Good evening and good day to everybody joining us remotely. Thank you for being here with us at our ESMO 2026 Investor Event. My name's Dave Fredrickson. I am the EVP of our oncology business, and it is wonderful to have you here. Here is the agenda that we are going to go through for the day, or the evening, over the next couple of hours. We are very privileged to have two esteemed guests with us. To kick things off, we have Professor Tom Powles, who is on the end of the podium and will be walking us through exciting data in bladder cancer from this year's ESMO. Professor Yi-Long Wu, next to Professor Powles, also joining us with an opportunity to talk through the exciting EGFR lung data that we also saw here and that was presented.
After that, we will have an opportunity to hear from Leora, Susan, and myself, who will go through the rest of the data that were presented. I will put it into a commercial context. Finally, Pascal is going to have an opportunity to come up before we go into the Q&A and put this oncology data into a broader enterprise context, which we thought would be useful to be able to do. I will note that we will take a Q&A session after Professor Powles gives his presentation. He does need to leave to go to another engagement, so we decided that we would take a moment to be able to give you an opportunity to ask him some questions before he departs. Professor Wu is also going to have to leave after his presentation. Just to set expectations on that.
If we could go to the next slide, please. What an exciting ESMO it has been for us. When we take a look at ESMO in general, certainly we are energized with the progress the field is making in transforming cancer care. We are also really proud that we are at the vanguard of really leading many of those key trends that are coming through. You see that with four presidential data sets at ESMO, delivering overall survival, showing that we are in fact delivering on some of the core elements that we believe are essential, replacing classic chemotherapy with ADCs, finding new ways to harness the immune system, delivering combinations, and doing that earlier in earlier stages where we think that we can get long-term durable responses.
We had data that spanned 27 approved and potential medicines across greater than 15 tumor types. You can see an unprecedented number of abstract acceptances that we had, 38 oral presentations, nothing short of remarkable. It is a good opportunity to thank our AstraZeneca teams for all the work that they do in order to make a meeting like this possible.
With that, and without further ado, I am going to introduce Professor Thomas Powles. Thank you.
This is my last talk of the meeting. I am super excited, I have got to tell you. Thanks for asking me. I really appreciate it. Also, thanks for involving me in the study. The study has been going on for a long period of time, and we are curing bladder cancer. I think we are doing that, and it is enormously exciting to be part of that journey. The journey is not yet complete. There are other things we need to do. This trial is an important step of that journey because what it tells us is we can give shorter periods of ADC therapy. We have, when we did the first trial, and I was involved in the first trial, we kind of gave ADCs forever because we felt we couldn't beat standard chemotherapy because no one has done it before.
We entered into this journey with good intentions, and we are now finding these drugs are super active together, and I am excited to talk to you about that. This study goes back a long way. It goes back pre-pandemic, when we designed the trial. The trial was designed with two very specific questions in mind. I am going to focus on one of those two questions today, but I am very happy to answer questions about the other question. The first question that we asked was, in muscle-invasive bladder cancer, these patients historically do really poorly. Until a year ago, these patients were getting cystectomy alone. EV pembro has superseded that with nine perioperative cycles with an operation. It is a huge operation in the middle, and it is not without its challenges because of that.
The question we asked, which is very different from that, is can we just give this short, sharp period of neoadjuvant therapy three cycles? Very brave in some respects, and I thank people on the panel for supporting that decision. Because when we started, most people felt one would need more treatment than that. The second arm, we thought, let us try and ask a second question at the same time. Let's try and escalate the intensity with CTLA-4 inhibition. I have been a fan of CTLA-4 inhibition in this disease, and that arm is actually ongoing. As I said before, happy to answer questions around it. The control arm, absolutely standard, and completed before EV pembro became available and was also the same control as previous trials in this particular space.
It is important to note that this is a study looking at cisplatin-ineligible patients, but also cisplatin-refusing patients. It is not uncommon for patients to refuse cisplatin chemotherapy. The drugs aren't great. The benefit overall is relatively modest. Actually, when you look at the global community, and indeed, if you go to countries like Germany, they don't give neoadjuvant chemotherapy at all. So, very justified control arm. When we look at the primary endpoint of the study, I think it is fair to say that while the study had about 230 patients in each arm, it was really balanced in terms of the characteristics of these two arms, and 25% of those patients were refusing, 75% of patients were cisplatin ineligible. The curves go apart, and they stay apart. The median follow-up is 23 months.
The statistical analysis plan was event-free survival in both arms with dual primary endpoints, and we then converged to do sequential overall survival. This was the first interim analysis of this data with 23 months of follow-up. Again, it was ambitious, but we were quietly confident that because of the EV pembro results being so impressive, that we felt these results would be impressive as well, and indeed they were. The hazard ratio, 0.51. The OS is also impressive, clinically meaningful at 0.58. The curves go apart and they stay apart. The landmark at 78% at two years is a really strong data point. When one goes back in time and look at previous studies involving this population, you can see that actually our control arm in this study actually performed quite well.
That I think is a neat endpoint, and of course it leads on to a forest plot, which inevitably with those very low hazard ratios, although the confidence intervals become wider, which you'll all be familiar with, show a benefit for the EV and the durvalumab combination. EV-D was associated with a higher PatCR rate. This was investigator-assessed PatCR, which was measured at 45%, and we were lucky enough to get ctDNA analysis. We performed a whole genome rather than exome ctDNA analysis. This is a more accurate, more sensitive test. In this study, we picked up 78% of patients being positive at baseline. In NIAGARA, a previous trial where we used a less sensitive test, we only showed 58% of patients were ctDNA positive. That increased sensitivity is an indication of the field moving forward.
You'll be aware that the Signatera assay is approved in the U.S., and actually even at my hospital in the U.K., we're using ctDNA at the moment. This is something that's going to be real, and I think ctDNA will supersede other surrogate-type endpoints, particularly in this space. I think this data's important. The 60% clearance is meaningful. Those patients do better. Obviously, the negative patients do about the same that remain negative. I was really pleased we were able to do this. The toxicity profile I think is also important. You'll see here that 30% of patients getting Grade 3 or 4 adverse events, 11% of patients having immune-related toxicity, and 11% of patients having disruption of that enfortumab vedotin neoadjuvantly. I think it's really important personally that we are able to deliver that period of neoadjuvant therapy efficiently.
Clearly, if you have toxicity problems and other issues, then that can actually affect your initial intensity and potentially compromise outcomes. The adverse event profile was in line with expectations, particularly most of it dominated actually by urology issues. The cystectomy drives a lot of these treatment emergent adverse events. If you focus on treatment-related adverse events, nothing new or unexpected. Actually, a higher proportion of patients got surgery in the neoadjuvant arm than the control arm. We've shown that in NIAGARA and other trials before. These drugs don't seem to compromise the ability to perform surgery. It's also true in the enfortumab vedotin-related adverse events. The skin toxicity was as expected because that happens in the first three cycles. But the peripheral neuropathy, which escalates with increasing numbers of cycles, was modest compared to other studies which we've performed in this setting.
I think it is very fair to say that this is a positive and clinically meaningful study for event-free survival, but really importantly for overall survival. It is amazing that enfortumab vedotin is so effective in this disease. It does not seem to matter with which ADC you combine the drugs, and we have shown you can give very short periods of therapy and get excellent results, benefits across subgroups, and the safety profile, attractive and patient-centric. So, I think it does support this as a new potential standard of care. As I said before, I am so lucky to be involved in a journey where we are curing what was a really common and really nasty cancer, and it is not quite complete, but this is an important step on that journey. Many thanks for your attention.
Okay, we have five minutes or so for questions for Professor Powles. Do we have a microphone that will move down? Yours, table one here in the front was very fast with hands up. Maybe.
Hi, thanks. Richard Vosser from JPMorgan. Maybe one question to Dr. Powles. How are you thinking of adopting the VOLGA regimen in your practice, compared to the EV-303 regimen? Is there a decision to be made between the type of immunotherapy that you use? Given the data, does that prioritize Imfinzi? Just thoughts there.
