AZNCF - AstraZeneca PLC (AZN) ASCO Investor Event

2023-06-06 07:17:10 ET

AstraZeneca PLC (AZN)

ASCO Investor Event

June 5, 2023 19:00 ET

CorporateParticipants

Andy Barnett - VP Global Head of IR

Roy Herbst - Deputy Director, Yale Cancer Center

Pascal Soriot - Chief Executive Officer

Susan Galbraith - Executive Vice President Oncology R&D

Dave Fredrickson - Executive Vice President Oncology Business

Sunil Verma - Global Head of Oncology, Medical

Leora Horn - Global Clinical Head, Lung Cancer and Lung Cancer Strategy

Osama Rahma - Global Clinical Strategy Head, GI Cancer

Anas Younes - Senior Vice President, Hematology

ConferenceCall Participants

Andrew Baum - Citi

Viktor Sundberg - Nordia

Chris Uhde - SEB

Peter Welford - Jefferies

Simon Baker - Redburn

Tim Anderson - Bernstein Research

Emily Field - Barclays

Harry Gillis - Berenberg

James Gordon - JPMorgan

Seamus Fernandez - Guggenheim

Presentation

Andy Barnett

A warm welcome everybody to this 2023 ASCO event for investors and analysts and thank you greatly for your continued focus and interest in our company. Just for your information, the presentation is now online, you can access it for those in the room by the QR code on your on your tables. You'll see all of our IR materials also listed in the same section.

Here's our forward-looking statement. Please familiarize yourselves with if you haven't done so already. Here's the agenda for today's call. Our prepared remarks will be delivered in two sections with Q&A's at the end of each section. Breaking up some of the content, it'll give you a chance to ask questions about particular subject matters in more depth. The first section will focus predominantly on lung cancer. And we're actually delighted to have Dr. Roy Herbst here but for that section. So I know it'll be hopefully very informative for all of us and useful to you in the room.

For those dialed in via Zoom, please use the raise the hand function for you to ask questions or if you want to type the questions in via the Q&A tab. That will also work we'll be trying to get to as many questions as we can during the allotted time.

ASCO is an incredibly important meeting for our companies, you know, in fact, Pascal was just telling me it's his 22nd ASCO in a row. So it gives you an idea of just how committed this leadership team is to this event. And making sure that we have key data showcase that the best congresses we can.

This slide details the speakers, but I also would like to introduce you on the right hand side of side a number of R&D leaders that are helping us to redefine how cancer is managed across a range of different tumor types. One of the depth and breadth of the talent we now have in the company is proven to be a exceptionally useful as you think about how cancer might change and evolve in time, and how we might be at the forefront of that and the way that we're designing our trials and bringing forward new medicines. So it's an exciting time for oncology. It's an exciting time for this company. And with that, Pascal, I'll hand over to you.

Pascal Soriot

Thank you, Andy. Good evening, everybody, as always a very exciting ASCO. And as Andy said, It's my 22nd. And it gets more exciting every year. And when you compare with what we had 20 years ago, it's just amazing. The number of options that are opening and becoming available for patients and the science is just amazing. So let me start by maybe a general comment on our company over all, because we have, of course oncology, but as you know, we also still have a very large presence in what we call biopharma, which is essentially cardiovascular, respiratory. And we are now starting to look at how do we build immunology within this.

And our Rare Disease division generated about 17% of our sales, and actually growing quite nicely as you saw in the first quarter. The important part of this graph is at the bottom there. And it is important because it shows you our ability to actually develop and commercialize our products globally. And it's also important because it enables us to build partnerships and tap into innovation where it is. And I'm sure you've noticed, it's hard to miss that Chinese companies are innovating at an incredible speed. And being present in China gives us both the opportunity to actually partner with them and help them potentially develop and commercialize their products globally. But it also gives us a first-hand experience of what is to come in terms of commercial competition. So far, we've done quite well as you know, Tagrisso is competing with local companies, and we still have dominant market share with Tagrisso in China. So we really are training ourselves in terms of getting the right competitive spirit, because this competition is going to hit up everywhere around the world.

And as you can see on the right-hand side here, we are growing in every geography. The emerging markets are doing extremely well. China is now growing again, but importantly outside of China, we are doing well everywhere, in Latin America, in the Middle East, Southeast Asia. So really, the company is growing in every geography very strongly, on the back of strong oncology goals, but not only oncology.

Now, this is really a very special ASCO for us as a company because it's our fifth plenary presentation. And so we were trying to think about who else as a company has had five successive plenaries and I tried to remember whether [indiscernible] had one but we couldn't find anybody, we are really quite excited and a lot of abstracts. An important piece is, ASCO is not today the only venue where companies present their data, their results, their clinical results. In the old days, it was mostly the ASCO, but today the ESMO is about the same size. And we have a very busy ESMO this year for us. And as you can see here, we have presenting important data at this ASCO.

We continue to work on building up leadership in a number of tumors that we have selected as priorities. We're looking at new modalities, and I'll cover this in a second. And of course, and importantly, we're trying to leverage the pipeline, oncology pipeline to develop innovative combinations, the future is going to be about combinations, it really makes it very exciting, but also very complicated and very challenging [Audio Gap] because combinations are going to be really fundamental to strategy. And so you need to have the product, you need to have the talent, you need to have the team to [Audio Gap] that can cost a lot of money. In the past, it was chemo so it was okay, now you more and more comparing to standard of care that is protected by patents and expensive. So the future development in oncology will become complicated and expensive. And of course, probably more lengthy because we're moving to earlier stages.

In terms of the modalities, we've continued to build on our historical strength in DNA damage response and tumor drivers as you can see here. But we've also introduced in the last few years, a new focus on antibody drug conjugates, in particular, and not only Enhertu and on HER2 that of course, our great products and everybody talks about. But we've started developing our own pipeline of ADCs and see Pooja here in the room, she's done an amazing job, we have quite a number of products that are exciting, in particular, the EGFR/cMET, ADC and B7 as well. It's was also interesting. So we really are building a pipeline of VGCs. We also on the immuno-oncology front we're working on bispecifics, as you know, and making rapid progress with those.

We have started working on immune engages. And there's one compound listed here that is looking quite exciting. And finally, we started making inroads in [indiscernible], it was a very different approach and in the near term we're looking at CAR-T. But in the long run, we have new technology, we hope will help us make a difference. As you can see here, we're really looking at a number of technologies.

And the last slide that we will show you is this one, we've had seven read outs in oncology in the last few months. And we were joking the other day seven out of seven. So that's quite nice. But I wanted to attract your attention, a couple of points here. The first one is, if you look at the left-hand side of this graph, Tagrisso, DUO-O, of course on top, and then you have AEGEAN, and then those two studies, plus, of course, the Merck study, what they show, I think is the need and the credits, enormous, I think, call for action to screen and diagnose people early. Because we now are starting to do in lung cancer, what we've been doing in breast cancer for many years, now we can only transform lung cancer, like breast cancer treatment has been transformed if people are diagnosed. And that's not the case today. So there's a big call to action, I think, for the community for us as a company with the community at large to diagnose those patients early.

Maybe another message I wanted to leave you with is the fact that we have a number of study with Imfinzi here that I've read out positively. So I think it really confirms the good activity of Imfinzi. And some of you of course, they was a long debate about PDL1 and Imfinzi is it as active as PD1? I think those studies show that it is definitely a very active compound.

And the final comment is, if you look at Enhertu the data that we presented this morning, in various tumor types, and then you look on the right-hand side, the DUO-O history, I think what happens here is we're going to see an earlier treatment of endometrial cancer with different regimen, as you can see here, that will create an enormous unmet need in second line, and that's where Enhertu can actually come in and feel this unmet need because patients are going to be treated earlier.

Endometrial cancer is expected to grow quite a lot, in fact, it's expected to double over the next seven, eight years in the U.S., because of obesity, it's a consequence of obesity, and it probably will be the same everywhere around the world. So, big opportunity here for Imfinzi. But also Enhertu to make a big difference in the treatment of fundamental cancer across several lines.

So with this hand over to Roy Herbst, who is going to present the ADAURA results, which of course, were the most exciting results for us at this ASCO. Roy over to you, thank you so much.

Roy Herbst

And thank you, Pascal. And it's great to be here. And it's, for me, as an investigator, it's an honor to be able to present the plenary twice with data that change practice, because I can tell you, I've started in this field, as a fellow at Dana Farber at 1994 and the progress we've made in this disease and the fact that we have results like this that's really makes me feel worthwhile. The work that I've done and collaborating with the whole team here, and many others around the world.

So I think most of you know the ADAURA, but I'll just briefly go through it again. This study is a Phase III double-blind placebo-controlled trial. And the idea was to take osimertinib, no third generation, more potent EGFR mutation selective, less toxic, CNS active drug, and to use it in the adjuvant setting. And this trial, of course, was possible because the drug could be given for three years, the drug had more activity. And the whole idea is makes a lot of sense that patients with lung cancer die from metastatic disease, so we want to bring our best drugs earlier.

