that bridge as we get a little bit closer into understanding specifically what the approach might be. I think within Europe, also, it's going to be country by country. In some countries, we're actually -- the entry of a new competitor won't trigger any changes to our pricing. I think that there are some other countries where you're right. That as we get to pricing renewals that, that's going to be something that we're going to need to take into consideration. I think our best defense really does continue to be an acknowledgment that continuing to deepen in the standard of care in frontline, second line and in the adjuvant settings and continuing to use our advantage by being ahead does continue to be our most important strength that we've got at our disposal and to continue to drive with our advantage. With that, can we turn to the second question that Andrew was asking.

I can handle it, Dave, if you want.

Yes, go ahead.

Yes. Thank you, Andrew. Actually, we announced and we have ongoing a study with patritumab deruxtecan, that is the anti-3 ADC of Daiichi Sankyo. This is a clinical trial collaboration that we announced a few months behind and is exploring the combination of Tagrisso plus patritumab. In patient safety, Tagrisso also has a potential with a small expansion also in front line. So the study is ongoing. The collaboration for the moment is limited to this tie up.

So the next question is from Luisa Hector.

So I have a couple of questions. Going back to nHER2, I just wanted to understand the timing of the start of your first-line study in the HER2 positives, D-B09. Just wondering what triggered that -- what gave you the confidence to move into that earlier line of patients? And how you're thinking about the management of the ILD in that patient group? And also the 3 arms to that study, just some explanation for the reason for the 3 arms? And then on Calquence, could you comment on the duration and the persistency of treatment that you're seeing in the frontline setting? I'm assuming if there's no progression and no major safety issues then patients just simply continue on treatment. And would you ever expect to see switching between BTK inhibitors?

Thanks, Luisa. So Sunil, can you talk about D-BO9 timing, ILD management and the 3 arms. And then Niko real-world DOT and switching for Calquence.

Great. Thank you. So thank you, Luisa, for the question. So I must -- I remember Jose, this was one of his favorite study. So it means a lot to speak to it. So number one, with respect to timing, given the data that we have seen previously with DESTINY-Breast09, where PFS of 19 months in a very late-line setting gives us the confidence that we can go earlier and do a head-to-head study. The second question about sort of the 3 arms. We do believe that pertuzumab potentially may play a role, both in combination as well as in maintaining patients on first-line treatment. So we have a Phase I/II study going on, DESTINY-Breast07 that shows that we can combine that together, and then we will be doing the study. So that's the rationale for having sort of the 3-arm to see whether patients do need pertuzumab. And then the third thing, which is related to ILD, I think we've made substantial progress in ILD. And certainly, what we're finding is that there is no cumulative toxicity associated with ILD with longer duration of therapy. That data was presented at San Antonio last year, updated as of this year, and it gives us the confidence to be able to maintain patients for longer treatment as we would anticipate in DESTINY-Breast09 without additional or higher rates of toxicity. So I think those were the 3 sort of factors that drove the decision. And as I mentioned, that study was just recently launched.

Yes. So I hope I got the question correctly that it was about dose-limiting toxicities with other regimes leading to switch over to Calquence. If that's correct...

Yes, there was -- Niko, there were 2 parts. That was the second part, and the first 1 was just real-world duration of therapy that we're seeing and if kind of -- are patients discontinuing? Are they continuing on therapy? Any insights into DOT.

So actually, usually, that's often a blind spot where you think the compliance is great because tolerability is great and then real-world data show you it's a different picture so far. From all the long-term follow-up that we see, we see excellent compliance with long-term treatment on Calquence. Actually really going towards 5 years on our clinical data. We have a large variety of real-world data sets on the way. The feedback from clinical users clearly is that they see the clinical tolerability profile significantly better. I mean there's great confidence in really putting patients on Calquence based on well-demonstrated efficacy, but really on a clinically differentiated tolerability profile, which makes a huge difference. We've also seen throughout the pandemic, where obviously oral administration has a huge advantage that we've seen continued compliance. Plus we're investing actively in monitoring support services for patients, so that we can really keep them on treatment. As of today, the continued treatment data also with regards to efficacy are clearly showing it's the best treatment option. We're eager to see other treatment modalities as well, but that's clearly what the data tell us.

Thank you, Niko. Just to take 1 more online from Christopher [indiscernible] . So what do we see as the bar for success in HER2-mutant non-small cell lung cancer, i.e., guidelines inclusion reimbursement, 14-month PFS is pretty good, but 1 KOL express got similar, that's not enough. Also thoughts about the tox profile for nHER2 and ARX788 and HER2-positive breast cancer, thoughts around positioning that?

So Cristian, maybe you can take the first question on HER2 mutant, and Sunil, the second, you can take on the nHER2 and ARX.