Yes. So Richard, it is a great question, and I think the answer to your question is that the plethora of durvalumab trials that we have seen in this space with POTOMAC that was positive, and NIAGARA that was positive, and now this positive trial as well, suggests that durvalumab is a strong drug in this space. In fact, no other drug has had so many positive trials. So I think that there is no reason why one would want to give this drug or pembrolizumab. It would be hard to say that pembrolizumab is a preferable agent in this particular cancer, and I think the two for that perspective are interchangeable. I can see three schools of thought in my mind.
I can see reimbursement individuals and reimbursement groups looking at this approach, then saying this is attractive, it is fewer cycles, it is cheaper, and it is effective, and it has got a hazard ratio of less than 0.6, and that is striking. I think that is going to be attractive. I think the second issue is when you look at community doctors, and most people in this environment do not actually 100 patients a year, but most people treat four or five patients a year in this setting. Those individuals will look at the overall survival set here, and the fact that in the previous trials with EV pembro, the nine cycles, 75% of patients did not make it in the 303 trial, did not make it to the nine cycles, so clearly not everyone is getting there.
Under those circumstances, the pragmatists I think will say, "Look, this is pretty attractive for my patients. It is easy to do, and actually they can recover well in the postoperative setting." I can see people pursuing that. There will, of course, be people who will say, "There are some patients who need more than three cycles," but we do not know who they are, and that was two ways of looking at that. We will say, "Well, less is more." There will be people who will say, "Well, you should keep going forever and ever." But I think we are moving away from that. I do think this will be competitive, and I can see there being a debate which will unfold, and I can see this being very competitive, and I have said it before in the meeting that this is an attractive approach for patients.
Thank you, Professor. Luisa?
Thank you very much. Luisa Hector at Berenberg. I wonder whether you could comment about using ADCs for that shorter period neoadjuvant. Is that something that we should be trying to explore maybe a little bit more broadly? What would you like to see next for your bladder patients, muscle-invasive, and could we eventually see surgery not part of it?
Luisa, I think when the original results of the 303 trial came out with a PatCR rate of 55% after only three neoadjuvant cycles, I was surprised. Standard chemotherapy in NIAGARA was 27%, and this is clearly much better than that. It is suggesting, the word synergy is not one I am particularly comfortable with because I have always kind of, one plus one equals three feels like magic to me. We are curing bladder cancer with this regime, so if that is synergy. It was not a surprise to me when we got the results of this trial, that they were so strikingly positive because clearly we were going to get similar results. As I said before, pembrolizumab and durvalumab very similar, it is the similar trial design. It was likely we were going to reproduce those results.
Do I think that short periods of ADCs in this disease are going to translate into other settings and other cancers? I hope that is the case. One of the things which I think is notable is EV pembro, which has been widely explored, has not been successful in multiple different cancers. That is a disappointment to me. When we first started this journey, I hoped we were going to cure two or three different cancers. I had hopes for gastric cancer and head and neck cancer. It turned out that was not the case. I do not understand yet why that is the case. I do not want to talk about personalized cancer vaccines today, but I could. I am not allowed to.
I think we need to be very careful when we move tumor type to tumor type, that we do not translate results from one area to another and assume they are all going to be positive. That might be the case, and I hope that is the case. I also believe in metastatic disease, you need more than three cycles. I would not be comfortable with patients with liver metastasis given three cycles. In fact, I am still in the camp with stable disease and liver metastasis. I am happy to keep my foot on the accelerator rather than the brake. In this particular earlier setting, it looks like we can get rid of MRD with relatively short periods of therapy in some patients, but not all patients. My second question. Very quickly, I will be very quick. We will stop doing cystectomies.
The way we are going to do it, we have got studies are rolling EV-209, EV-309, and in those trials, what is happening is we are giving nine cycles of treatment, and we are not doing the surgery in the middle. For those patients who go into clinical CR after four cycles, which should be 60%, we are not going to do the surgery. I am confident that group of patients will go off durable remission without that surgery. I think in three or four years' time, we will be sitting in a room similar to this saying we are now curing bladder cancer with short periods of systemic therapy, this perioperative cycle, perhaps more than three cycles in this bladder-sparing approach.
Under those circumstances, instead of people wandering around having this debilitating operation in their 60s, 70s, and 80s, which many never really recover from, we will actually be in a situation where we are curing the disease with pre-systemic therapy.
Thank you, Professor Powles. I think we have time for one more question, which we will take here in front.
Thanks, Pete Verdult, BNP. Just two questions, Doc. Thank you for your time. Firstly, when are we going to see the third arm with Imjudo? When do you think we are going to see that data? If I was to ask you to sort of crystal ball gaze, do you think there will be actually a need to add Imjudo on top? Then coming back to the first question.
Some of the doctors we hosted and spoke to over the weekend, and you have alluded to it, are pretty welded to EV pembro, and you mentioned it is competitive. So when you talk about this data with your U.S. colleagues and peers, sorry to focus on the U.S., but you understand why. Just how challenging is it going to get these docs to sort of consider something other than EV pembro? Thank you.
The third arm is the treme arm, is that right? Yeah. We did see that in the meeting. I am really sorry I did not present it for time reasons.
My bad, sorry.
I apologize, but can I give you 30 seconds on it? Is that okay? We showed, and I did not show it because I did not want to, but we have seen it before, and I wanted to focus on the regime that is going to get used and have that discussion. The results, the hazard ratios were 0.58 for EFS and the hazard. Sorry, 0.61 for EFS and 0.77 for OS. They were not quite as good as the doublet, but they were in the same ballpark, and we showed that the intensity of EV that we were able to give during the first three cycles was slightly lower, and my interpretation of that was the intensity of the EV pembro during that cycle was reduced because we gave the treme. We showed more immune-related toxicity, and that probably compromised our ability to give the two really active drugs.
I think treme's active in this disease, but it might not be as active as the other two. One of my takeaways from this in other settings is if we're going to play with active doublets with new drugs, we need to make sure we either get the intensity of that doublet right or the third drug we're bringing in is much more active than the first two. Because if you take away one of the active drugs and replace it with a slightly less active drug, then you're going to have problems. The second issue, I think, is a really good question, and actually, I don't know the answer to this question. I can see this debate and discussion happening two ways. Changing people's mind to move away from something that's very, very good is challenging.
I can see there being a discussion around those lines. It's also true EVP in the perioperative space hasn't been around for that long a period of time, but it has been in the metastatic space for some period. So this is not necessarily established in the same way as it would be in metastatic disease, for example. I can see there being a discussion, and I can see some doctors, particularly in the U.S. In Europe, it's slightly different, as I mentioned before, because reimbursement is relevant, and I think it's going to be very competitive from that perspective.
I can see people saying, "I want to stick with what I know. It's easy. I don't want to make the change." It may be that some doctors end up saying, "I'm going to be more pragmatic about the number of cycles I'm going to give." But I think there will be other doctors who will look at the protocol that we've done, which is precise and clean, and say, "This is a good way of achieving that goal with the three cycles," and say, "That's the one I want to go for." There will be a piece of communication which I think is very important around those. I think if this isn't communicated well, then inevitably we'll say, "Well, I'll just stick with what I know, but I'm not sure." But if one communicates well into the community with this data, the data set, I think, is quite compelling.
Thank you very much, Tom. I think just the one other thing that I'd add to this is that Tom highlighted the fact that with POTOMAC, NIAGARA, and now with VOLGA, you see an opportunity in the U.S. in particular to incorporate Imfinzi across multiple settings, which I think is an important part of establishing comfort with Imfinzi in this setting. For as much as there is very good enthusiasm for EV, we also know that not all patients are necessarily EV candidates, and there's therefore optionality with Imfinzi, both in combination with EV, but also with the NIAGARA approach.