So this trial, basically, patients had to have complete resection, Stage 1b, 2 or 3, and they could have had chemotherapy, this was the choice. It was based on stage and also a choice between patients and physician. There were about an equal number of patients who had chemotherapy in both arms, it was somewhat stage dependent, and the patients were randomized with three stratifications by stage, the three stages wouldn't be 2 or 3a had an equal number of patients in each stage, but the EGFR mutation type, they only included the two most canonical mutations in this trial, Ex19del, Ex21 point mutation [indiscernible] and race Asian versus non Asian.

Patients receive standard of care plus or minus [indiscernible] to them. And we used a placebo this trial because there was no standard of care to use an EGFR inhibitor before this. As I showed at the plenary yesterday, there have been a number of trials that maybe showed a hint for DFS, not significant, nothing showing survival. So this trial truly broke a new ground, and it was Tagrisso 80 milligrams once daily, versus placebo for three years, you can see we randomized 682 patients, worldwide effort, plan treatment duration was three years, the primary endpoint of this trial was disease free survival.

We expected this drug would be active, but it was powered for hazard ratio for DFS of 0.7, a 30% benefit. I still remember getting the call it's a little bit more than three years and a few months ago, that trial actually unblocked -- we reported two years earlier than expected because the results as I'll show you, in a second, were so much better than even exceeded already high expectations. And that was the first endpoint DFS that we had at ASCO, three years ago.

So here are those data. And I still remember when we got these data, it was, I think about a Good Friday that year and actually ended up on the ASCO plenary, because the program committee, this is lung cancer, look at these data. On the left, you can see the primary analysis stage 1b to 3a disease. And you can see that the hazard ratio is 0.20, meaning highly significance getting an 80% improvement in these three survival. Primary analysis that was stage two to three disease, this is adding in one visa, who were patients that actually do even better on their own.

So really these are very impressive DFS, which resulted in the drug approval many places, but not all reimbursement in many places, but not all. And that's why these new data are so important. And then you can see on the right, the updated data we did at 50% maturity, meaning 50% of patients having DFS events, we updated it, it's in the JCO, this last January. And there you can see that the hazard ratio remains quite good. It's point 0.27, the curves coming a little bit together after all patients have stopped maybe a little bit, but still 0.27, 73% improvement in disease-free survival. So these were the data we had before the current ASCO and quite impressive and I think on the next slide we added in the brain, because that's what makes a difference to patients, I can tell you, every patient I care for is always worried about the brain and recurrence in the brain.

And if you look at the right, we can see this drug has activity in the brain. And you can see this is the DFS curve for brain metastases as the first side of progressive disease and the hazard ratio is 0.24. So a 76% decrease in the chance of that and other metastatic sites as well. So here, you're taking the best surgery and the best chemotherapy if needed, and then you're adding this drug and you're preventing metastatic disease. Now, we've all thought that that would have an effect on survival. But there were naysayers. You all know, you read the same Twitter I do and the same posts. And I have surgical colleagues who would often tell me, where's the survival data? So well, we did not want to disappoint.

So here it is, and, and again, we all waited anxiously for this, this was event driven. Of course, you never want to see this happen, because it means people are -- 20% of the patients had to have events, but this happened earlier this year. And then there's a process that occurred for data review analysis, but I still remember sometime in March, the first day, I was able to see this.

Again, I expected there was some leaked furs, of course, from Japan. But still, I expected this would hit survival, but I wasn't sure. And but to have it with hazard ratio of 0.49, look at 60 months, and the median follow up is about five years in both arms, no medians reached, by the way, as far as survival yet, but look at the landmark 85% versus 73% of patients alive, the hazard ratio across the whole course of the curve, 0.49 that's a 51% improvement in finding deaths. So 51% fewer patients died across that curve. It's just really a phenomenal results. It's, again, high expectations, but we even exceeded those. And this isn't a stage 2 and 3a patients then when you add the 1bs in still has sort of 0.49, P value 0.001. And you can see, again, the 51% decrease in deaths.

So really very significant results, I can tell you, I see patients myself, I do research, I do administration, I do a lot of things. But I can tell you, everyone that I've seen in the halls, I've not seen any one at this meeting of my clinical colleagues who hasn't said, Wow, this is really impressive, they even the most harsh critics and invite you to talk to them too.

So then this is an exploratory analysis. So this is a secondary analysis, secondary endpoint. So this is exploratory in the secondary. So taking it that and some of the groups are small, and of course, in the group, so the earlier disease, there are fewer events. But for the last part, the point estimates are off to the left of one. And they range between 0.35 and 0.68, but pretty much and this is in our paper, it's in the supplement, if you want to get a copy of that in the paper, the New England paper that came out yesterday, you can see that pretty much all the different groups, whether it be sex age, smoking history, race, stage, EGFR mutation status, acumen chemotherapy. That's an important one. I showed those curves yesterday, whether you had it or not, there's a benefit. So I think this really shows the broad impact of this drug in the adjuvant setting.

There are toxicities, no drug is going to be less than a placebo. But it is interesting that if you look the hail yesterday, I wanted to highlight one number for the plenary, I think I did the grade three events. And if you look at any grade three, first of all, there were no deaths on the study, no grade five events, but it was 23 to an a grade three was 23 to 14. So there were a few more grade three events in the patients who got the drug, patients, even though this is an EGFR selective agent, patients still might have some rash, some low grade rash and GI side effects, skin changes, on the nail beds, maybe the eyelashes, but these are things we've learned to manage through.

I can tell you for the most part, and I've had patients that care for myself, patients can make it through three years, but I think now having the survival data that'll be important for the patient who might be having a challenge for that.

And then here's the conclusions. So in the primary analysis, we had already demonstrated a statistically significant and clinically meaningful DFS benefit versus placebo, along with improved CNS, DFS, and a tolerable safety profile that existed before today. But now, the survival data, both in the primary population of stage 2 and 3a patients, you can see with high confidence across level of 0.49 and P value 0.0004. And the overall population adding in the 1bs, 0.49 P 0.0001. As I said, generally consistent across subgroups, including, most importantly by disease stage. I showed those curves yesterday, they're in the paper and prior acumen chemotherapy.

So, conclusion and I believe strongly, it's the first global Phase III study to demonstrate statistically significant and clinically meaningful overall survival benefit with targeted treatment in this population. It reinforces Tagrisso as a standard of care for patients in the 1b and 3a setting who have had resection, I think it's also a new paradigm in the entire field, that a targeted agent, no, that's been honed over 25 years, first used in patients in the refractory setting, then used in in patients in the frontline setting. Now, actually, the trial with a lot of foresight started before the drug was even a fully approved in the frontline setting.

Now, now we see that we're bringing targeted therapies earlier and disease. As Dr. Soriot said, I think we have to screen more patients. We have to profile more patients. One of the things and certainly through the societies I have involved in the [indiscernible] and others, I think we need to get the word out. We need to screen patients. We do a very poor job of that in the United States and around the world. We need to do profiling our patients because now at a tumor board, this is very relevant. And I think that with these data out there with the push has gotten from this meeting, I think we'll see more of that. I think that's my last slide. And I'm happy to take questions later. Thank you.

Susan Galbraith

Thank you, Dr. Herbst. So I'm just going to now summarize some of the other data that were presented at the ASCO in the lung cancer and then Dave is going to set the scene of what that means. And we can take some Q&A on the lung cancer portfolio.

So let's start with Dato-DXd, you can see the design of this drug on the left-hand side design has a best-in-class TROP2 targeting antibody drug conjugate with a high potency TOPO payload with a short systemic half-life optimized drug antibody ratio of four in this case, same tumor selective capable linker, as we have with HER2 and the bystander effect of the warhead once cleared, because it causes cell membrane.

The three areas of focus for the development program, we're examining it as a potential to replace chemotherapy or component of chemotherapy as a backbone. We've got further outcomes that we're looking at in terms of novel combination regimens, including with IO combination agents. And we're working actively on assessing the predictive value of TROP2 biomarkers because of course, the data that we've seen so far with this molecule is to date an all comers patient population, in contrast to the date that we had with in HER2, it's all in HER2 selected patient populations.

So we already have seven ongoing Phase III trials across non-small cell lung cancer and breast cancer. And you can see those highlighted here. And I can go through those designs in a little bit more detail.

So at this meeting, we've presented some updated data from the TROPION-Lung02, this is a Phase 1 base study investigating Dato-DXd and pembrolizumab, with or without platinum-based chemotherapy, and a mix of first line and second line, metastatic non-small cell lung cancer patients. I think the other thing I'll draw your attention to is the two different doses that were examined in this study, 4 mg/kg and 6 mg/kg and you can see that across the cohorts here.

So the dose expansion within patients with less than or equal to one line of platinum-based chemotherapy and treatment naive across those different cohorts.

So this is now -- listen to the embargo. So I can show you the spider plots and that will be presented before you go -- on the left hand side, the Doublet therapy on the right hand side, the Triplet is not randomized cohorts, and there's a little bit more maturity on the Triplet that's under Doublet arm here. But again, you can see really good waterfall plots with the vast majority of patients having some tumor shrinkage. And the other thing I would point out is that there's good durability of response from those spider plots, including across different levels of PDL1 expression.

