Status Update

Sep 21, 2021

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Thank you for waiting. We are now ready to start Daiichi Sankyo's conference call to present ESMO twenty twenty one highlights. Please note that today's call will be today's call will be recorded, and the language of today's presentation and the Q and A is English. Doctor Takeshita, please go ahead. Yes. Thank you very much for the introduction, and, thank you to all of you for joining this call. My name is Ken Takashita, Global Head of R and D at Daiichiankyo. And, welcome to our conference call to present our ESMO twenty twenty one highlights. And I'm going to follow the slide deck that you have in front of me. Slide number two, you got usual statements and disclaimers. So go on to the slide number three. And then four, three represents our agenda for today. We'll give you the introduction followed by, highlights and, actual ESMO presentation from three clinical trials that we would like to highlight. And then, of course, there is a very lengthy appendix you have in front of you at the end. So slide number four, we want to emphasize here today that, this year's ESMO marks a major turning point in diet science transformation into a global leader in oncology. We had four late breaking presentations including one late breaking presentation in a presidential symposium. We also had the chance to, present the first clinical data in DS-seven 300 program, which is the fourth DXD ADC in the clinic. And these data really show this growing leadership of Daiicheng Chao to create transformative medicine and really also demonstrate the strength of our ADC technology across multiple cancers and also, of course, across multiple ADCs. Okay. So now we're going to go to the highlights, for ESMO, starting with Slide number six. So just a brief summary of these, four late breaking presentations. The first one is the Enhertu DESTINY Breast three clinical trial. This is a Phase III randomized clinical trial in the second line setting for HER2 positive breast cancer. And this was the first late breaking presentation in the Presidential Symposium. And as such, it was a very important clinical trial that the ESMO organizers recognized. This is a head to head trial in breast cancer showing superior efficacy of NKTR2 compared to another ADC called TBM1. And the data showed unprecedented highly statistically significant and clinically meaningful improvement in progression survival. So these data provide, definitive data for Enhertu to become the new standard of care in the second line HER2 positive breast cancer patient. And also at the same time really significantly increases our confidence for Enhertu studies that are going on now in many different settings for HER2 plus breast cancer. So again, a paradigm shift in the treatment of HER2 plus breast cancer. Next one, on Slide seven, is the ENHER2 clinical trial again but in a different disease called DESTINY-one hundred and one. This is a single arm Phase II clinical trial of patients with non small cell lung cancer with HER2 gene mutation. And we were able to show a very good response rate and durable responses in patients with these HER2 gene mutated non small cell lung cancer. And this is very important because currently there are no drugs specifically approved for these particular groups of patients. And the data were, of course, impressive enough to merit the publication in the New England Journal of Medicine as a simultaneous publication along with the ESMO presentation. And again, NITHER has the potential now to transform patient outcomes in these patients with mutated non small cell lung cancer. So now this really demonstrates that HER2 has activity not just in breast cancer but also in lung cancer as well, of course, our already approved indication in gastric cancer. Slide number eight. I just want to very briefly mention that two other late breaking presentations. One was the NHER2 DESTINY gastric two clinical trial. This was a single arm Phase II trial involving Western patients treated with NHER2, which showed very impressive durable tumor responses, very similar to the original gastric one data that was principally conducted in patients who were of Asian in Asia. So this new study, gastric zero-two, allowed us to confirm that the activity seen in Asian patients also applies to Western patients. And finally, the fourth late breaking presentation, the DACO DXV Tropion PanTumor01. This is not in HER2 but the ten sixty two program in which the TROP2 is the target and not HER2. And subgroup analysis of this clinical trial in non small cell lung cancer patients with actionable genomic alterations, AGN showed encouraging efficacy, again gaining a lot of confidence for us in the development of this agent in the AGA population in lung cancer. And finally, in Slide number nine, we did present very brand new data in a brand new ADC called DS-seven 300. This was a Phase phase onetwo study in solid tumors in which 7,300 was studied. 