Could I add a last comment, if I may? I think this is relevant. Three or four years ago, a minority of patients with muscle-invasive bladder cancer were getting systemic therapy. It is actually muscle-invasive bladder cancer is common. I have two or three patients every week in my MDT. Probably only one in six or one in seven of those were getting systemic therapy, and probably three or four of those were getting cystectomy, two or three were getting nothing, and one was getting radiotherapy. I think all of those patients, or nine of those patients, will now get a go with EV pembro or EV durvalumab. When people say this is shorter periods, this is actually expanding the space. It is turning into a systemic disease.
I was having an MDT discussion with a number of my U.S. colleagues at this meeting recently, and what they are saying in the U.S. is what is now happening is instead of saying, "Let us plan the operation and get that sorted, and maybe we will give something as well before or after," they are now saying, "Let us start systemic therapy first." The discussion before was let us start EVP first, and now the discussion is going to be, is it EVP or EV durvalumab? The proportion of patients getting treatment is going to expand, and actually the number of patients we are going to cure because of that is going to expand because now we are treating 10 patients and we will cure six of those. Before, we were treating four and only curing two of those.
Thank you very much, Professor Powles. Thank you for joining us. Congratulations again on your presidential, and thank you for your collaboration. Let me use this opportunity to now move on to our next section and welcome Professor Wu to come and talk through the EGFR section of this conversation. Thank you very much.
So good evening, everybody. I am Yi-Long Wu. Today I will introduce the two clinical trial for the EGFR mutant lung cancer patient. The topic is the independent role of the backbone therapy. In this ESMO meeting, we have the two very important clinical trial. One is in the second line, the international global clinical trial. This is for the failure of the EGFR mutant patient. The second important clinical trial is in the first line. We are combining two drugs to treat the EGFR mutant patient. This is the first that we introduced, the SAFFRON clinical trial. This clinical trial targets the population, the EGFR- TKI, used after failure, and then developed resistance. This trial targets a very special population, the MET aberration, including the amplification and the overexpression. The patient randomized the two arms.
One arm is the Tagrisso with the MET inhibitor, savolitinib. The control arm is the standard chemotherapy, and then the patient treatment, the disease progression. The primary endpoint is the BICR evaluation, the PFS. The second endpoint including the overall survival and the MET subgroup and the disease control rate and so on. This is the survival curve for the PFS. Showing you this here, these two combinations significantly improve the PFS versus the standard chemotherapy. The median PFS is 7.5 months in the combination treatment versus the 5.4 months standard palliative chemotherapy. The hazard ratio, 05, and the significance. Now this is the overall survival. The overall survival shows you here the patient, significant 4.9 months overall improvement with this new combination. I show you the side effects. Note the new significant side effect discovery.
Most safety related to both drugs, such as the peripheral edema and then the same, but this side effect very lower. I think this is very important. This trial provides one double oral targeted treatment, free chemo in the second-line treatment. This is the first time, and based on the biomarker selection. I introduce another, the SANOVO clinical trial. This also explores the potential of the Tagrisso with the savolitinib in the first-line setting. As you know, in the former setting, we had the three treatment strategies. One is the monotherapy. The second, the Tagrisso with the chemotherapy. The third, the [MARIPOSA], this means the bispecific antibody with the third generation TKI. Now today we report this is also the double oral drug, free chemo and free intravenous treatment. All the patients, based on the IHC-3+ and the IHC 2+ .
All the patients, randomized patients to the Tagrisso with the savolitinib versus the chemotherapy. This is standard, then the treatment of the disease progression. The primary endpoint is the PFS, the second one including the overall survival. This is also the first time based on the biomarker selected in the first-line setting. This shows you the SANOVO, the PFS. The MET IHC-3+ population, the PFS also prolonged, 24.5 months versus 11.3 months. The significant, the probable significance. Then the MET IHC-3+ population, MET, this is the primary endpoint. Then we extend the patient to the ITT population. The ITT population including 3+ and 2+ also showed a significant improvement in the PFS. This is the overall survival, very beautiful, the Kaplan-Meier.
This combination treatment, the overall survival 44.5 months versus the control arm, about 44 months. Also, this is a very significant result. The SANOVO side effect, this is very similar to the SAFFRON. Note that also increased the peripheral edema, but pretty fine here. Very low, about Grade 3. The intellectual treatment, also very low. I think this is my conclusion. The SAFFRON, first provide the one, the new choice in the second-line treatment, also improving the patient PFS and overall survival. The SANOVO provide the new combination in the first-line setting. I want to express this is based on the IHC biomarker status. As also today, I presented this data or the comments this is very easy and test and clinical relevant methods to find some patient. Thank you so much for your attention. Thank you.
Professor Wu, I know that you need to leave. May I ask you one question just before you depart us? How do you think now about incorporating rebiopsy into routine clinical practice? It is one of the questions that we hear a lot as we think about moving from the SAFFRON data to real-world use.
Yeah. This is a very good question. In clinical practice, when the patient failure the first-line treatment, in general, we want the patient take the biopsy because we want to base on the biopsy to find the resistant mechanism to select the new treatment. In China, I think almost 60% the patient will give the patient the rebiopsy. The global, I think also 50% the rebiopsy.
We will work hard to grow that as well. All right. Thank you very much, Professor Wu. Thank you again for being with us.
Okay. Thank you.
I will invite Leora Horn to come up onto the podium.
Building on backbone therapies in lung cancer, it was very exciting as well to see the results of DeLLphi-305. This was a randomized phase III trial for patients receiving induction platinum Imfinzi, patients who had benefit from induction therapy, so complete response, partial response with stable disease randomized to Imfinzi plus Imdelltra or Imfinzi monotherapy. The primary endpoint was overall survival. We saw a standing ovation at the presidential yesterday when Jacob Sands presented this amazing overall survival, a hazard ratio of 0.42, a median overall survival of 21.1 months compared to 12.7 months. We see an immediate separation of the curves in both overall survival, but also importantly in progression-free survival, which was also very clinically meaningful, 7.4 months compared to 1.9 months with a hazard ratio of 0.34.
What we also saw from the data when tarlatamab first came out was the safety profile, and what we see here is a very manageable safety profile. Very few discontinuations due to treatment-related adverse events, CRS and ICANS that were very consistent with the known safety profile of tarlatamab. What we see from the DeLLphi-305 data, building on Imfinzi in small cell lung cancer with a significant improvement in overall survival, progression-free survival and response rate of 58% improvement in the risk of death and a 66% reduction in the risk of disease progression or death. The survival benefit was extended against multiple different cohorts, including patients with brain metastases, liver metastases, and regardless of the response to induction therapy.
We believe that DeLLphi-305 outcomes support maintenance therapy with Imfinzi and Imdelltra as a new standard of care for the first-line patients post-induction with Imfinzi and chemotherapy. Moving on from the doublet therapies that we presented at ESMO, I am handing over to Susan.
Thank you, Leora, and thanks to all of you again for joining us for what has been a really incredibly exciting ESMO. I want to talk to you a little bit more about unlocking the power of ADCs. As you have seen, and I hope are now convinced, ADCs have the potential to improve on outcomes, meaningful outcomes, including overall survival in multiple different tumor types. We are well-positioned at AstraZeneca with the pipeline that we have got that is developing with six clinical stage assets that you have got beyond the progress that we have already made with Enhertu and Datroway. In the preclinical space, we are continuing to build our preclinical pipeline with novel payloads, dual payloads added to what you have already seen here, because this is something that we continue to see a place of innovation in.
In terms of the late phase portfolio, you can see that we've been expanding our phase III development for late-stage ADCs. CLARITY-Gastric01, of course, is the first pivotal readout for Sone-Ve in the second-line plus Claudin 18.2 gastric cancer setting. We already have the first-line study ongoing and enrolling very rapidly in combination with both nivolumab and an arm with rilvegostomig in the first-line setting of Claudin 18.2 positive gastric cancer. As I'll discuss in a little, we now have the potential also to do a combination with ivonescimab in this setting. In the gynecological cancer space, we're moving puxi-sam or B7-H4 forward in the Bluestar-Endometrial01 in the second-line plus B7-H4 endometrial cancer space. We have three ongoing phase III trials for torvu-sam, our folate receptor alpha ADC.