So in the first line, the response rate was 50%, in the Doublet 57%, in the Triplet, the median progression free survival is immature at this point, which is why I would focus on the durability of response on the spider plot. And these data are supportive of the ongoing pivotal Phase III first-line trial TROPION-Lung07 in the non-squamous population, without actual genomic alterations in the less than 50% PDL1 TROPION-Lung08 in the greater than 50%, PDL1 and the AVANZAR study, which is also testing predictive marker of TROP2.

Here's some of the safety data. As you would expect, if you're adding platinum-based chemotherapy, you're going to have some difference in the safety profile. And we've called out some of the rates of anemia, decreasing platelet counts, neutrophils and neutropenia at the bottom. Grade 1, 2 in the darker shade and grade three in the lighter shade. So we didn't see any new safety signals here. We didn't have any grade four or five ILD is attributable to Dato-DXd. The rate of Grade 1 or 2 ILD was 20%. And that rate of Grade three or more ILD was similar to what you expect to see from KEYNOTE-189 study. Hematologic toxicity was manageable with lower rates observed obviously in the doublet arm. And again, this safety is supporting the six-month [indiscernible] dose in the first line.

So I guess, this is like a summary of some of the trials that we have ongoing. You've got the Phase III TROPION-Lung01 study and I'm sure that you were confident that we are eagerly awaiting those data. We've got the Phase 2 study, the TROPION-Lung05 study. We're looking in each of our mutant space in the Phase 1 Orchard study in combination with Tagrisso. And then as I've described, you've got the Lung-08 and Lung-07 and the events after these.

So we have different opportunities here. As I've said before, we can replace current chemotherapy with the TROPION-Lung-01, looking at novel combinations in the Orchard study, and we're wanting to move Dato-DXd earlier in treatment paradigms in combination, and look at that level of TROP2 biomarker.

So finally, I'll end with just a preview of the ARTEMIDE. One study, this is our PD1[indiscernible] by specific volrustomig, if you're interested. We've got some preclinical data showing some differentiation for this molecule versus coadministration of two agents together. The data that we're presenting so far is a data set in patients that have had prior checkpoint inhibitor, lung cancer, you wouldn't expect to see really high response rates in such a patient population based on that mechanism of action. But now that we have the safety and the PK well established in this setting, with no surprises, we're now opening, we've got cohorts ongoing in checkpoint inhibitor naive on small cell lung cancer patients. We're planning to initiate Phase III trials for this drug this year.

So I'm going to hand over to Dave, who is going to walk you through the landscape.

Dave Fredrickson

Thank you, Susan.

All right, so if we just take a look at two slides that look at the program first, overall for Tagrisso. And I want to talk overall for the lung cancer program. I think that after we had an opportunity to listen to Dr. Herbst, what you can really see here is that we've got a very, very comprehensive program with Tagrisso to really establish as the backbone of therapy to treat as soon as possible, an EGFR disease. Obviously with ADAURA, this really solidifies within the stage 1, 2, 3 population within those that are resectable. I think what's important to note about ADAURA and Dr. Herbst mentioned this, I mean, I think that despite the fact that DFS data were positive and been available for quite some time. And we do have a number I mean, many, many countries across the globe where approvals have taken place, there are still many care gaps that exist, care gaps in the sense of only 80% testing rates, maybe only 75%, adjuvant treatment rates, referrals to multidisciplinary teams also not being as high as they can be. And so those sets of care gaps, add up and create a number of patients who really we see these data is creating an imperative and urgency to be able to go out and make sure that we're able to get treated and to use this obviously, to grow the brand across the globe.

Reimbursement, we've got a number of countries that while approval may have taken place, reimbursement hasn't taken place, a number of large ones still ADAURA in South Korea, Brazil, Taiwan, Hong Kong. These are places where there's opportunity now to use these data to secure reimbursement for ADAURA and creates opportunity. FLAURA, of course, remains the standard of care in Frontline. We look forward to sharing the FLAURA2 data which we'll do later on this year. FLAURA2 as we've talked about in the past, we really do see that this is going to offer a chemo combination exactly which of patients will want to be treated with that combination. Obviously, we're going to want to engage with the community and see how they see the data and look at those data. We continue to believe that monotherapy is likely to be the standard of care for the majority of patients, oral, benefit risk profile as the way that it is but we are really excited about FLAURA2 for what it represents and also for the competitive aspect in light of anticipated Mariposa data.

And then lastly, I guess what I'd point out is that in the second half of this year, we look forward to LAURA study reading out, which is in the unresectable Stage 3 population. And then, lastly, NeoADAURA; NeoADAURA will read out in 2024. And we have an opportunity there.

We showed this at the last quarter, this is the extent of all of the work that we're doing within lung cancer, I think what's really important about this slide is that we are really developing a scale of breaths in lung cancer that I think is pretty unique and unparalleled relative to the others that are within the oncology space. And what you can really see here we've just talked about Tagrisso as a backbone of treatment within the EGFR setting. IO within Imfinzi, really clearly been well established with Pacific in the unresectable setting. And we've got a series of various Pacific, a two through nine studies that are really looking to build on that backbone and serve as an opportunity for us to be the one that beats Pacific if anybody beats Pacific.

Of course, we're advancing the ADCs to replace systemic chemotherapy. We've got approvals already within HER2 and the HER2 immune population. But of course, we're all looking forward to the data readouts, which we anticipate the first step soon. Novel combinations then becomes the opportunity to gather not only with obviously durvalumab, but also novel combinations as we move into -- with our bispecifics.

So hopefully, you can see within this, we've got an incredibly extensive program in lung cancer, we hope to be able to reach the overwhelming majority of patients to be able to have eligibility for our medicines in the future. And we've got a significant investment and a great number of assets in order to be able to get there. So with that, we're going to take a pause at this minute to do Q&A. And I invite you Pascal up to moderate the Q&A.

So we will ask in this session, if we could we'll do a lung-based Q&A, since we've got Dr. Herbst here to be able to go through that and then we'll present some other elements from ASCO afterwards. Thanks, Pascal.

Question-and-Answer Session

A - Pascal Soriot

Thanks, Dave. So if we have mics, there's one coming.

Andrew Baum

Thank you so much, Andrew Baum, Citi. A couple of questions for Dr. Herbst. So when your patients ask you, how long should I continue after I've been on the drug three years. What you tell them and how their insurers react? The second question, I'd be interested in the views on the Chrysalis-2 data that was presented at this conference, particularly in met negative patients, and I'm just trying to reconcile the Chrysalis-1 data with the Chrysalis-2, it's confounded, because obviously one is first line, the other second line, but one is also Asian versus another population, which is non-Asian. So to what extent can we think about potential differences in ethnicity as it may impact, mutational profiling EGFR, or the frequency of met mutations, as we think, particularly with regard to Mariposa, and the competitive dynamic with degree, so based therapies? Sorry, for the long question.

Roy Herbst

No, I can answer the first. The second, I might need some help from my colleagues on the panel, since I've been sort of tied up with other things. But I haven't seen that presentation. But I would say that, the trial was for three years. And we chose three years of therapy, because we knew that previous studies with older generation drugs at two years had failed. And could it have been longer, yes, but we also wanted to try that could get completed, and we wanted to have the results. At three years, we stop and sometimes patients are concerned about that they're doing well. But we stop and that's, we have samples, by the way on those patients now. And we'll be analyzing them at some point to look at CT DNA and so forth.

But at this point, it's three years, there is some hints that perhaps in some patients, it might be better to give longer. We saw that in a DFS update, where, after stopping, if you look at the CNS relapse rates, they do tend to slightly go up. So I think at some point, we might want to give longer therapy and there is a trial known as TARGET, as you saw, that is looking at five years of therapy. I also think some patients might need less that maybe we've cleared everything in there, they're done with one or two years. So we're at right now, of a treatment is for three years, I think there will be studies in the future that will address longer treatment. Of course, if someone fails, retreatment these are all things that will be addressed as time goes on, but right now, I think the discussion with the patient is, this is the period many are very happy to stop, they've been on and they don't have to worry about it anymore.

As far as the other question, I don't know Susan, do you have…

Pascal Soriot

Maybe Dave, if you want to add something and then for the second question, we could ask [indiscernible] unless.

Dave Fredrickson

I would like to add-on the first question and I think that Andrew you ask an important elements around element around how long will patients want to stay on therapy. But then your second question for insurers, what we are seeing is that the, in the U.S. patients are able to stay from a payer perspective on therapy two to three years. But I'll also note is that we've talked in the past about how Part D reform, while it has elements of costs that it comes with it that the affordability elements and the smoothing elements, as it relates to copay capping is something that we see is beneficial.