Yes. Yes, I would like to discuss with this KOL. Why you see this data not comparing up? I mean we are speaking about second, third, fourth line patients that with PFS that sometimes you don't even achieve in frontline. And actually, this -- I was mentioning before, this allowed us to achieve a breakthrough designation. And we are discussing with the agency the potential fallibility of this indication based on that study. Let me tell you, actually, this level of confidence, this level of activity is telling us that we are ready to move in frontline versus standard of care, because -- as a monotherapy in this mutant subgroup. So this is -- and this is -- of course, has been pressure tested externally with multiple experts, and everybody is incredibly confident that we have here a drug that will create another segment in nonsmall cell lung cancer after mutant.

I think also an important point here is that we received an NCCN listing in March 2021 based on these data. And again, I think that's another proof point to exactly what Cristian is saying on this. Sunil, do you want to comment on nHER2 and ARX?

No. So certainly, there is a strong interest in, of course, ADC platforms. I think what differentiates nHER2 is really the potent warhead and the unique MOA with topo I inhibition that the breast cancer patients and the breast cancer cells have not seen before. The requested question related to ARX has a tubilin warhead that has been tested previously with other drugs, such as T-DM1. And there's limitations, both from an efficacy perspective and also tolerability, specifically in neuropathy, and in this case, with this drug potentially ocular toxicity. So we do feel that with our potent warhead and the duration and the durability of response that we have a very differentiated, and I think, best-in-class profile with an ADC targeting HER2-positive disease.

The next question is from Peter Welford at Jefferies.

First, just going back to OlympiA. Wonder if you can tell us when we might be able to get the data from the subgroups and the patients who have had prior platinum therapy and also in the ER-positive patients. I think this is a topic discussed at ASCO and your thinking around the subgroup effects. And then secondly, just going back to the BTK, I think we've got coming up soon data on Zanu coming up, I think, this coming weekend. I wonder how we should look at that and what your thoughts are in focus areas [indiscernible] considering those at risk competition in the future?

Great. I mean I think maybe I can just quickly comment on the OlympiA data unless there's something more to this. I mean obviously, continued work will be done to go into the subgroup data and look forward to lots of additional subsequent work that we're going to be doing to look into that. I think that we probably aren't going to provide specific timings. But look forward to that being data that absolutely we are going to be sharing. I would also point out, and I think it's important to note that New England Journal of Medicine Publication also came out at the same time as the publication itself. Sunil, anything you'd add to that?

No. I think Dr. Andrew took the PI -- addressed this quite nicely that there appears to be a consistent effect across subgroups and age or positive. The event rate just is lower, because those patients came a little bit behind. But if you take a look at the OlympiA data, metastatic, the benefit was seen in both HR-positive and HR-negative. So there is a strong rationale why this drug should work irrespective of the HR status in patients harboring BRCA mutation.

Yes. And I think also the similar point was made on not drawing too much out of the platinum element of this as well, just given the small sample sizes. Niko, and perhaps Anas, can you speak to BTKis, and really, the question is asking as much as anything about Zanu and how we sort of look at Calquence in the context of the Zanu data?

Yes. Thank you. So first of all, I think it's fair to say that generally we're encouraged to see that the top level data seems to show that, that selective BTK inhibition actually leads to a better tolerability profile. There is several points to point out with regards to differences in the trial. One of the most important, this is very early data, around 15 months. Obviously, with an endpoint that is different to the one that we have in RR, where we're looking at PFS, which we consider clinically very meaningful, while response rate is an early readout for disease that actually has an often year-long clinical career. The other point is that we have been looking into a high-risk population relapse/refractory while the zanubrutinib data will be in all comers. Clinically, the most important point that I want to make is that we really need to look at long-term follow-up on the safety data. Because safety data occur at any time of the disease treatment, and obviously, there the short-term duration observation is a very early data point. And we certainly need to see these data mature to then put them into overall clinical context, so that would be the points I would offer here.

Thanks Niko. We've got 3 more left. We'll try and squeeze them in. So Matt Weston.

Two questions, if I can, please. You've had ADAURA on the market for some time now in the U.S. You said at launch that it would require a change in practice to see clinicians screening for eGFR in that adjuvant setting. Dave, I'd be very interested in what progress you've made. Are you seeing penetration of screening increase that's driving an acceleration of uptake in adjuvant eGFR mutant? And then secondly, a question on DESTINY-Breast04. It's a trial with a lot of investor interest. Can you confirm the proportion of IHC-2 versus IHC-1 patients in the study? And can you also help us with the statistical plan? Are you going to look at the 2s first before you look at the whole HER2 low group? Or how are you going to split that up?