As you can see here, the TREVI-01, TREVI-02, and TREVI-03 trials in both platinum, refractory and relapsed, as well as platinum sensitive in the first-line HRD-negative ovarian cancer setting as a maintenance treatment. We've invested heavily in the ADC portfolio, and what we want to do is maximize the potential of our ADCs by combining it with multiple other opportunities. This is the core rationale for the strategic collaboration we have with Summit. We've already announced that we're wanting to do combinations with Sone-Ve and ivonescimab with Dato and ivonescimab in breast and lung cancers, but we also have the potential to expand this to other planned assets. This enables us to just think about maximizing each of our ADCs in the portfolio by adding on relevant other assets and positions AstraZeneca then as a leader in the ADC and the next generation IO bispecific space.
If you think about this visually, conceptually, you can see as we've built out the value and the clinical development plan for Dato. You start off with the monotherapy, and we've got the same approach with the CLARITY-Gastric01 here. There's real value as you move into the earlier lines through these combinations and actually, a significant proportion of the overall value is through combinations. Just as you've seen, we're continuing to build value for both Tagrisso and Imfinzi with the combinations that we have done, both with our own in-house assets and with other combination partners as appropriate with the trials that you've already heard discussed here. This is a maximize the ADCs approach to our collaboration here.
Now let me move on to CLARITY-Gastric01, which enables us to establish Sone-Ve as the leading Claudin 18.2 ADC and the only one to have global data with positive overall survival data in the second-line plus patient population of gastroesophageal cancer, covering the Claudin 18.2 in a much broader patient population than the current Claudin 18.2 targeted therapy that is available. Just to remind you, Zolbetuximab is indicated in patients who've got a more than 75% tumor score, which is around 30% of the patient population roughly. By expanding this to the more than 25%, you're almost doubling the patient population to around 60% of the patient population. This trial was run with primary endpoints that was in both PFS in the ITT and overall survival in the third-line plus, and then going to the overall survival in the ITT patient population.
We initially started randomizing two dose levels, 1.8 mg/kg and 2.2. But after the dose was selected, which is the 2.2 mg/kg, it is randomized one-to-one against the investigator's choice of therapy. Again, I think you can see here the additional secondary and exploratory endpoints. Here is the data set in the primary endpoint of overall survival in the third-line plus patient population and Sone-Ve reduced the risk of death by 53% versus investigator's choice of therapy in this setting. A hazard ratio of 0.47, and you can see there at the one-year landmark, you have 38.1% versus 18.1% of patients that are alive. This overall survival hazard ratio point estimate favored Sone-Ve across all the clinically relevant subgroups in this third-line plus patient population.
Importantly, it was also consistent across both the less than 75% and more than 25% subgroup, as well as in the more than 75% subgroup. Again, we also met the endpoint for overall survival in the second-line plus patient population with a hazard ratio here of 0.58 and a median OS of 10.6 versus 6.4. You can see in the third-line setting on the previous slide, there was a doubling of the median overall survival. Again, consistency across this different levels of the cut point, which is really different compared to any of the other trials that are ongoing with other Claudin 18.2-directed therapies at the moment. Here is the forest plot showing again general consistency across these endpoints. Of course, patients with the GEJ junction, that was the only group that had a point estimate the wrong side of one. All the rest, you have good consistency here.
I think one important thing to point out is that 60% of the patient population enrolled into this trial had peritoneal metastases. In the peritoneal metastasis group, this is a group that generally does poorly on standard of care chemotherapy and has a poor prognostic. The hazard ratio is 0.5 in that group. That is important in both the second line and the third line setting as well. Again, we are very pleased with the consistency that we see here across the endpoints. In terms of the safety profile, again, because Claudin 18.2 is obviously expressed on the normal stomach, you do see with these agents some GI side effects, including nausea, but this was well managed in this group and the overall rates, particularly the higher grades of rates, was lower than you perhaps see with just the antibody.
I think perhaps the half-life of the ADC relative to the antibody might help to contribute to that difference there. Again, you actually get a lower rate of overall Grade 3 adverse events compared to the investigator's choice with lower rates of bone marrow toxicity overall. Again, we were pleased with the safety profile. There is a low rate of discontinuation in this study overall. In conclusion, CLARITY-Gastric01 showed that Sone-Ve improved overall survival with a manageable safety profile in that second-line plus setting. I have given you the hazard ratios and the medians before, so I will not say that again. I would note that I have not shown you the PFS curves here, but the PFS by BICR in the second-line plus did not reach statistical significance. But the PFS by investigator did show a treatment effect with a hazard ratio of 0.59.
Again, remember, there is a significant proportion of patients with these peritoneal metastases that tend to spread in a diffuse manner and are more difficult to measure, and particularly for a blinded independent central review when those people are making that judgment do not have the other clinical context. I think that can help contribute to the difference here. I think we saw an enhanced response rate. The endpoint that really matters is overall survival, and with the results of this data, we think Sone-Ve sets a new standard of care in the second-line plus setting for patients with advanced or metastatic Claudin 18.2 positive with that new cut point of more than 25% across gastroesophageal carcinoma.
With that, I am going to hand over to Dave, who is going to put this into a commercial context across all of the trials that you have heard about today. Thanks.
Thank you, Susan. I opened talking about four presidentials, and obviously that is exciting for the science and what it means for patients. It also really is something that is an opportunity to generate good commercial opportunities for the company. I think we unwind an important amount of risk, not only for the contribution to the $80 billion target for 2030, but also with medicines like Sone-Ve beginning to also lay an important foundation for the sustainability beyond. If I start first with the CLARITY-Gastric01, and Susan walked you through the detail of the study itself. When we take a look at this opportunity, first and foremost point out that this is a large prevalent and incident population with gastric cancer representing 50,000 patients across the G7, over 20,000 patients within China.
The split from an epidemiology, about a third of those would be third line plus, and then second line would represent 2/3 in terms of thinking about the importance of those two different lines or sets of lines, if you will. As Susan also points out, expanding the definition of the biomarker-positive population from around 35%, which is what is associated with greater than 75%, to 60% with the greater than 25%, really creates a differentiated opportunity to offer Claudin 18.2 ADC to more patients. It is both a first to market as well as to more patients, and really it is the efficacy benefit of a greater than 40% reduction in the risk of death versus what we saw within the control arm that really does serve as an outstanding reason to believe within this.
This is a potential blockbuster opportunity, and it really lays the foundation for the $3 billion-$5 billion range that we shared when we gave the first high-level results from this. Hopefully, what you have seen from this dataset reinforces that. From beyond that blockbuster opportunity, we have opportunities to go early with CLARITY-Gastric02 to expand into other tumor types with biliary and pancreatic cancer, and then, as Susan mentioned before, to expand above and beyond the combinations that we have with in-house and to solidify opportunities to establish Sone-Ve as a foundation through Ivo combinations, which I think allow us to have even more opportunities to get to the upper end of that range.
Now turning on to VOLGA, and we had a great opportunity for a discussion on this with Dr. Powles. Again, I think very importantly, this consolidates the role of Imfinzi across the spectrum of MIBC, but also indeed including non-muscle invasive bladder cancer, where in the U.S., we have opportunities right now that we are launching with POTOMAC. We cover a wide number of different settings with Imfinzi, and I think that this is a very important patient-focused, differentiated regimen and an opportunity to really bring a unique approach with more limited finite EV as we have gone through and described. This is a very competitive marketplace.
There is no question about it, but I think that what we have got is a very good hand to be able to play, and as we think also in markets outside of the United States, remember, EV is not available in many different markets. And that is something where, one, I think the NIAGARA regimen continues to be an important option in those spaces. But also, I think that from a budget impact perspective, finite EV may indeed be something that becomes compelling in certain jurisdictions.