And I think that in the ADAURA setting, this is particularly going to be an important spot to see as you take a look at and the cumulative impact of three years of copay for Medicare Part D patient who has to be able to make the copay. I think that this is an element where persistence, as it relates to getting duration of therapy out to that three years. And in fact, we talked to patients. Dr. Herbst, I don't know if you want to I mean, we talked to patients who they say, well, gosh, I'm not sure I even want to stop at three years, at least from a patient perspective, in terms of what their emotional sentiment is. So I do think that Part D reform is beneficial to the economic situation for patient affordability here.

Roy Herbst

I agree. There are some people that it's very -- with all these drugs, whether it be TARGET therapy, right, they are very reluctant to some people are very concerned about that. So it would be nice to have the action.

Pascal Soriot

All right. Anybody wants to help with the second question? Otherwise, maybe what we could do is move to the next question and come back to Chris. I think you're with second guy.

Viktor Sundberg

Yes, thank you. Viktor Sundberg, from Nordia. So I've seen data here at ASCO on perioperative studies in non-small cell lung cancer, but all studies are very different from each other in terms of baseline characteristics, and I think regulatory agency, representative voice or prestation, over this year at ASCO, but given the lack of comparability among trials, do you see a risk that AstraZeneca [indiscernible] becomes second or third option among the choices of drugs. If physicians just look at the data at face value, or the absolute numbers between trials, thank you.

Pascal Soriot

Oh, do you want to take this one?

Susan Galbraith

If you're comparing Keynote-671 to GN. Again, I think the data that you're seeing are very similar in terms of our past CRE compared to their past CRE. Actually, in GN, we had a more real-world patient population in that Keynote 671 was limited to cisplatin. I think what the agency was discussing, Harpreet Singh comment was, the benefit of that adjuvant component. And I think Mark Awad had a nice presentation showing that there was more of a flattening of the curve in Keynote 671 with that adjuvant and you're seeing the curve continue to go down in 861. Our OS maturity still immature. And you know, we were at lower maturity when we presented at ACR. So with time, we'll learn about that benefit of the adjuvant component. But I certainly don't think that we come in second or third, I think that there's strong data. And you now have three perioperative studies all showing that benefit in IO sensitive non-small cell lung cancer.

Pascal Soriot

I think the point that they have made about cisplatin combo is really important, because if you think about Europe, of course, cisplatin is more common. But it's possible likely, we'll see that these are the labor or the reimbursement or both actually is limited to cisplatin in the U.S., tends to be a little bit more flexible, but still not having combo in a labor actually going to mutation very commonly used in the U.S. as you know.

Viktor Sundberg

Maybe one final question for Roy Herbst. Also. I was wondering if you plan to do a subgroup analysis, that overall survival for patients previously on placebo, but I got [indiscernible] and give a subsequent treatment or if that sample, at the moment just too small to see anything meaningful or if you plan to do that in the future perhaps.

Roy Herbst

We've been asked about that. What do you think, you want to comment.

Susan Galbraith

Yes. We are continuing to follow the patients. The good news is not many patients have progressed. So we're continuing to follow that and we'll be able to update that data in years to come.

Roy Herbst

I think that was a long discussion. That's why I said, in the last slide plans are underway to do that. So, again, with more maturity, a little bit more ability to make those determinations.

Pascal Soriot

I think there was a question at the back if whilst we get a microphone there, maybe Susan, do you want to cover the Chrysalis question?

Susan Galbraith

Yes. Andrew, thanks for the question. So, there was clearly data, from that updated data showing there's activity in the met, non driven group as well as the met driven group. I think that's your point. I think the data set for Chrysalis-2 still remains relatively small, in comparison with what we had for the OPAL-2 data ahead of FLAURA2. So we're obviously looking forward to sharing the FLAURA2 data when we got the chance to do it congress, hopefully, later this year.

I think, what we can say from the OPAL data, is that you got a regimen there, that was well understood toxicity profile, you can stop the permit check says, during the treatment, if that becomes a problem, tolerability profile doesn't stop, you're taking the important medication of the osimertinib. That's a really important point to bear in mind. And so whilst it's activity that I still think we have to just wait and see what the overall benefit risk profile is, there's still safety, side effects that are seen with that regimen that I think represent a challenge is what we're hearing for some of the patients that are on it. And what we've always said is that there's going to be a choice for those patients that wants a combination.

I think the profile of what we've got with FLAURA2 based on the OPAL data is one that offers a very reasonable choice for patients that want some intensification of therapy. So let's have this conversation again, once we've actually seen the FLAURA2 data.

Pascal Soriot

What we hear actually on those who have used this regime and the Mariposa regimen is that tolerability is really a big issue. So we'll have to see and in fact, as they've said to someone a therapy is likely to return a pretty substantial position actually for simple reason that it's easy to use and very well tolerated and the impact on people's lifestyle is minimized.

Unidentified Analyst

[Jonny Ram] [ph] from Macquarie Capital. So a quick question about the TROPION Lung-02 data that you guys released this morning. There's nearly 20% pneumonitis ILD. So just wants to ask the panel in clinical practice how difficult it is to manage ILD, hear different conflicting views from thoracic oncologists. Some say it's pretty manageable. others say that lung cancer patients are prone to dyspnea to begin with. And also, did you guys see a different thing I already between the doublet and the triplet? Did you deploy the mitigation strategy? Thank you.

Pascal Soriot

Leora, do you want to cover this one.

Leora Horn

Sure. So the majority of ILD is actually Grade 1, 2. In fact, the rate of Grade 3, we had no Grade 4 or 5 in the Grade 3 ILD is actually the exact same as what you see in Keynote 189. So Roy can definitely add in for lung cancer patients with Grade 1 ILD means you see a little fuzzy thing on imaging. And so the safety data that we're seeing is consistent with what we've seen that the six milligram is a safe regimen. And for the lung cancer patients, it's not a reason to discontinue therapy. So the safety data actually is quite encouraging. And don't forget, it's a mix of first and second line patients in there. And we know that the more lines of therapy patients have the more likely or at risk they are for things like ILD.

Roy Herbst

I was going to say, obviously, the same thing just waiting for Leora to confirm that was mostly low grade. Yes, if it's low grade, we're quite used to that from our experience with IO, and taking care of patients who often will have abnormalities on their x ray. So I think that would be clearly manageable in the clinic.

Pascal Soriot

If we could also have a microphone here on the front. Yes. Go ahead.

Unidentified Analyst

Thanks for the question. [indiscernible] from TD Cowen. As it regards ADAURA, Dr. Herbst, you mentioned naysayers. They've you mentioned care gaps. I was wondering if maybe you could help quantify that. Dr. Herbst, is there a number of prescribers that you think might adopt the ADAURA regimen now with the overall survival data that didn't before? And if so, roughly? How many do you think that could be? They have same question for you.

And then a second question is on anti-TROP2 ADC data from Merck and Cowen, very early stage data, small number of patients, but I'm just curious of your first impressions, how it compares to Dato-DXd, Dr. Herbst, if you saw that poster, I'd be curious. But also, of course, your AstraZeneca colleagues do comment.

Roy Herbst

Right. So I think, absolutely, it's clear that this will have an effect, because 90% of patients are taking care of in the community. And patients have to be profiled. So I think with these data out there, there'll be more profiling, the whole funnel is going to increase and they'll be more patients profile, you have to have that EGFR number, when you first discuss the patient going to surgery and everything, it's important to have that in advance, especially with other approaches available these days. So I think that's going to make a big difference.

I think I've heard from surgeons, I've gone to a number of surgical meetings, one of the nice parts of having presented the plenary three years ago as I became invited to surgical societies, and that's important. And what I've heard is many are waiting, whereas the survival data for that more and more, and even in my own shop, I've had a couple of surgeons who have made comments that when we've had strategy meetings at Yale. So I think definitely this is going to make a difference there.

I also think patients, the advocacy group for patients is quite strong. You saw the discussion yesterday, people to patients do worry. So I think, now with more reassurance that there is an overall survival benefit there. I think more patients would be willing to commit to that. Then, of course, as we've heard the effect on policymakers, the fact that we -- not only the approvals in different places, but the reimbursement and trying to keep it as minimal to the patient cost as possible.

So I think that this is definitely going to have an effect, it's quantitative, I think we can, I mean, more than double and even more, certainly, in countries like the U.S. where EGFR permutations are only 10% to 15%, I think this is going to very much increase the denominator and give more patients the opportunity for this therapy.

Unidentified Analyst

Roy, can you maybe comment on the Stage 1b patients versus Stage 2, Stage 3? And how that comes into play as well?

Roy Herbst

Right. Well, when we allow Stage 1b in, the scheduling has changed since we began the trial. But the patients with three centimeter or more tumors. And I think that here in the U.S., I think there'll be a large number of patients with early stage disease, the Stage 1 will go on the study and I can tell you that it's already, again, in the centers with tumor boards are happening, this is occurring, in the community, I think more and more people now are joining tumor boards and discussing these cases. So I think we'll see many more people on this regimen.