7,300 is directed against an antigen called b seven eighty three. Currently, there are no B783 directed therapies, and 7,300 showed very promising clinical data in patients with several types of advanced public tumors that we'll get to a little bit later, as well as a very good safety profile. And so we're very hopeful that seven thousand three hundred will follow the footsteps of its older siblings and provide new effective treatment strategy across several types of cancers. So this again is a demonstration not just of seven thousand three hundred itself but really the underlying ADC technology that we have at DysenQual in the area of antibody drug conjugate. Okay. So Slide number 10, just to summarize here that we had 18 abstracts that were released at ESMO. And we have included the full slide deck in appendix on all the presentations that we made. And for the rest of our meeting today, our conference today, we're going to focus on three presentations that are described in the lower left. Infert to DESTINY Breast03 Phase III data, the DESTINY Lung01 Phase II clinical trial data, and finally, the DS7300 Phase III clinical data. Okay. So now let's now skip on to Slide number 12. So first time the first clinical trial that I will present today is Destiny Breast three. This is a randomized Phase three study in which trastuzumab deruptecan, TDXT, is compared against PDM1, another ADC. And PDM-one, as you know, is standard of care currently today in pretty much around the globe for the second line treatment of patients with HER2 positive metastatic breast cancer. Slide number 13 shows some important characteristics and differences between the two agents. As I mentioned earlier, both are antibody drug conjugates. The one on the right is from Daisangqiu, and the one on the left is from, Daisangqiu. And of course, one on the right is from Roche Genentech. And it is the current standard right there. And you can see on this table here that there are some very important differences in how these ADCs were engineered. In terms of the payload, trastuzumab derx TCAM, the TDX T has a topoisomerase one inhibitor compared to TDM1, which is an antimicrobial agent as the payload. The antibody drug ratio is quite different. You'll also see that with TDXD, there's an average of eight of these payloads per antibody molecule compared to three and a half for TDN1. TDXD also has been engineered to have a cleavable linker that is tumor selective. That is to say that in the tumor microenvironment, the linker is cleaved and thereby releasing the payload. And what is also very important to note here is that the payload itself is cell membrane permeable. What this really means is that tumor cells that are in close proximity to the actual targeted tumor cells can also be killed by bystander tumor antitumor effects in which the payload is released, passes through the cell membrane to the neighboring tumor cells. So these are very important engineering advances that were made in TVXD. Okay. So, slide number 14 shows the, general study design for breast cancer, three study. It's a randomized study for patients with metastatic HER two positive breast cancer previously treated with trastuzumab and taxane. And the patients are randomized one to one to TDXD or TDM1. The primary endpoint was progression free survival, and the key secondary endpoint is survival. And what we are showing today is the interim analysis for progression free survival. The data cutoff was 05/21/2021. And even though this was an interim analysis, the IDMC, the Independent Data Monitoring Committee, recommended that the study be unblinded because the efficacy data was already positive. I should note here that the key secondary endpoint, the prespecified P value have to be less than 0.000265. And we chose that number because it was an interim analysis. And you'll see that, the P value for overall survival did not quite make this boundary. However, you'll see of course that the boundary for progression free survival far exceeded the P value boundaries set forth in the original statistical analysis. Okay. Patient disposition is shown in Slide number 15. There were six ninety nine patients screened, of which randomized patients, five twenty four, distributed evenly between the two arms. Slide number 16 shows the baseline characteristics. And you'll see that for pretty much all the characteristics there is even split between the two arms whether it's a lesion, HER2 status, ECOT performance status, hormone receptor status, etcetera, brain metastases and lymphadenopathy. In terms of prior therapy, again the two arms are evenly split between the two. And I should also mention that there was a sizable number of patients who had received not just trastuzumab but also pertuzumab as a prior treatment regimen. Okay. Now Slide number 18 is really the key slide and it's really impressive separation of the two curves for the progression free survival. You see that hazard ratio is 0.28. P value is zero followed by 22 zeros and seven eight. It's an incredibly impressive hazard ratio and an equally impressive p value. You can see that the progression free survival in the control arm was six point eight months but has not yet been reached for the experimental arm, the TVXD arm. Okay. Now slide number 19 shows that progression free survival analyses in key subgroups. And you'll see that in every single subgroup analyzed, the hazard ratio is far to the left indicating tremendous benefit in every single subgroup