Thanks, Matt. So let me take the first question on ADAURA progress, and then I think Sunil, I'll ask you to take the second question. So we've been quite pleased, Matt, with the progress against the key performance indicators that are most essential to understand how we're moving with ADAURA. I do think that it's important to, of course, note that obviously the incidence of stage Ib through IIIa lung cancer is lower than sadly what we see with stage IV so the number of patients showing up in the office is smaller than what we have for stage IV. But what we see that's quite encouraging is that we are seeing increases in eGFR testing. We are seeing increasing and also referrals being made by surgeons to medical oncologists, which is key in order to actually make sure that adjuvant therapy is being administered, and we're also seeing increases in adjuvant therapy and when that increase is taking place it's with Tagrisso. So all of the key performance indicators are moving in the right direction on ADAURA. I think that we've commented on this, and it does bear repeating in first quarter in particular, but also throughout the second half of last year. We do see headwinds in lung cancer in general just because of lower diagnosis rates from patients not coming into the office to the same degree that they were pre-COVID. And I do think that some of that is masking likely some of the ADAURA growth that's taking place. But when we specifically take a look at the KPIs, I mentioned before, we've been pleased with the progress we're making. We think that, that's going to result in longer-term TRx strength for this brand over the coming years. Sunil, do you want to speak about IHC 1s and 2s?

Thank you, Dave. So it's a really good question and a very important one, and D-B04 remains very pivotal study, not only for AstraZeneca, but for the breast cancer community because it's going to help redefine HER2-low breast cancer. What I can share is we are confident that there is activity that is seen in both 1 plus and 2 plus. The data that we have shared previously and has been published in the Journal of Clinical Oncology this past year showed that nHER2 was active in patients with HER2-low breast cancer and the activity profile was in the 30%, both for 1 plus and 2 plus. So that gave us the confidence to evaluate both of those patient population. We can, of course, sort of get into the splits. But I think what I can share with you, just general understanding, is that there's probably roughly about 60% of patients who are HER2-low are 1 plus and about 40% are 2+. But depending on that subset, it may be sort of variable because pathologists are more keen on evaluating 1 plus, 2 plus. So we don't -- we won't be sharing DESTINY-Breast04 numbers at this point, but what has been presented previously and published is that about a 60-40 split, but we see efficacy both in 1-plus patients and 2-plus patients.

So I think we've got 2 more questions. One for Stephen Scala and then the last one will be from Mark Purcell, and then we'll wrap up.

Just to clarify, is the Serena-2 study of your SERD powered for noninferiority or superiority versus fulvestrant? Will the Phase III study be versus fulvestrant? And lastly, Sanofi believes it has a best-in-class SERD and further believes cardiac and ocular tox are not class effects. Now that you have the benefit of more data, I'm just wondering what you think of those assertions.

Sunil?

I think Cristian addressed some of the really important points earlier as well as what we feel is -- differentiates us. We feel that we have the efficacy profile. We have the combinability profile, and we also have the duration of responses we shared at San Antonio. That gives us the confidence in efficacy. We won't sort of comment on Sanofi's. I think it's a really sort of, I think, promising drug as well. With respect to Serena-2, this is an important study that will help us sort of assess, how does fulvestrant comparison happen. We eagerly await those results versus fulvestrant. Our profile, however, and our interest remains that we think that with the endocrine backbone of choice, we want to extend and move forward in the first-line with Serena-4, and also as Cristian outlined previously, address resistance in first-line CDK4/6, and there are more to come there in the next really couple of weeks. And with respect to monotherapy ambition in later line, we think that there may be a role. But as patients progress on CDK4/6, we may have to look at beyond monotherapy with the right combinations. So more to come in that space for endocrine-resistant patients. Cristian, I don't know if there's anything...

Yes. Just to reinforce a little bit the point on some of the Sanofi claims on the safety profile. Let me reassure you that the dose that we picked to move into Phase III, 75 mg, we do not have a fundamentally symptomatic bradycardia or any other events that induce dose reduction of those interruptions. The drug is very well tolerated at this dose. Actually, what our investigators are telling us is that they are very pleased not to observe any GI toxicity with this drug or hot flashes that is reported with other molecule. So we believe Sanofi thinks that they are the best-in-class profile. We believe maybe we have the best-in-class profile.

Thanks, Cristian. All right. So I think let's just then turn this to Mark Purcell.

Can you hear me?

Yes.