Dave Fredrickson

And I think, just add to that, and I made some of the comments in the remarks that I made before. In terms of quantifying it, it's a situation where you get, like I said, 70%, 80% are getting EGFR tested, and then 70% to 80% get referred to a multidisciplinary team that includes a medical oncologist and then 70% get adjuvant treatment. So it's a bit of a death by 1000 cuts. And so in some respects, I think, actually, Roy's suggestion of -- there's actually quite a few patients that are out there, that we've got an opportunity to be able to now get on therapy, because at all different parts of the funnel as Roy described it, there are patients that we're missing out on. And so that's a situation where it's well established in the U.S. and Europe.

And as I said before, if you just take a look at some of the countries that I mentioned, where we don't today have reimbursement, overall survival, I am confident is going to give a boost to our ability to be able to get payers to have a compelling message and a lot of those are in Asian markets where EGFR rates are pretty high and substantial. And then lastly, driving screening rates is something that I think that there's a greater sense of urgency around than I've ever seen before, and that's positive as well.

Pascal Soriot

So reimbursement that is an important one, right? I mean, there was a debate in the community with this PFS benefit drives, noise benefits. So you can imagine a lot of payers were playing on this to delay reimbursement. So we, in China, we don't have reimbursement, hopefully, because we didn't want to sacrifice the price. Hopefully, the source data will help us to negotiate the price better, so many opportunities and of course, longer treatment duration. Susan, do you want to cover the second one?

Susan Galbraith

Yes, sure. So you're asking about the TROP2 antibody drug conjugate? Again, I think it's important to look at the components of the design of the ADC. So I think, we probably have the choke to ADC with the most stable link. And I think that affects the toxicity rates that you're seeing in terms of the hematologic toxicity, which -- when you then met might want to combine with some elements of the chemotherapy regimen like we showed that we're doing with the triplet and part of TROPION-Lung02 that potentially raises a more of a challenge in terms of being able to do that and flexibility to do that. So I think the data on other ADCs, as you can see from the whole Congress, there were several new ADCs that are coming into play. Good news is that we've got a lot of data now that we've that we've added on to the Data Program and the other programs that we've got. And we will continue to move at pace to develop those in combination along with a strategy, but we are absolutely have no element of complacency here. And we will move at pace in order to help develop that because I think we have a really exciting construct with Dato and it's a drug that I think is going to be an important part of many different regimens that we want to go.

Pascal Soriot

Thanks, Susan. We have a question online from Tim Anderson. Tim, do you want to go and ask your question? And by the way, Andy, remind me if we are running out of time. So Tim, do you want to go? Maybe another question. Any other question in the room. We have got one here.

Chris Uhde

Chris Uhde from SEB. I wanted to ask about the CD73 program and whether or not you're stratifying PACIFIC-09 by CD73 expression? If so, what's the cut off you are using and how did you get it? I noticed the pancreatic poster, and it didn't say much there about that. And then, following up on that, do you have a clear idea of why the time has gone by, why the control arm in COAST underperformed what you would expect of PACIFIC?

Susan Galbraith

So I can take those questions. Thanks very much. So first of all, just a reminder that the COAST randomized Phase II study was in the PACIFIC type setting. We know that CD73 and NKG 2a the other target that was tested in that are both up regulated following radiation therapy. So what you would need to have is biopsies post radiation and pretreatment to really understand the biomarkers that might be relevant in that setting.

So the answer is, we don't have that insight. And we are, it's an all comers population in the PACIFIC-9 setting. So depending on the setting in which you might use that kind of target, it might depend on whether or not there was potential for biomarker enrichment with CD72. So we do intend the NEOCOAST-2 study is an important place where we're taking these drugs into the neoadjuvant setting. We have a number of agents in the portfolio at priority that are in that NEOCOAST study. So we will look in neoadjuvant setting as well.

The second part of your question, sorry, can you just remind me.

Chris Uhde

Yes, sure. It was just the underperformance of the COAST arm.

Susan Galbraith

Okay. So we did do a propensity matched analysis of that when you actually correct for the poor prognostic group that was in COAST versus PACIFIC, you get much closer to the expectation of the outcome from the PACIFIC. So it's just a poor prognosis group that was enrolled into COAST.

Pascal Soriot

Thanks for that. So we'll take one last question and then move on to the next section.

Peter Welford

Hi, I'm Peter Welford of Jefferies. Coming back to some extent SKB264 for the sort of the [indiscernible] but more importantly, more bigger pick up on that, given what we've seen with ADAURA, I guess it clearly we see that in the EGFR population, we get quite suitably more profound efficacy potentially with the top two ADC. I think all your studies have it saying exclude patients with AGAs in the lung studies. Is there any plan to look at data in that population? And equally perhaps for the Dr. Herbst currently on the new ADAURA patient or an ADAURA adjuvant patient who then goes on to relapse? What is your current standard of care at the moment now for a patient who has gone through that?

Roy Herbst

Well, fortunately not too many have relapsed on the treatment arm. But if they do relapse on the treatment arm, I guess it would depend on when they relapse, was it on therapy or soon after stopping therapy or has there been a gap? I would probably having the resources, we probably do a rebiopsy or at least get a liquid biopsy and see if there are any new mutations that have developed at that point one good to see if there's a new target. This is where we have to resistance is a problem in this area. This is where says like the Orchard, which, as we heard contains an arm with a truck to mine might be reasonable, certainly for patients that relapsed on the control arm, we would give them nice regimen.

Susan Galbraith

And so to address your question about [indiscernible] to TROPION Lung-01 includes a cohort with actionable genomic alterations in it. And of course, we are examining as I said, in the Orchard study, the combination of this with Dato-DXd in an EGFR mutant patient population is relapse following a third generation inhibitor.

Pascal Soriot

Thanks, Susan. So we are exactly on time. Over back to you. Thank you.

Presentation

Susan Galbraith

Thank you very much. So we had some other exciting datasets that we were able to present here at ASCO. So I'm going to just move on to first of all, the Ovarian cancer setting. Very pleased to see the results of the DUO-O and Phase III been a leader in developing novel regimens in ovarian cancer. So this is a setting with newly diagnosed Stage 3 or 4 high grade epithelial, ovarian cancer, PARP inhibitor and immune mediated therapy naive, and that patients were able to have either primary debulking or plan interval debulking surgery but importantly, patients enrolled into this study did not have germline or tumor BRCA mutations. So there were three arms in the study.

One, was the sum of the care chemotherapy and Bevacizumab with Bevacizumab maintenance of 15 month. Two is the addition of Imfinzi both in on top of the chemo birth component and then in terms of the Bev and the maintenance with a total of 24 months of Imfinzi. And then in ARM 3, we've got the addition of Lynparza on the back of the maintenance period of Bevacizumab and Imfinzi. Primary endpoint with PFS research per investigator in ARM 3, this is ARM 1 in the non-T BRCA mutant but HRD positive and then the ITT population with secondary endpoints of ARM 2 versus ARM 1 in the ITT and OS.

So here's the comparison, first in the HRD-positive group. So, of course, non-tumor BRCA HRD-positive on the left-hand side which was just under 40% of the patient population and then the ITT on the right-hand side. We saw an improvement in the median PFS from 23 months to 37 months. 37 months for this patient population is the longest median PFS that has been seen in the trial. And even though the PFS is counted from cycle two of the chemotherapy, we got four months longer than you did for example, in the PAOLA study, that is still even accounting for that longest median PFS that has been seen.

The hazard ratio was 0.49 in that HRD-positive group and then in the ITT group, you can see as well an improvement with a hazard ratio of 0.63 in the ITT group. If you then layer in the arm two with the infinity again, you can see that there's a trend to improvement in the HRD positive group with a hazard ratio of 0.82 in this setting. And the hazard ratio was closer to one ratio 0.94 in the HRD-negative but there was something tantalizing aspect of a potential tail on that curve, which needs more maturity to follow up.

So in terms of how we think about these data, we saw a statistically significant and clinically meaningful improvement in progression free survival with the addition of both Imfinzi and Lynparza to chemotherapy and Bev. This builds on the data that we'd seen from the MEDIOLA study, but we'd looked at this triplet in the MEDIOLA study and seen 87% response rate with good durability response in that setting. And we saw that PFS benefit across the subgroups including those patients with HRD-negative disease, although, as I've shown you there was a bigger effect in the HRD-positive there was the numerical improvement in PFS for the addition of Imfinzi to chemotherapy. And there were no surprises in terms of the safety generally consistent with a known profile.

So when we think about what this means, we have data now with Lynparza across the newly diagnosed ovarian cancer space. Obviously the data that we've seen from this study and more robust in the HRD-positive group and I think in terms of the potential impact we're probably going to need to follow for overall survival which is immature at this point, particularly for that HRD-negative part of the question population.

So, just want to of course remind you that we have announced that we've seen positive high level results from the GOE study in advanced endometrial cancer and Pascal referred to this already. So again, this combination of Imfinzi plus Lynparza and Imfinzi alone are significantly improved progression free survival when added to chemotherapy. And you can see the design of the study here. Of course, we look forward to presenting these data in an upcoming Congress. But I think if you put the DUO-O and DUO-E data together, this biological mechanism that has been hypothesized about the interaction between PARP inhibition, and immune checkpoint inhibition, we're starting to see examples of where that interaction is potentially playing out into clinically meaningful data in the gynecologic cancer setting.