category that we have studied and analyzed. Okay. Slide number 20 is the overall survival data. And, you can see that the header ratio is 0.56 with a p value that is quite small, 0.007. So as I mentioned, the prespecified boundary for overall survival was, as listed at the bottom here, 0.000265. So we did not cross this boundary most likely because of the immaturity of the overall survival data. It's very likely, of course, that the P value will cross the boundary at the time of the next overall survival analysis. So here are the some additional information of interest. Response rates, You can see that the response rate was 79.7% in the TDXZ arm compared to 34% in the TDM-one control arm. It's very notable that the CR rate, complete remission rate was sixteen point one. So these are patients who are really disease free, no evidence of disease, sixteen percent in the PDXC arm. Okay. Now in terms of overall safety, I think you'll see that the safety profile was quite acceptable and manageable. This slide here shows all the drug related treatment emergent adverse events and drug related treatment emergent adverse events. Approximately the same between the two arms. And on Slide number 23, it shows some of the details of the individual adverse events that were reported. You'll see that for the most part, there is somewhat greater, incidence of toxicities in a TDXC if we look at, any grade toxicity. But when we look at grade three and worse, I think the numbers are quite acceptable and certainly, justifying the risk benefit for TdxD in this clinical trial. And you'll see that most of the drug related TEAEs are either gastrointestinal or hematological in nature. Slide number 24 shows two adverse events of special interest. One is drug related IOD, interstitial lung disease. You'll see here that in the TVXD arm, the incidence was ten point five percent for any grade ILD. But more importantly, think it's very notable that most of the ILDs were grade one and grade two, and we did not see any grade four or grade five. In contrast, in a TDM one arm, the incidence of ILD was one point nine percent. In terms of, left ventricular ejection fraction decrease, very few patients, showed a decrease in LVEF, two point seven percent in the TDXD arm and zero point four percent in the TDM-one arm. And none of them were Grade three or worse, only Grade one and two. In conclusion, this is first randomized Phase III clinical trial in breast cancer for TDXC. And we demonstrate highly clinically meaningful and statistically significant improvement in PFS compared to the current ADC standards, standard of care TDM-one. Has a ratio of 0.28 with a very, very small p value and consistent benefits in all patient subgroups And of course, encouraging overall survival trend. And safety profile that looked quite good. And these data really support TDXD becoming the standard of care for second line HER2 positive breast cancer. And Slide 26 shows the next steps for this clinical trial. We were granted the RTOR by the FDA back in August. And of course, we have much more confidence now, of course, in our other clinical trials in which ENHERT2 is being studied in ENHERT2 positive breast cancer, BEST nine study and the BEST five study. And these are ongoing study, which we hope to report sometime in the future. The next clinical trial that we want to highlight is TESTEDY LUN-one study. This is a Phase II trial of TZXT again but in a different disease HER2 mutated metastatic non small cell lung cancer. Okay. And so HER2 mutations are seen in about three percent of non squamous non small cell lung cancer. And currently there are no approved HER2 targeted therapies for patients with this disease. And because, TZXT is a HER2 targeting agent, we were very interested, of course, in studying HER2 in patients with HER2 mutated non small cell lung cancer. And these are the data that we're about to see. So LUNG-one study had several different cohorts. There were the HER2 overexpressing Cohort one and 1A and HER2 mutated cohorts, which are called Cohort two and Cohort two expansion. Cohort two studied a dose of six point four milligrams to three weeks, whereas the Cohort one studied two different doses of six point four milligram and five point four milligram every three weeks. And the primary endpoint was response rate. And so now we're going to focus really on the Cohort two, which are the, HER2 mutated cohorts. There were a total of ninety one patients, as you can see on Slide number 30 now. Ninety one patients, thirty four percent were Asian, forty four percent were Caucasian. And this was a clinical trial conducted in Asia, Europe and North America. You can see this then that the majority of the patients had a kinase D domain mutation. In terms of prior therapies, the median number of prior therapy was two. So these are really third line patients. And most of the patients have been treated with a platinum agent and a checkpoint inhibitor, namely an anti PD-one or PTL1. And Slide thirty two shows the overall response rate of fifty four point nine percent. This is, of course, a very high number, including, one point one percent of the patients who had a complete remission, fifty three point eight percent with a partial remission. The