Moving on to SAFFRON and Tagrisso together with Orpathys and the combinations that we have. I really want to highlight two things that I think are really essential about this in terms of the commercial importance. The first, and which is very, very clear, is there is 34% of patients who have MET-driven lung cancer in the second line following, or actually I should better say following Tagrisso use. And that is an opportunity to deliver an overall survival benefit in this area of very high unmet need with a biomarker that allows us to really precisely identify the patients who would benefit and those who would not.
But more importantly, I think, than that is we heard from the discussant, we also heard here from Professor Wu, and we heard from the presentation from Lu Shun about Tagrisso as a backbone. This notion of starting with Tagrisso and staying with Tagrisso and that the combinations are what become available to us in second line is an incredibly important differentiator. This notion of by starting with Tagrisso, there is the opportunity to then in second line be able to use Tagrisso plus Orpathys because it is a well-understood approach to the science and the mechanisms of resistance that emerge gives us a great opportunity not only to establish in the second line but to solidify the importance of Tagrisso in the front line. And that also then just gets further reinforced as we have opportunities with TROPION-Lung15, SANOVO, and also TROPION-Lung14.
Just to put this into a visual, you are familiar with the tumor maps. I think that this one is particularly impressive to see the breadth of where we have invested to establish Tagrisso, and this is what maximizing a clinical development plan looks like. We have got, with Tagrisso, a medicine that has been growing at very good rates across the globe and across geographies. And I think that we have got the opportunity to be able to continue that. You can see with, obviously FLAURA2, also with the SANOVO data, multiple approaches to mono or combo approaches in the frontline. We look forward to the TROPION-Lung14 data, which would hopefully be able to expand from a FLAURA2 approach to also then combining with Dato. And then continuation following utilization with Tagrisso into the second line.
Again, multiple opportunities, whether it's with SAFFRON, TROPION-Lung15, to be able to think about how to continue utilization with Tagrisso and another medicine to be able to get overall survival benefits for patients. This is true across lines of therapy. Of course, we added Zegfrovy, which gives us an opportunity to have an even further leadership footprint across EGFR, and we are excited about the recent launch in the United States with second line, which happened last week. We look forward to bringing frontline quickly as well, and there's opportunities to move into adjuvant and other mutations.
Lastly, I want to talk about small cell lung cancer and the way in which we continue to raise the bar in small cell. We helped establish a standard of care with CASPIAN. We have been a part of then moving from extensive stage into limited stage with ADRIATIC, and now the opportunity with DeLLphi-305 to have Imfinzi be the foundation of what really is, I think, the next standard of care.
It's a great opportunity to be able to continue to grow the Imfinzi leadership within this small cell lung cancer space. It is a unique and differentiated clinical development plan that we've developed, and we've got really an opportunity to be able to have incremental to CASPIAN today, we believe, a blockbuster opportunity. I think that the data that you've heard from really speak for themselves in terms of the opportunity that's there. Our teams are really looking forward to bringing this across the globe as a new option to be able to build on the well-established Imfinzi backbone.
With that, I want to turn it over to Pascal, who's going to look at the future of AstraZeneca.
Thank you, Dave. Good evening. Very exciting ESMO once again. Exciting in many ways, actually. First of all, of course, four presidential presentations is exciting. Beyond this, it's really exciting to see the progress the field is making. For someone who's been following the progress in cancer care for many years, it's just amazing the number of technologies that are emerging. Some of the things that I think come out of this ESMO are, first of all, as I said, the number of technologies, emergence of TCEs and their role. That certainly is a technology that will grow. The importance of combinations. Also finally, the emergence of Chinese leaders and the number of presentations we've all seen and heard from Chinese leaders presenting data coming out of, very often, Chinese innovation. That is suddenly changing the field.
This is something that I believe is not going unnoticed by leaders here in Europe in particular, globally, but very much in Europe. It is really a reminder that Europe as a whole really needs to work hard to maintain the attractiveness of the continent in terms of investing in manufacturing, investing in R&D, investing in clinical trials, because an ecosystem like the one that exists today takes years to build but can definitely disappear relatively quickly under the competition that is coming out of the U.S. and China very much. I like this chart, which we showed you the first time in May 2024. That was our roadmap, the roadmap we showed you at the time. It is very nice to see that we have experienced, of course, that is less nice, the impact of IRA and loss of exclusivity, and we are working through this.
We are growing this year, even though we have lost patent protection for Farxiga in a number of large markets. But the existing portfolio, if you look at it, is really growing across products. Wainua, of course, has experienced a bit of a setback, but everything else is growing. Really what is exciting is to see that products like Imfinzi, Tagrisso are growing through the lifecycle management that we are delivering. Calquence is actually doing very well. Ultomiris is doing very well, even though many years ago, people thought the C5 franchise of Alexion was going to be facing challenges. It is nice to see Ultomiris is replacing Soliris and beyond. It is growing nicely. That is one exciting piece. The second very exciting piece is, as you see highlighted here, a number of products that when we presented this chart, where hopes and dreams are becoming reality.
Etcamah, Datroway, Baxfendy, Klygefa are now approved and launched in a growing number of countries. We have products that are in the regulatory review process but have shown good data, like in particular, [Tozo] and efzimfotase alfa. We also have Sone-Ve as an ADC, and the rest is making good progress so far. Finally, we are also making good progress with these platforms, these technologies that we mentioned back in May 2024, where our focus for us, our focus being growth post 2030, and we are suddenly making very good progress here that we will share with you at subsequent meetings. This is the main phase III readouts of this year. We have had a lot of focus on Wainua in ATTR-CM and the fact that we had a setback. This study didn't work out.
Of course, it is always painful when you have a study that doesn't work, especially in such an important disease like cardiomyopathy due to ATTR accumulation. But look at the rest. We have had so many positive readouts, and those are very important ones. Just let me say a couple of words about some of those. First of all, tozo has enormous potential, and we are now developing it beyond COPD. Ultomiris again is a blockbuster opportunity. I also want to come back to what Dave mentioned a few minutes ago, this Tagrisso franchise. Because again, a few years ago, we were told Tagrisso is going to be challenged and suffer because of the launch of the two MARIPOSA regimens. Look at what we have done.
Look at the build of this franchise, Tagrisso itself, and the combinations that actually not only extend the treatment duration we can expect for Tagrisso, but also protect it. This oral regimen, but also injectable combinations. We really made enormous progress progressing Tagrisso, which I think has more potential than even the consensus considers today. VOLGA is another example of building Imfinzi and building this franchise, Sone-Ve, et cetera. I think fotase is a $3 billion-$5 billion product, depending on the type of label that we get. You can see here that we have quite a number of substantial addition to our growth potential. This slide here says $10 billion in risk-adjusted peak year revenue. Many of those are at risk now. They are positive studies. They are sometimes even approved product.
I believe that there is an enormous potential, much more than $30 billion in this slide alone. Beyond this, we're working on these enemies. I know you are all very quantitative. You are good in math. I want to help you calculate the total turnover peak year revenue that is on this slide. You have 12 that are more than $5 billion, and of course, they are not forbidden to be bigger than $5 billion. Then there's a few that are $3 billion-$5 billion. Not everything is going to work. That's really the important message because when something like Wainua doesn't work, it's painful. We are disappointed. It's important to look at our pipeline and our portfolio in aggregate. You cannot really focus on one or two events.
You have to look at the aggregate progress of the pipeline across so many products and indications. Finally, I want to close with this. This is 2027 and the readouts we expect. It's going to be a very rich year. One thing that we are announcing here is the readout of AVANZAR. We like to keep the pleasure lasting a little longer. We will only have the readout in Q1 next year, and it's simply because the events are coming slowly. You can read whatever you want in this, positive, negative, hopefully positive. If the events are further delayed, then we will get the readout in Q1 next year. Again, if you look at the whole list of events here, readouts, not everything is going to work. But you have a non-risk adjusted peak year revenue this time, $20 billion, more than $20 billion actually.
Importantly, I want to highlight this also because people focus on one or two events. AVANZAR is important, of course, but it's one event, and I hope it will be positive. I believe there is a good chance it will be. But it's one event. Look at the right-hand side of this chart. It represents 40% of the peak year revenue that is on this slide. I'm saying this because the whole series of small, mid-size readouts that fall below the radar screen of most people. But it's important, again, to look at those because you can only assess the potential of our company, of our pipeline through an aggregate view.