So now I'm going to just highlight the destiny and tumor O2 data that was presented earlier today. This is the design of the study and HER2 was used at the 5.4 mg/kg three-week regimen across a number of different tumor types. With around 40 patients different per cohort, primary endpoint was confirmed overall response by investigator with secondary endpoints of duration of response, disease control rate, PFS OS safety.

Trial criteria was patients that were advanced solid tumors not eligible for curative therapy is a second line plus actually quite heavily pretreated patient population. And patients could have heard to expression by IC either three plus or two plus local testing was allowed for enrollment. And then central testing was confirmed by [indiscernible] test if local testing not feasible, and the patients that were enrolled on local testing were subsequently centrally tested. And prior HER2 targeting therapy was also allowed.

So you've seen these response rates, we think is quite impressive, particularly in the gynecologic cancers. In more difficult to treat tumors, like biliary tract cancer, and pancreatic cancer, those tumor response rates are lower. But I would note that in the pancreatic cohort, there were a number of patients with quite durable, stable disease. And we also see response rates in bladder cancer. So the overall response rate was 37%. And the median duration of response was close to 12 months in the overall patient population in the IHC three plus population [Technical Difficult] response with 22 months with 61% overall response rate.

So what you can see here is that activities split out by IHC three plus, and two plus across the different tumor types. And again, I would just emphasize that durability of response, which is really quite impressive. And again, the standard of care expectations differ across these different tumor types, for example, in endometrial cancer that Pascal previously highlighted. In this setting, such heavily pretreated patient population, you might expect them at a 10% response rate in patient and certainly the durability of response will be much shorter.

So I think the other aspect of this is how frequently is HER2 two plus and three plus patient populations are across this setting and Dave's just going to highlight that and put it into context.

Dave Fredrickson

Thanks, Susan.

All right. So when we did the deal, on in HER2, we talked about three pillars, HER2 positive disease and breast cancer, HER2 low in breast cancer, and really opening up and HER2 and being able to move and other tumor types. And obviously, gastric and the work that we've done within the HER2 mutated lung cancer population has been really important for that. But these data that Susan just walked us through, albeit for a single arm study, really represent transformational way of thinking about how to now actually take in HER2 and move it into a population whose diseases and driven by the Enhertu, but where the receptor actually serves as a great way of being able to target the warhead.

And so if you take a look at what this means, and you take a look across populations, between 8000 and 12,000, 3rd line plus patients have HER2 express tumors in the U.S. Now, obviously, the splits out by those that are the highest expresses IHC three plus and you've got the IHC two plus and you can see how it works through here. You can see the prevalence rates, and obviously there's variability and prevalence that's influenced by the timing of biopsy and a number of other factors that come into it. And there's certainly educational needs and infrastructure that needs to be built in order to establish testing across these elements. But with that said, I think that there's an opportunity that comes from here, where we've got an opportunity to be able to have a meaningful discussion with health authorities about the possibility of tumor agnostic label.

We also have an ability to be able to use this as a beachhead to be a will launch frontline studies in areas that may very well make sense. And I think that there's very much also going to be interest from guidelines committees in terms of how they think about taking these data and incorporating those into guidelines. So there's a lot that we still need to understand around this before we will be able to probably properly quantify the commercial opportunity, I guess I'd say that in advance of some of those questions that will undoubtedly be coming up. But I think that we open up a whole area that previously was back to my comments before this was in the upside case of the deal as we were doing it and thinking about bringing it in.

What I'd like to do now is invite Anas Younes to present a couple of important slides on the MAIC data that we presented for Calquence and then after that, I'll come back on stage and we will do a Q&A. Anas.

Anas Younes

Thanks, Dave. Hey, good afternoon.

So I have a couple of slides to present as all of you know in relapsed CLL there's two head-to-head, randomized trials comparing first generation BTK inhibitors with second generation BTK, first generation is, namely Ibrutinib. And the second generation, there's two of them a acalabrutinib, calquence and zanubrutinib. And in our trial, which was head-to-head again, acala versus Ibruitnib, the data has been published, there's similar efficacy, improved safety in favor of the acalabrutinib. And the trial reported by Beijing last December, again, it was head-to-head Zanu versus Ibrutinib. There was improved safety in favor of a Zanu, but it was also improved efficacy and people started to extrapolate does this mean that Zanu better than acalabrutinib.

So you really cannot compare apples with oranges, you really have to do proper comparison using proper statistical analysis, which is called MAIC stands for Matched Adjusted Indirect Comparisons, very well-established methods, even acknowledged by regulators, actually, for rare diseases. And the reason for doing that, you need to make sure that the baseline characteristics is similar before you do the comparison. That's what we did here to do a cross a trial analysis. You can look at the baseline characteristics right now. And you can see that they're properly matched. And then you can do the comparison in terms of PFS between the two compounds. And that's what you see right now, exactly superimposable in terms of efficacy.

So if you look at the right side part, which is safety, again, there's very comparable, but there's an edge in favor of acalabrutinib in couple of spots, mainly in for hypertension, and a few others. So based on that, I think acalabrutinib remains the best-in-class BTK inhibitor. There's no evidence that anything else is better so far, and I hope this will remain for a long time. That's what I have to say. Thanks.

Dave Fredrickson

All right, great. Thank you, Anas. Okay, so we're going to open it up for questions now. And we invite you to go beyond lung cancer, by all means, and ask about anything that you're interested in. So all right, as well. So Simon, please.

Question-and-Answer Session

Simon Baker

Thank you. So Simon Baker from Redburn. Two if I may. Just going back to DESTINY-PanTumor02, you said you're now in discussions with regulators. So I shall ask the unfair question of what comes next. What do you think you'll need to do? And also picking up on a comment from the discussion this morning? You talked about human agnostic indications. There were suggestions about histology agnostic indication. So taking all that together how big could this become to Enhertu incremental to what we've already got? And then a second question onto something that you've not talked about we have presented, but not in all on camizestrant. We have the poster couple of days ago looking at the data split by ASR1 mutation. And there's clearly very strong efficacy indicated in the mutant group. Could you just update us on what the incidence of ASR1 mutation is both in that second line setting in first line, is SERENA-2 typical of the incidence we see there just trying to get an idea of what the scope is for the cert in that setting. Thanks so much.

Dave Fredrickson

Sure. So maybe I'll start on the discussions with health authorities. It's not too much different Simon than what I had explained. I mean, obviously, I think that we've got a pretty compelling data set. There's a path that's existing for tumor agnostic labels, particularly in heavily pretreated later line populations. And these data are I think ones that are, as we saw from the receptivity, here from the community ones that have the interest within health authorities. In terms of where we go next with it, Susan, I mean, you want to talk a little bit about how we're thinking about some of the development decisions that we'll be making from here.

Susan Galbraith

Yes. So I think, again, these are really exciting data. And I think a paradigm change because there's been other HER2 targeted therapies that have been tried in these kinds of patient populations and haven't worked, I think that comes back to the design of the ADC and the principles of those designs. So I think it creates a great opportunity. Now, obviously, the prevalence, as they've shown differs by genotype. But it was an opportunity, I think, to go into earlier lines of therapy, there was an opportunity to build on the data that you've got with monotherapy, through some of the combinations, and I think we'll be looking at those and you can imagine different combinations for the different settings.

So I think there's a number of quite exciting opportunities to really change the standard of care and carve out another new area of cancer as defined by, first of all, the IHC biomarker, but I also hope that we can continue to improve on the currently available biomarkers and potentially provide both liquid biopsies as well as improved computational pathology tools that will better identify the right patients to treat. So as always, it was a trial with great data, it creates a great set of opportunities of the next things that we want to do.

Dave Fredrickson

And then in terms of camizestrant, ESR1 mutation?

Susan Galbraith

The data that we saw in SERENA-2 is roughly the prevalence that you would expect in that second line patient population, of course, the prevalence of ESR1 mutations increases with line of therapy. So it's less common in the first line, patient population. But it does increase resistance. So it was roughly in line. With that to answer your question.

Dave Fredrickson

Thank you. We're going to go next online to Tim Anderson. Tim, please go ahead.

Tim Anderson

Thank you very much. Just starting off with Dato-DXd. So everyone's waiting for TROPION-Lung01 perceived as being late, making folks nervous, just your latest confidence that this is going to be a positive trial and thread the needle appropriately. And then second question on MEDI5752, which you didn't talk about today. This was your PD1 and CTLA for bispecific. You talked before about moving in a five two-day trials as a very broad program. I believe you're sitting on more of these two data that you haven't released publicly? If that is correct. Are we going to be seeing more of that data throughout the course of the year? There was nothing at ASCO, of course.