median duration of response was nine point three months. Slide number 33 shows the classic colon waterfall plot. You can see that the majority of the patients had tumor shrinkage experienced. And down below on the lower half are the details of the kind of mutation that the patient had. There's a lot of detail in here, but really a take home message here is NHER2 that appears to be quite effective in any kind of mutation, whether it's exon mutations or gene amplification. So very encouraging for these patients with many different types of gene alterations of the HER2 gene. Okay. And you can see here again that in terms of efficacy analysis by subgroups, you'll see that the kinase domain patients had a response rate of 57.6, very similar to the rest of the patient population. In terms of the prior therapies, patients who had platinum based therapy only had a fifty four percent fifty three point five percent response rate. Those who had platinum plus an anti PD L1 still had a very high response rate, about sixty four point nine percent. And those patients who had asymptomatic CNS metastasis at baseline did just as well as those who had no CNS metastasis. Very encouraging for all these patients. Slide number 35 shows the spider plot. You can see that the majority of the patients had a response that was sustained over many, many weeks. Some extending as much as almost well, really more than two years really now. So these are really amazingly durable responses. Okay. Slide number 36 shows the progression free survival curve and overall survival curve. And you can see the median progression free survival was eight months and median overall survival was seventeen point eight months. And these are quite encouraging because these are really third line patients who had exhausted standard of care treatment for their disease. Okay. Now we're going to go to safety data in slide number 37. You'll see that the overall safety summary here, all treatment emergent adverse events, drug related TEAEs, as listed here. I think it's very important to just really mention that these are very tolerable safety profile. In terms of individual details of what the adverse events were, that's listed on Slide number 38. Most frequent adverse events were things like nausea, vomiting, alopecia, vomiting, and some hematological adverse events. In terms of grade three adverse events, the most frequent grade three adverse event was neutropenia. Okay. Now in terms of, the drug related interstitial lung disease, what's reported in this clinical trial was that twenty six point four percent of the patients experienced drug related IOD. And some of the details are shown here in terms of the time to onset of one hundred and forty one days, median duration of forty one days forty three days. And, we do recommend that steroids be administered with these, ILD and pneumonitis. It was interesting to note that, not all steroid treatment was administered as per ILD treatment concept. Okay. So finally, the conclusion for this slide is in Slide number 40. TDXD demonstrated robust and durable anticancer activity in patients with previously treated HER2 gene mutated non small cell lung cancer. And the efficacy of about fifty percent was consistently observed in every subtype of patients including those patients with stable CNS metastases. And the drug appeared to be active in many different kinds of HER2 gene mutations as well as in patients with gene amplification. The safety profile was consistent with previously reported studies and most of the ILD cases were of low grade. Just a reminder that this data was generated with a six point four milligram dose. And currently the five point four milligram dose is being explored in future studies to evaluate optimal dosing regimen for these patients with HER2 mutated non small cell lung cancer. But for now, I think we can conclude that LUN-one study provides compelling evidence of positive benefit risk in the second line plus setting. And it is a potential new treatment standard for these patients. In terms of next steps for this program, Slide number 41, we are discussing the filing strategy for these data and the second line HER2 mutated non small lung cancer with the various health of patients. And I would also like to note that we have a new study called the Lung four study in the frontline setting for previously untreated patients with locally advanced metastatic non small cell lung cancer with the HER2 mutation. This is a randomized study against the standard of care, which we just initiated, believe, last month. Okay. So the next few slides are just a summary of the entire clinical development program for Enhertu. I think this you have seen previously. So there's really no change really in breast cancer program. In the gastric cancer program there are in the lung cancer program there are two new studies that are shown as with the white bars. One is called the gastric six China Phase II study. This is really for registration in China. And, of course, the lung cancer four study I just mentioned, this is the randomized study comparing in HER two versus standard of care chemotherapy for patients with previously untreated HER two g mutated noncancer lung cancer. So we just initiated that