Yes. I've got 2 questions. The first 1 is just going back to the ALPINE trial with zanubrutinib completely get the point that the data are ready. But obviously, the trend is very strong. This 95% versus 84% 12-month PFS versus IMBRUVICA. But also there's quite a significant distinction on AF 2.5% versus 10% discontinuation, 7.8% versus 13%. So just sort of thinking how quickly Calquence is getting share from IMBRUVICA in terms of new patients, could you sort of help us understand where you thought this will go? When zanubrutinib has its first-line data? Obviously, you're always going to be ahead in terms of the maturity of data, the size of the database, et cetera. But could you sort of talk to the threat here and whether if the first line data looks -- is broadly in line with yours, whether they may end up taking share? And then sort of secondly, maybe 1 for Susan. Susan, talking about your ADC strategy longer term, could you sort of help us understand aspirationally the targets you're looking at -- other payloads you're looking at. We discussed in the past that [indiscernible] is synergistic with PARPs. And you talked a little bit about the PARP1 selected compound AZD5305. So I'm just trying to understand with your ambition behind ADCs, how broad are you're going to go in terms of potentially replacing traditional chemotherapy with your ADC portfolio?

Thanks, Mark. I think -- why don't I start on the first piece on the BTKs. And maybe, Anas, I'll ask you to comment on kind of how you view and some of the things that we're hearing from hematology community on ALPINE. I think some commentary also around the control arm within that study might also be useful just to get some of your thoughts there. And then we can transition over to Susan for the second part. The -- I think the thing, Mark, that I guess I'd point to is that, obviously, you alluded to this, the uptake that we've seen in terms of new start share among new to BTKi's has been quite brisk with Calquence. So I think that this is owing to the fact that there is an unmet need that exists that physicians are believing is being satisfied well by Calquence. And I think the real-world experience that physicians are having in patients as well with the medicine is strong. I would point out that, while obviously, it hasn't happened in the context of the ALPINE data that Zanu is approved in MCL. And we haven't seen the same level of uptake into the relapsed/refractory MCL setting, as we did with Calquence when it certainly entered in into the 2017 timeframe. Now that's not to suggest that CLL will be the same as MCL, but I do think that it speaks to the fact that certainly there was an unmet need that Calquence was meeting. Whether or not Zanu will actually be able to satisfy more than what is already there, I think, remains to be seen. And so part of the question really does get to how much do we read into any differentiation from the competitive studies relative to what already is being offered through Calquence. Anas, do you want to speak to any of that?

Yes. So again, it's good to see that there is a second BTK selective inhibitor doing favorably compared to the first one. So that's good and consistent with our own data. But I would be very careful making cross comparison between Zanu and acalabrutinib for obvious reasons. The trials are different. They take all comers. We took mainly the high-risk patients. But the most important obvious one is that when you look at the comparator arm, which is ibrutinib, it somehow underperformed. The overall response rate in the ALPINE trial was only 62%, where you would expect at least 80% response rate in a similar patient population. This is what has been reported in a RESONATE trial. This is what we reported even in the high-risk patients with the [indiscernible]. So we're cautious about this cross-trial comparison. We haven't seen the data. We read the abstract. We need to see the data, and we need to wait for the full report. Keep in mind, this is still interim analysis. So we need to wait for the full report to mature before we make any conclusions.

Thank you, Anas. So maybe, Susan, you want to finish and wrap up on the final question from...

Sure. So in general, I would say, I'm bullish about the opportunity for ADCs broadly. I can't -- obviously, at this point, share with you the targets that we're looking at. But I think we've got extensive protein engineering capability and extensive antibody portfolio that -- so you can imagine by looking at those opportunities. I do think as well -- the ADCs have been in the clinic for 2 decades. It's taken the industry broadly, I would say, a while to work out the components of the system that you need to do. 1 element of that is understanding both the expression of targets [indiscernible] and then how they internalize the traffic. And I just call out that in addition to the protein engineering capability and the understanding of what we take to that system, we also have capability in computation of pathology, which I think is going to be very important in terms of understanding which are the right patients to treat with different ADCs that we've got. So I look forward to sharing with you some more details, and I'm sorry to only be teasing you with that today and not actually sharing data, but I look forward to sharing those data in the coming months and years.

Thank you, Susan. Much appreciated. So with that, we'll bring this session to a close. I want to thank everybody for continued interest in AstraZeneca. It has been an exciting ASCO for us, as we tried to highlight as we went through it. Really yet, again, another set of historic data from AstraZeneca medicines at this year's ASCO, which we hope will continue moving forward. Oncology is, I think, the fastest-growing therapeutic area across the industry. We are among, if not the -- among the fastest growers within this fastest-growing therapeutic area. We appreciate you all staying along with us. We know that it went a little bit over, but we have so much to cover because of the great science that's taking place. And hopefully, you also enjoy having an opportunity to meet more members of the team, which does contribute a little bit to the amount of time that it takes, but hopefully gives you a flavor of some of the great talent that we've brought on board and that the people who are really the wonderful stewards of these fabulous medicines that we're continuing to work through. So with that, we look forward to seeing you all soon, and hope you all have a great evening and afternoon. Take care.