Dave Fredrickson

So Susan, I think both questions for you. One TLO1, in terms of timing there. And then obviously the second on –

Susan Galbraith

My goal on TROPION-Lung-01 is to be entirely consistent and totally boring. With what I said at the prior results, which is we said that we're expecting the results of this by the first half of this year, it's obviously it's an event driven child, we have to wait for the readout, et cetera, that confidence in it being positive, is based on the Phase I data from the J101 study with a high durability of response of 10.5 months that was seen in a 28% response rate, which when you take and compare with the standard of care, I think, provides the confidence that we've seen, and of course, the safety profile has been well understood. We're managing the key safety side effects of stomatitis. And the other elements, well, I think across the program. So what can I say watch the space.

So we are excited about the potential and opportunity for the bispecific molecules to go into different segments of the diseases. Obviously, with CTLA4 as a mechanism, we feel that we've gotten the design of all of us to make something that mitigates the key, what has been a limiting factor for CTLA4 currently, which is the toxicity we all know, based on the prior data that the more you can give a CTLA4, the more efficacy you get, but it's the tolerability profile, which is the challenge.

And so, the other thing that we also know where the CTLA4 mechanism is that you need to see the -- you need to wait to get the benefit of the tail of the curve. So the key data that we have been generating across our program is what's driving our internal decision-making. And that's our priority at the moment is the internal decision-making and the build to enable us to move the Phase III program at pace. And we're all highly focused on doing that.

Dave Fredrickson

Thank you, Susan.

Chris Uhde

Hi, Chris Uhde from SEB again. Thanks. So my question, I guess, following up on two of these here. So, PanTumor, so in terms of the label effort, would you be thinking second line or third line plus? And all levels of HER2 or not? And to what extent does the low efficacy and PDAC and BTC complicate an agnostic strategy from a regulatory perspective? And if there's any help you give us, I guess, it's fair to assume that the prevalence of HER2 biomarker increases with lines of therapy.

And then for the second question, coming back to the CTLA4, we saw some very nice PCR data from the stride regimen in HCC. And it made me wonder, which I'm sure many others are whether or not patients who did not achieve PCR should be getting another pulse of [indiscernible]? Thank you.

Dave Fredrickson

All right, super. So perhaps I'll address the first part of the PanTumor question. And then Osama ask you maybe for your point of view, one the HCC question. Again, here, we'll take the data, you've seen the data, and we'll have conversations with health authorities in terms of where there's an opportunity to consider those data as being sufficient for a label. And I think that where you know, that the conversation is most likely to resonate is where the highest unmet need exists. And that is in these later lines of therapy. And I think that there'll be a discussion around how to think about expression levels. And so at this point, it'd be really premature to be able to make a prediction about how that'll net itself out, I think that the data that we have are ones that we'll take forward. And they'll undoubtedly be needed for us to continue to supplement those data. And we'll do some of our own work to bring it into earlier lines. But I think that what we have here is even more than a proof of principle. I mean, I think that we've got something that's very meaningful, that'd be able to drive forward.

Introduce somebody who you may not have ever met before, but who certainly you see up here have Osama Rahma, who as you see as a clinical strategy head in our GI cancers, and we certainly are enthusiastic about HIMALAYA and TOPAZ, the things that are happening within GI and obviously we spoke about the MATTERHORN high level results. Osama do you want to address the question.

Osama Rahma

Thank you so much, Dave and thank you for the question. So for the STRIDE regimen, we know with one dose of tremelimumab we can really get the tail of the curve. And your question about whether rechallenging patients is actually an important question. As Susan highlighted, we have few platform clinical trials that we are actually optimizing CTLA4 or systemic. And we are looking actually to answer some of those questions to move to late development eventually. For the BTC part, so we're very excited, very happy that we are the first and immunotherapy indications and BTC in frontline and HER2 data really make our position very strong in BTC in this very, very heavily -- very poor prognosis patients and we're seeing actually activity within HER2 even in very poor prognosis gallbladder cancer, where 50% of those patients are gallbladder so you can only imagine what we can do when we move in earlier setting.

Dave Fredrickson

Thank you, Osama.

Viktor Sundberg

Viktor Sundberg, again from Nordia. Thanks for taking my question. In the PanTumor study, I was wondering if we saw very low ILD rates in this across all indications. Do you think that's mostly due to biology or resource apart here where physicians are perhaps doing a better job managing ILD in general and can we extrapolate that maybe too early lines of treatment in let's say, breast cancer [indiscernible]?

Susan Galbraith

Yes. So first of all, we do understand some of the risk factors for ILD and absolutely this is the by the disease that you are treating. People have said before that, if you've got other comorbidities that affect lung and respiratory symptoms is a high risk, if you've got multiple lines of prior therapy, particularly by lines of chemotherapy, there's a higher risk. So it differs by disease, and it differs by prior treatment. This was a heavily pretreated patient population, but not one that necessarily associated with some of the lung comorbidities that you might see in other diseases. So that's point number one. And I do think that will likely make a difference.

I think the second thing is that absolutely, we've learned across the program, as we're being got more experienced that we've spent a lot of time educating investigators, physicians about management of ILD and the ability to identify patients when they're at the early lower grades, evolution of this adverse event so that you can actually prevent the onset of the more severe growth. So I think it is both elements that are contributing to the lower right.

Emily Field

Hi. Emily Field from Barclays. Thank you for taking my question. Just two kind of on the back of some of the presentations from the metastatic breast cancer session. That's today. Firstly, the pattern one study update. At the end of that, they said that that underlies the rationale for the SERENA-6 study. But in that they converted patients who have [indiscernible] upon detection of ESR1. So how does that compare to the design of your study where I know the inclusion criteria, you have to have the ESR1 mutation, but does sort of time matter? And then the study on sort of the dynamic nature of her to low status, sort of stress that, give biopsies when practical that I guess, sort of how does that translate? Or do you see that translating into the real world to perhaps expand some of those triple negative patients into HER2 low population so that they could receive in HER2?

Dave Fredrickson

Perfect. Ingrid? Got it. Sunil, please, for both of us.

Sunil Verma

Yes, no, thank you. So I think the PALOA-1 was really the proof of concept that was behind the SERENA-6 study design. And what we learned from PALOA-1 was, when does the emergence of ESR occur. And what we know is that it doesn't tend to occur in the first six months after exposure of endocrine and SDK46, it tends to occur later on. So the way SERENA-6 designed was created was really with the thought of when ESR1, so I think we had that consideration and what the data that was presented by [indiscernible] and the team certainly reinforces our belief for the SERENA-6 study and the rationale behind the SERENA-6 and how we're thinking about camizestrant.

The HER2 low evolution is, it's certainly an important topic for discussion. So what we do know is about 60% of patients who are hormone receptor positive have HER2 low. The question is that was -- that you're referencing is how does HER2 evolve over time. And that was, I think, related to what was asked previously as well, is that we do see that there is an evolution of HER2 over time, and generally in triple negative breast cancer as a result of treatment adoption, that you may tend to see previously IHC zero patients who now express IHC1 or two plus. So the clinicians now are biopsying patients upon recurrence, certainly, and also patients who are not progressing to look for that IHC 1, 2 status.

So what we have shared before is that if you think that 60% of all HR positive and half of all currently classified HER2 negative or IHC 1 plus, 2 plus, we expect that number to evolve? Now that there's more biopsies happening, more follow up and more consideration of what IHC represents. So what that number will equate to in the future state is still unknown, but certainly clinicians are re-biopsying patients to look for the IHC1 signal.

Harry Gillis

Hi, there. Harry Gillis from Berenberg. Just another long question, if that's all right. So the overall response rates in TROPION-Lung02 look pretty comparable with Keynote 189 and 407. So I just wanted to sort of ask how you think about these relative to one another, of course, with the usual caveats of cross trial comparisons, and then perhaps how reflective these Keytruda first line data are, of what's seen in the real-world setting, because we've seen a number of sort of trials recently where the comparator or active arm sort of seemingly underperformance compared to this. Thanks.

Leora Horn

I think it's important to look at the responses by PD1 expression, and the waterfall plot doesn't quite break that down. And so I think that's where you're assessing the data and the spider plots with that durability of response. So I don't think you can just look at the response rates in totality, we are seeing deep responses. And if you look, for example, that triplet, that's a great response rate when the majority of those patients are PDL1 less than 50%. So we're continuing to watch that data that data is maturing, but it's not so much you can just look at the response, you've got to really take note of that PDL1 expression there as well.

Dave Fredrickson

Thanks, Leora. I think this is an important point. And hopefully that starts to come out. And the way that we begin to describe the slide that I showed on the lung cancer map and how we are looking at just the sub-segmentation, the fact that we're really moving away from this belief, obviously, of a homogeneous population to really understanding patient selection and the importance that that's going to play as we think about tailoring different combinations, but also the sequencing that needs to be gone through lung cancer is definitely an area that is becoming, I would say, more sophisticated and nuanced in terms of patient selection than it's been so far.

James Gordon

Thank you, James from JPMorgan. Just one question on DUO-O. When I went to the presentation, the discussion wasn't actually that excited about HRD-positive, they were more excited about the negative. And they were suggesting for the positives, you could just use PALOA-1. And you might not need the extra talk from giving someone a triplet therapy because they already get quite good efficacy with the doublet. So is there any risk that you don't get the HRD-positive approval? If you do, you don't get much use there, people just want to double it. And it's only really an opportunity in HRD negatives.