I know it is a lot of work to go through all these products and all those indications, but that is the only way to get a good view of the potential growth we have, not only to 2030, but also more importantly, because I know that the post-20 period is the question people have on their mind today. This will generate growth post-2030, and there is a lot of it. Again, not everything is going to work. I hope everything works, but it would be maybe too optimistic. You can see here that there is a lot of things that have a very good chance of succeeding. A lot of this $20 billion, more than $20 billion peak year revenue should actually become reality over the next few years.
With this, I will close out and open for Q&A. Thank you.
Okay. Thank you, Pascal. We have Q&A. We have got about 27 minutes. We will start with a couple of questions in the room, then we will go to online. It would be fabulous if we could do one question because we have got a lot of people online, and that would just be great if we could try. With that, yes, yours. Luisa is right here.
Can you hear me? All right. Thanks for taking my question. Qize Ding from Rothschild & Co Redburn. I actually have one question for Susan regarding the folate receptor alpha ADC in ovarian cancer, because some of your competitors have shown encouraging clinical data in platinum-resistant ovarian cancer. I think my question is that after seeing their data, how do you see the competitiveness of your folate receptor alpha ADC in ovarian cancer? Just a quick follow-up question. Given the folate receptor alpha upregulation in other solid tumor indications, any thoughts about the potential indication expansion opportunity for this ADC?
Yeah, great. Thank you very much for the question. Yes. We are excited about the opportunity for torvu-sam, and we think if you look across both torvu-sam and puxi-sam , we have got a very good linker payload here with, I think, a very competitive profile in terms of the adverse events, particularly low bone marrow toxicity. You are seeing around a 60% response rate and really good durability of response with low discontinuation rate across those assets. So I think we are well positioned. Obviously, one thing I want to point out is that we have already got a study ongoing that is looking head-to-head versus mirvetuximab in the folate receptor alpha high.
I think that is a testament to the confidence that we feel in the profile to be able to be the current standard in that setting, but it also extends in the folate receptor alpha low, and we've also got cohorts that we presented at this congress in the ultra-low as well, where we're also showing good activity. There's an opportunity here for us to cement the position with the other data that we've got, including with combinations. Thank you.
Thank you, Susan.
Sorry, just to answer the second part of your question a little bit about the other indications. Yes, we are testing folate receptor alpha in other indications as well. Torvu-sam.
Yeah, sure, Miki.
Thank you very much. Thank you. Hi, Miki Sogi from Bernstein. I have a question regarding how do you see the future of IO? I understand that multiple PD-1 bispecifics are trying to become next to Keytruda, basically. You have already in-house bispecific such a rilvegostomig, which you are already doing in a combination study with Dato. Now also you have announced collaboration with Summit. How do you see this next generation IO space is going to be? Is it going to be multiple drugs rather than only one drug dominating? How you are trying to navigate your development?
Well, Pascal alluded to the investor event we had in May 2024, and at that one of the things I highlighted then, which I still feel is consistent at the moment, is that I think the IO space will evolve and will be more segmented. You are clearly seeing data, not just with Ivo, but with other agents in this class that are showing activity in a number of different tumor types. I think it is clear that this is going to become a mechanism that is likely to be used in different settings. In a world where that is likely to be true, having the opportunity to combine with one of those as well as with our own bispecifics, I think is really important from that viewpoint of maximizing the value of each of those individual assets that we want to combine with. That is the rationale.
I think there will be a bit of segmentation. For example, even in the lung cancer setting, because of the restriction based on bleeding risk, not every patient is suitable for a PD-1/VEGF. I think for the rilvegostomig program, what we have focused on is the higher end of the PD-L1 expression. You can see that there is going to be slightly overlapping, but not completely overlapping patient populations there. Again, I think that is important. I think the second thing that you are starting to see with studies like the DeLLphi-305 data set in a tumor type that is actually harder to treat than pancreatic cancer currently with a lower five-year survival with the current previous standard of care.
You're now starting to see overall survival data that's really moving the needle there and establishing T-cell engagers in solid tumors, not just in hematologic malignancies, is another important mechanism. We have our own T-cell engagers. We haven't talked that much about them in these conferences, but we've got progress being made with T-cell engagers, not just surovatamig with the CD19, CD3 in hematologic malignancies. We have a Claudin 18.2 T-cell engager in gastric cancer. We have a STEAP2 T-cell engager in prostate cancer, for instance. We have others coming through the portfolio. I think the other thing that we're going to see is a different mechanism of IO agent being introduced as well.
I'm also pleased to see that we had some really encouraging data here for our cell therapy in solid tumor, our GPC3 armored CAR-T that was presented earlier today. That's another area where you can see that the way in which we're addressing IO is going to change, and it has the opportunity for really changing the standard of care in other tumors as well.
Can I just add that? Going back to your question about IO bispecifics, I think you have to look at the bispecifics in two parts. One part is their role and their potential as agents, and in that context, as Susan said, you'll have different patient groups that may respond to different agents. But the second part is the role as a combination with ADCs. Here, if we want to maximize the value of our ADC platform, we have to recognize there might be different bispecifics ultimately in the market. We don't know yet, but it's likely there will be different ones. So if we want our ADCs to be maximized, we have to combine them with different IO bispecific.
Thanks, Pascal. I'm going to go to a question online before coming back into the room. Sachin Jain, Bank of America, please go ahead.
Thanks for taking my question. I will just take one on AVANZAR, given the slight slippage you announced. Do you still retain a view that the control arm is performing as expected, or as you have reviewed event rates, any change? Perhaps you could comment to the sac-TMT data at the conference. As read for AVANZAR, that is now showing 16-month PFS in two separate studies. Thank you.
Please go ahead, Susan.
Sure. Let me take that one. Thanks, Sachin, for the question. A couple of things just to clarify because I know this is a study where there has been a lot of discussion and questions. Let me just a couple of them. First thing I would say is that, and we do not normally make this is an exception that I am going to make today, given the level of interest in it, is we do not normally make a comment on interim analyses. But I just want to clarify that when we designed this study, understanding the importance of OS, we designed it so that we would not have an interim analysis for progression-free survival, and that at the time of the final analysis for progression-free survival, we would have sufficient maturity in OS to be able to characterize the OS at that time.
We continue to want to get to the number of progression-free survival events that is specified in the protocol. That is now moved into Q1, as Pascal has said. But we do not see anything in terms of. I know one question was, is there a difference in the censoring, for example? There is nothing different about what we have seen in the characterization so far of this that would make any change. It is really just the progression-free survival events with a normal censoring rate that we are seeing that is leading to this change into the first quarter. Just to be clear, I am not going to generally comment on interim analyses across the rest of our trials.
Sus, that sac-TMT was a second component?
Yes. I think in terms of sac-TMT, again, we have said a number of times, and I maintain this view that I think we have got a best-in-class TROP2-based ADC here based on the design. The stable linker and payload, and you can see that in terms of the trials that we have presented so far. We have got very competitive response rate, progression-free survival, and overall survival in the settings where you have got the ability to cross-compare across the class and a low rate of bone marrow toxicity, which uniquely means that we can actually combine with platinum-based chemotherapy, for example, in the AVANZAR study. Just as a reminder, the AVANZAR study is the only global phase III first-line study that goes across PD-L1 levels. It includes PD-L1 less than 1%, the 1% to 49%, and the greater than 50%.
The OptiTROP-Lung06 data that was presented was in the PD-L1 less than 1% in a China-only data set. I think the data that you have seen there from an efficacy perspective is encouraging from the opportunity in a first-line setting for a good TROP2-based ADC plus IO to actually beat standard of care chemotherapy. From my perspective, I hope I have been consistently optimistic about the opportunity for AVANZAR. I remain so, and these data, I think, are just encouraging in that regard. But I think we have got a differentiated approach, and we are going to be the first company to have a first-line readout for that across PD-L1 less than 1%, 1% to 49%, and greater than 50% with what I think is the best-in-class TROP2 ADC.