Dave Fredrickson

Can I comment first on maybe one of the commercial aspects. And Leora, I'll invite you to comment on this as well if you'd like to within the U.S. experience, but for even within ovarian cancer with the success that we've had, obviously with the SOLO-1, allowing us to move into BRCA. And with PAOLA giving us a compelling promotional narrative to be able to have around that HRD positive population, there is still a number of ovarian cancer patients who are not being treated with the PAOLA regimen who are HRD positive. And so I think that if we take a look at the opportunity that even with these data, which is the longest ever PFS that we've seen in an HRD positive population, I think that even if that was to result in a belief that there's an imperative to be utilizing Lynparza plus Bev within this population, even with or without a triplet. I think that that's something that's a really important opportunity for us to be able to pursue now that's obviously distinct from the other part of the question, which is the HRD negative element. But I do think that there's a great opportunity here even just to reinforce the role of PARP plus Bev within that population.

Leora Horn

Just let me add color because I agree with what Dave has said. So 37 months is the longest that we've seen and this is non-BRCA mutant HRD positive, the equivalent group in PAOLA gives you a 28-month meeting, PFS to put it into perspective. So even though you're now counting from cycle two, so you get a discount that element, there was a worst prognostic population included in [indiscernible] because you will allow a patient that had stable disease, not just partial response after the initial chemotherapy as well remember.

So this is worst patient population but with longest median PFS even in accounting for that, that that difference, and that is meaningful. I mean, I think that is that the meaningful piece, obviously, what we want to see is the evolution of those curves and see if what we're getting is, plateauing even more than we know, then we saw with, with PAOLO as well. And as we said, the LS is immature and other things.

So I would echo what Dave has said, I think this reinforces that we can raise the bar further in the first line setting and the HRD positive. And of course, comparing with PAOLO, we didn't see the trend for PFS benefit and the HRD negative but I think in that patient population, getting the mature OS data will be important to understand what that trend looks like.

Dave Fredrickson

Thanks. I mean, I do also think that just with the IO component and the tail aspect, the mature OS is even more important as a result of being able to see some of the contribution of that to the regimen.

Sunil Verma

Can I just add something, Dave, I think that just talking to clinicians, investigators, having that Bevacizumab backbone in this regimen, there's still a lot of clinician investigators who are on the fence of the value of Bevacizumab in ovarian cancer and I think that sort of reinforces that combination is actually showing that robust efficacy and I think that's really helpful for HRD positive patient population as well.

Seamus Fernandez

Seamus Fernandez from Guggenheim Securities. So two quick questions. So first on TROP2, can you just help us understand the importance of testing? As you advance into earlier lines of therapy? Obviously, you're starting to incorporate that into some of your clinical trials. So just trying to get a better understanding of that at Merck's meeting just now they were sort of trumpeting their expertise in developing biomarkers, et cetera, et cetera, and kind of characterize that as a vehicle for catching up to Astra and Daiichi. So just hoping you could maybe comment on that. And then separately, as we think about the opportunity to show a survival benefit in the second line setting for or in TROPION-Lung01. Could you just, perhaps comment on that, and also where we are currently, I believe the final PFS event hasn't yet been achieved. But just trying to understand how far along we're likely to be on overall survival events in that context. Thanks so much.

Dave Fredrickson

Okay. So Seamus, just to make sure on the second question, this is a question around when we see the data that's coming up, where do we anticipate will be with overall survival? Is that the question? Okay, we are I think those are two questions, one on importance of biomarkers as we move earlier. And then the second, which we just reiterated.

Leora Horn

So the first question, the importance of the biomarker AVANZAR, as Dave mentioned, is one of the first line studies, it's ongoing, and the [indiscernible] biomarker is in there. And so, we know how to do biomarkers too. And that study is up and running and enrolling. The second question, the OS data will not be mature. So, when we get that PFS data, and Susan already spoke to that the OS data will be immature, it's a good thing for lung cancer patients are living longer. And so we'll just have to wait. Again, it's event driven.

Dave Fredrickson

I mean, I think the only piece that I'd add on this as obviously in the later lines based on J101. Certainly believe that the biomarker is something that may not be necessary in those later lines. And we'll see in the frontline. I think this is one of the reasons why it's valuable, as Leora points out, and as we showed before, that we've got multiple shots on goal in that frontline setting, and the ability to be able to incorporate a biomarker approach. I think that is something that's important within there. And I appreciate that Leora added that we do know a thing or two about biomarkers. I think we've got a few products that we've been able to demonstrate that way.

Unidentified Analyst

Thanks very much. On DUO-O again, I guess a few questions around the data that came out. So in terms of HRR testing, was a negative test really a negative test, is one question? Then is it possible to tease out evidence of IO activity because there's no Lynparza arm with placebo instead of Imfinzi? So I mean, perhaps outcomes by mismatch repair status that wasn't shown. Yes. I guess that's it.

Susan Galbraith

In contrast to endometrial cancer, there's not a high incidence of mismatch repair in Ovarian cancer just to answer the last question first that that it will be different in DUO-E versus DUO-O. The HRD test that is used as a standard HRD test, it's a genomic scar-based test with a defined cut off so what was used in DUO-O is entirely consistent with what is used in clinical practice. And what was used in the PAOLO study. And coming back to the PAOLO study. That is a study that has a patient population that has the [indiscernible] control that you're looking for, so I do think it will be helpful to have cost comparison across those trials matched for the slightly different patient population that we that we talked about. I think that will be a helpful piece that can potentially be provided at a later point.

Unidentified Analyst

I had a question on the earlier line IHC programs that you highlighted on your slides, [indiscernible] and B7-H4, any color on when we might be able to expect data and I noticed that B7-H4 you recently expanded the trial. So is that a vote of confidence?

Susan Galbraith

So, first of all, [indiscernible] which have our own proprietary linker and topoisomerase warhead, the first was the B7-H4, if you rightly call which is DH-05, the second A-39592 which is EGFRmet bispecific ADC which is in Phase I dose escalation. And there's going to be a third one with an IND open shortly, which is the folate receptor targeted with a topoisomerase and warhead. So those are products of our own internal discovery group. We've also licensed Claudin 19.2 with an MMAE Warhead. From key med biosciences, we will expect to share some updated data from these programs within the next year or so I would expect upcoming congresses, but we are moving all of those at pace. So I would expect you will see data sometime in the next year.

Dave Fredrickson

Great. All right. Well, maybe just in summary, and what I wanted to take an opportunity to share here, as we come to the end, we really have set out over the last couple of years to build a truly transformative pipeline that looks to build scale across tumor types, really advanced scientific platforms that are meaningfully building upon the standard of care, advancing ahead of the standard of care, and then looking for ways to find how we can use combinations, precision medicine, to really be able to make sure that we're able to deliver the best therapy to patients across each of these dimensions. And here at ASCO, this year, you can see the number of studies, the number of presentations that we had across each of these different tumor types. And you can see the breadth and the depth of the portfolio. And it really does reinforce the potential and transform patient outcomes across these key tumors. I think that the depth that we have within lung cancer is something that we spent a lot of time talking about today. I want to once again, thank Dr. Herbst, for joining us today to speak through the ADAURA data. We spend a lot of time talking about obviously, the work that we're doing with Dato and bringing that ADC and the bispecifics, we look forward to really have an opportunity to share more about as the year comes along.

In breast cancer, I think certainly clearly within HER2 demonstrated within HER2 both within the HER2 positive as well as within the HER2 low populations, the opportunities that are there. And we see a number of important studies that we'll be reading out over the course of the horizon. With bringing couple of assertive, we hope very soon for approval, and then later on camizestrant.

Hematology, we've been building very actively on what has been an outstanding Calquence foundation within hematology. I think that the one that we'll see the most data and most recently from and that we've already begun to see data from is 0486. In terms of the furthest along, that's the CD3, CD19 T cell engager. And that we really worked actively to advance that pipeline. And there's quite a number of other studies that we've been moving rapidly into clinical studies.

GI is the place that in the last 12 months, we've made the most significant amount of progress and inroads into it has been the greatest source of the driver of our commercial success with Imfinzi and bringing [indiscernible]. Clear standard of care with TOPAZ1 across the globe, HIMALAYA making good inroads. And then, obviously, we've got great opportunities that sit in front of us where we are looking forward to read out some of the Emerald studies, which we think are very important within this setting. And building within that.

And then lastly, within the GYN and GU space, certainly very pleased to be able to see propel approvals across the globe. We've got an opportunity through DUO-O, DUO-E and also through the PanTumor work to really see an opportunity to bring in HER2 into these areas.

So with that, we'd like to just say thank you very, very much for joining us today. We know that there are multiple of these sessions going on. We appreciate your interest in AstraZeneca. During this we think it's been a very successful ASCO for the company. I can't promise that we'll be at a plenary every single year, but we will certainly continue to do try to make sure that we make that happen and I look forward to seeing everybody at one of the congresses soon here later in the year. Thank you all very, very much and safe travels some. Thank you.

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