Thank you, Susan. I am going to take one more online and then we will come back into the room. Graham Parry, Citi.
Great. Thanks for taking the question. There is a question on Sone-Ve and exactly what you would expect to get on the label and what is included in your $3 billion-$5 billion. In the discussant session, there was some suggestion that the results were really driven by the third-line patients. Do you just expect a third-line label? Why do you think it was that the second-line patients did worse? Does that lower your expectations in any way at all for efficacy in the front-line setting? Thank you.
Susan, do you want to start on just the label discussions, and I can talk about what is in the commercial? Component?
Okay. I think the data that we have seen across second-line and third-line is very consistent in terms of the response rate, durability of response, and what that leads through to in terms of the overall survival readout. Obviously, in the second-line patient population, the vast majority of those patients that were on the investigator choice of therapy received paclitaxel and ramucirumab. Just as a reminder, paclitaxel and ramucirumab is not available across all countries. It obviously is in the United States, but not generally everywhere. In the discussions we have had with investigators since we have shared the Sone-Ve data from CLARITY-Gastric01, there was strong endorsement of the desire to have availability for this in the second-line patient population as well as the third line.
I would also emphasize that, as I pointed out when I was presenting the slides, 60% of these patients have peritoneal metastases. These patients generally do worse. If you actually look at the patients in line that have peritoneal metastases, I think this is a compelling argument for access to this drug. Our intention is to be looking for a broad label across second line and third line, and that is what we have got support from the investigator community for.
Yeah. Thank you, Susan. Just to reiterate that the support from the investigator community is strong on the need for new options and more options in the second line, as well as in the third line plus. In terms of, Graham, the commercial components, I had mentioned that in terms of incidents, about a third of the incidents is in the third line plus, and there is 2/3 that are in the second line plus. So, second line is twice the size of the third line setting. It is an important contributor to that blockbuster opportunity for CG-01 that I referred to. Let us come into the room. Yeah, yours here.
Hi. Thanks. Richard Vosser, JPMorgan. Maybe just one question on CAMBRIA-1. Just thinking, I think we have not seen you since the SERENA-4 data came in. So just your thoughts on that SERENA-4 data. Probably has not changed anything to do with CAMBRIA-1, just your thoughts whether it has changed that. Maybe if you could give us some of the latest feedback from Etcamah use in the metastatic setting early in the launch. Just feedback from doctors, the monitoring requirements for Topse, just what is going on. Thanks.
Super. So, Susan, do you want to start? If, Leora, you want to add on the CAMBRIA-1 and in the context of SERENA-4, and then Sunil can talk about Etcamah and what we are seeing from the launch in SERENA-6.
Yeah, sure. So obviously we are disappointed with the results of SERENA-4. What we tried to do, as I have said before, is enrich based on clinical characteristics for the more endocrine-sensitive patient population. I still believe there is an endocrine-sensitive patient population beyond those patients that go on to develop ESR1 mutations. But those clinical characteristics were not sufficient to drive an overall positive result for SERENA-4. But I think what we have seen with SERENA-6, first of all, is an excellent safety profile, low discontinuation rates, will obviously present the safety data from SERENA-4 at an upcoming congress. But what we have seen there from a safety perspective is entirely consistent with what we saw in the SERENA-6 patient population.
Low rates of GI side effects, low rates of discontinuation, well-tolerated regimen overall, which I think sets us up for the truly endocrine-sensitive patient population that is in the adjuvant because almost all those patients are endocrine-sensitive. Of course, what we've done is we've, in both CAMBRIA-1 and CAMBRIA-2, patients that have the really high Ki-67 factor are excluded from those trials. You're going after that intermediate to high-risk patient population, the patients that can really benefit from intensification of the endocrine backbone. I think the totality of the data that we've seen gives us confidence that we've got a good chance with both CAMBRIA-1 and CAMBRIA-2.
Okay, great. Thank you, Richard. I think it's wonderful to have, of course, this approval. September 4th is when we received the approval, and we have now approval in EMA and of course, FDA, and of course, PMDA in Japan. We have seen strong clinical enthusiasm for this approach, and we are seeing some really important points as well to support that. With increase, as we take a look at testing rates for first line, there's actually been an uptick in increased testing that we are starting to see from different labs, and we're starting to get those reports. We've also, I think important to note when we talk to clinicians, they feel that the monitoring is very manageable. There is an increase in testing, and also the ECG component is something that they're used to doing already with riboci. This is not a significant uplift for them.
That has been really, I think, supportive as well. Finally, I think with a view of SERENA-4, as Susan mentioned, we were quite disappointed. However, this is now the only first-line study that has camizestrant with CDK4/6 across all three CDK4/6 available. The clinicians are excited about having the opportunity to use this in first line, and SERENA-6 positions camizestrant quite well for that.
I think the one piece that I'd add is, as SERENA-4 reads out as the way that it did, SERENA-6 has greater opportunity. We obviously had assumed some cannibalization from SERENA-4, significant cannibalization from SERENA-4 and SERENA-6. So now Etcamah is the only SERD that has a frontline indication. I think that there's really good enthusiasm, as Sunil points to, and I think that the greatest leading indicator, just to reinforce what Sunil said, across the U.S., but also in the many other countries where we've launched. In the U.S. in particular, we're seeing and hearing from the labs a notable uptake in ESR1 test ordering that's coming through. So, that's a very important leading indicator. Here in the room, please.
Thanks. Pete Verdult, BNP Paribas. If I may, Pascal, I will just have a yes or no Q&A with you, and then one for Susan. You mentioned the China thematic this weekend. The China thematic. The other thematic is the heralding of personal cancer vaccines coming, making a breakthrough. The yes, no question is there an appetite at Astra to enter that space? Then for Susan, can we go back to the first question? That Rina-S data was stunning, right? In terms of developing folate receptors going forward, how problematic is that for you? Then more broadly over ESMO this weekend, a lot of talk about how many ADCs there are, lots of new targets, but a lot of them are using Topo 1, and is that going to have acquired resistance, and are you going to be able to sequence?
Just how problematic does that become going forward?
The first question, this has been a topic of very, very many internal discussion, and I think the answer is yes. We are looking at it. Our R&D team has done a lot of work in the last couple of years on immunotechnology, and we believe we can actually do something in the field, and you will hear more about this in the months and years to come.
Again, if you compare across the class of folate receptor alpha drugs, notwithstanding the fact that the Rina-S data is a significant advance, I think we have got a drug that has a better safety profile, frankly, and I think that is going to be important in combinations. There are multiple other combinations that we were going to want to look at, not all of which you will see currently. I think this is a really important piece, which is when you look at the value of each individual asset, the proportion of it that is coming from the initial monotherapy versus the proportion that comes from the ultimate combinations, it is a minority that comes from the initial monotherapy and the majority that comes from the initial combinations. That combinability and the ability to go into the early lines is where there is an ultimate longer-term competitive advantage.
There's no question that you've got to be able to move at pace across multiple of these programs, but I think we have the scale of our R&D capability to be doing that effectively. Breast, of course, is the place where you've got now multiple ADCs now approved with Topo payloads. I think in general, you are going to need different payloads, and I've alluded to the fact that we have in the preclinical space for our next wave of innovation, different payloads, dual payloads, other things that are coming. I think that's well-positioned. Again, there are still some tumor types and other things where you haven't yet had that ultimate success. I think there's room to expand the ADCs into multiple different other tumor types. That is our intent.
Absolutely, we're going to need different payloads, and we've got that as part of the plan.
I'd like to build on this as well. When we in 2024 at the investor event talked about the opportunity with the wholly owned ADCs, we labeled as a $5+ billion opportunity. With Sone-Ve on CLARITY-Gastric01 being positive, we carved out a $3 billion-$5 billion opportunity, and we maintained that the other bucket of ADCs was at $5+ billion. I think that as you see and as we believe that we have more and more confidence in our ability to both have our internal discovery and development of ADCs together with partnering where it makes sense to go through and do, we have a chance to be leaders here. You combine that with the biomarker work in QCS and precision oncology expertise that we have, we think that that gives us an advantage.
The breadth of combination opportunities, and I think a willingness to combine, as Pascal and Susan have spoken to before, within our own portfolio, but also wanting to make sure that we've got combinations with other leading agents that allow for leadership. I'm thrilled to see two years later that there's competition within this space because two years ago, there was question as to whether TROP2 was going to be an ADC, and I think that there was questions as to whether Enhertu was the only one. I think what we see is that we've made a very good bet on a sustainable modality for the future, and we'll have to make sure that we stay leaders within it.
James Gordon from Barclays, over to you.
Hello, James Gordon from Barclays. Thanks for taking the questions. One was about Summit and the most exciting combo options. The question was how much of the interest in Ivo was about the Claudin ADC combo potential versus Dato combo potential in lung? Did you make the move at the time you did because you had got more excited about the upcoming HARMONi-3 lung readout? Was that why you did it this time? The other one, just a follow-up, please, which was on AVANZAR. Some investors have been saying to me they felt they detected some caution from Pascal in terms of the AVANZAR comments on the call in terms of it only being one readout. Could you just reiterate or remind me, how confident are you in the AVANZAR readout, and do the delays make you any more or less confident?
Maybe I can start with the first question, and then Susan, I will give you the pleasure of the AVANZAR question. She is just gotten so good at them. Practice makes perfect. Summit, James, we see an opportunity to be able to combine across multiple AstraZeneca medicines or future potential medicines with Ivo. What you saw in the announcements was Sone-Ve together with Dato. As you could imagine, it is a little faster to move towards agreements when there is two parties involved versus a tri-party. I would say that that is functionally more of what drives the timeline on what you saw as opposed to anything else.
You also saw an announcement of a memorandum of understanding, which is an intention to be able to have an even more ambitious clinical development plan that would allow for combinations as we learn more about where our ADCs are headed and also where the PD-1/VEGF may make the most sense to be able to combine. Susan, do you want to talk about the AVANZAR?
Let me tell you about some new data that we presented on Dato at ESMO, which was the NeoCOAST-2 data from our neoadjuvant platform study. If you look at the data that we have got there, we have got a significantly higher pathological complete response rate with Dato plus Imfinzi than was seen in the Imfinzi plus chemotherapy treatment in the AEGEAN trial. That also translates through into an improved event-free survival. Obviously, this is a small phase II data set, not a large randomized phase III data set, so the appropriate caveats. I think that is consistent with the profile that you would expect, and you have just seen Professor Powles was very eloquent about the opportunity for ADCs in IO in an early space in a different disease.
We are seeing something that is consistent with that. The profile that we've overall seen with Datroway, for me gives us the opportunity to have a best-in-class, and I think the AVANZAR study is going to be the first global study in the first-line setting across all of those lines, and I see no reason for not being optimistic about it. Sorry, that was British. I am optimistic about the opportunity for AVANZAR in the first-line setting based on all of the data that we have seen so far. We all need to wait till Q1, and then we'll see the results.
Great. Maybe Luisa, in front here, yours.
Thank you. Luisa Hector at Berenberg. I have a question on China and the data that's coming out of China. Can you give us any more thoughts on how to interpret the phase III from China? It's going to be relevant. You've got Ivo data, probably your assessment of sac-TMT, and then you have your own data, SAFFRON, SANOVO, to look at. But I think on the whole, we're expecting efficacy to wane a bit from the China phase III to a global. But perhaps we're seeing a bit more toxicity, so should we be ready for different levels of toxicity, maybe different willingness to bear that load as a patient in China versus more globally?
Then I have a hopefully short question. Imfinzi, amazing growth driver. Are you working on a subcutaneous formulation?
Dave, to you.
Yeah, so maybe the China question, Susan, we can start with you, and Leora, you can comment on the Imfinzi.
Okay. I think when you look across the China data sets in general, I would say there is reasonable consistency when you are seeing a big effect size that then that comes across into the Western patient populations. The exact hazard ratio may differ. And that may depend on the nature of the control arms, et cetera. But I would just say in terms of the quality of how these trials are run, there's good quality. There's lots of experienced sites now and investigators in China across. But as with any trial, sometimes the effect size can differ between one experiment and another. And you're right, for individual toxicities, there may be some differences in terms of the implications of toxicity in terms of discontinuation for a particular grade of adverse event.
I think we always have to sort of try and understand the context of the clinical practice of the predominant patient population. And I think that's what the regulators are looking for as well, which is understanding that relevance in the context of the patient population that's ultimately going to get treated. But in general, when you're seeing a really big effect size, it's not something that you see disappearing when it comes into a Western patient population, if that answers your question.
Yeah, I think just adding to what Susan said, I think we have a perfect example with savolitinib at the SACHI data, which was in the second line, EGFR mutation-positive patients with acquired resistance who are MET. Same population as SAFFRON. Very similar hazard ratios for progression-free survival and overall survival. So between global and Western, we are seeing that and depends on disease biology. And yes, we have an ongoing phase I study with Imfinzi subcu.
Thanks, Leora. Thanks for the additional color on the China element, too. We'll go to the next caller, Rajan Sharma, Goldman Sachs.
Hi, thanks for taking my question. Just sorry to come back to AVANZAR, but just given the timings now, is there any possibility that we may see data from TROPION-Lung07 or 8 before AVANZAR? Could you maybe just talk to your relative confidence in a positive readout on those trials relative to AVANZAR, bearing in mind some of the learnings from ESMO and some of the competitive data sets that we've seen? Thank you.
Yeah. Thanks for the question. Still anticipate that AVANZAR will be the first, as I've said, I think twice already, the first global phase III trial in the first-line non-small cell lung cancer setting. Of course, it goes across all of the PD-L1 levels. TROPION-Lung07 is in the less than 50% PD-L1. TROPION-Lung08 is in the greater than 50%. In those two different patient populations, there will be a different estimate, if you like, for what you would expect both control and experimental arm to do because there's a bit of a prognostic difference between the PD-L1 lower and the PD-L1 higher. Right? I think that's the key driver of potential differences in those event rates.
Again, given that Dato is the consistent component of those trials, confidence based on what we've seen so far should go across those different levels, but the comparator is obviously a little different. That's all. My confidence that we've got a best-in-class TROP2 ADC goes across all three trials.
Great. Maybe we have a chance for one last question from Miki.
We started talking about TL07. TL07, it's a great study with the triplet, doublet, and also looking at ITT as well as the QCS positive at this point. We understand PFS and OS for each of the population and each of the arm is part of the primary endpoint. It sounds like there are eight primary endpoints, and how is the alpha allocated for these?
Maybe on the endpoints, just as a reminder, maybe I'll help out on this. We've got PFS, OS, ITT, biomarker. Those are the endpoints.
[audio distortion] What about triplets and doublets?
You are talking about in 07?
07, yeah.
Oh, sorry. I was giving AVANZAR because we were getting so good at it. Leora, do you want to talk about 07 and maybe talk also, and we can end on kind of the breadth of optionality that comes from the program?
Yeah, so we do not disclose the alpha allocation. But I think it gives an opportunity for doublet or triplet. We are also generating similar data in a medical affairs study called Patagonia with carbo-dato-durva and dato-durva. So the platinum, the lung investigators have been very attached to that. We know it deepens response rates, and I think we will see when TL07 and Patagonia reads out how that depth in response can lead to a benefit in both progression-free survival and overall survival.
Just to be clear, Miki, the answer that I gave was for AVANZAR, so that wasn't in 07. I appreciate all the clarification. Well, thank you very, very much for your attention and your time here with us at ESMO 2026. It's been an exciting one for us, and we look forward to a strong finish to 2026 and an opportunity to carry that momentum into 2027. We'll look forward to seeing or hearing from most of you on Friday. Take care. Bye.