very recently. And and just to complete the picture, we do have other cancer indications that are being studied, colorectal cancer and other tumors. But there we don't I don't have any new studies to report to you for today compared to our last update from ASCO. Okay. Now finally, I would like to go over with you a data from a brand new ADC called 7300. This is an ADC directed against an antigen called B7 H3. H3. Okay. Now slide number 46 shows the background and rationale. So B7 H3, also known as CD two seventy six, is a trans membrane protein that's overexpressed in various cancers including lung cancer, prostate cancer, esophageal cancer, breast cancer, head and neck cancer, etcetera. It's a wide spectrum of cancers which makes us very interested to really understand whether or not there is a broad profile of activity with this particular ADC. And then as of today, we're just in the very early stages of having a good understanding of how widely or how broadly efficacious this ADC is going to be. Slide number 47. Just a little bit on the background and the scientific rationale. It is 70, it is an IgG1 directed against the B7 H3 with the standard payload of diruxetecam. Drug to antibody ratio is four drugs to one molecule antibody. And as with in HER2 and other ADCs, it has some of the features, that we have engineered into the ADC such as stable linker payload, tumor selective cleavable linker and a bystander antitumor effect. And this is a very Slide number 48 is a schematic of our Phase I study design. It was a dose escalation study studying various doses. And you can see that we started at zero point eight milligram per kg, and we actually reached a very high dose of sixteen milligrams per kilogram. Okay. And so we're really going to be reporting to you that some of the early data from this clinical trial. Okay. So slide 49 shows a summary of the patients enrolled with their various types of cancers at the various doses that were studied from 0.8 all the way up to sixteen milligrams. And you can see that so far we have studied a total of 70 patients at various doses that are listed here with the various different types of cancers. Slide number 50 is a summary of the overall safety divided by dose. And you can see that in general there is a suggestion of a dose dependent increase in the incidence of grade three TE and E including a couple of cases of IOD at the two highest doses at the twelve and the sixteen milligram doses. The most common AEs, are listed here. They were typically gastrointestinal, nausea or vomiting, decreased appetite, etcetera. But these are really low grade, grade one or grade two. In terms of grade three toxicity, the most frequent was anemia. Okay. Now let's get to the sort of the interesting part. Efficacy was is shown on the slide number 53. Of the seventy patients enrolled, there were fifteen partial responders, which is quite encouraging as well as, of course, the thirty two patients with stable disease. Slide number 54, is a waterfall plot, again showing activity of this agent in patients with really quite refractory cancers. And it is we think that there is a very interesting pattern of responses in patients with small cell lung cancer and possibly prostate cancer. So we're very interested in these indications as possibly something to pursue initially. Although as I said that this antigen is broadly expressed in many cancers. And, we are very anxiously waiting to see, what activity of this ADC will have in these other cancers besides small cell lung cancer and prostate cancer. Yes, conclusion for Slide 55. This is the first in human trial of a single agent DS7300, an unknowable ADC directed against B7 H3. And we observed, of course, very encouraging partial responders, fifteen of them actually out of 70. And we're particularly focused on small cell lung cancer, prostate cancer and possibly esophageal cancer that we may see some signal. But of course, we're not anywhere close to having a good look at other cancers either such as non small cell lung cancer, breast cancer, etcetera. So very a lot of high hopes for this ADC. Okay. So in conclusion, what I'd like to show here on Slide number 56 is that these are really evidence of further maturation of Dai Fang Kyo's ADC program and really growing leadership in creating transformative medicines for patients with cancer. So why is important here? So first of all, we can see that the BREST-three study was a direct comparison head to head against another ADC. And so we can see now that the superiority of the ADC technology, all the engineering that went into creating these new technologies, new ADCs within the Kyo research labs that really paid off. So it's a confirmation of the technology we have here in Daichung Choe to create new MVCs. And I think the second significance of this is that we are able to identify many different ADCs beyond just the HER2 ADC. As you know, we have ADCs directed against HER2, TROP2, HER3 and now a new one, E783. So it really it's again a testament to the robust technology capabilities we have to create new ADCs beyond just the HER2 ADC. And as noted on this slide, our entire R and D portfolio will be updated at the R and D Day on December 14. Okay. So that concludes my slide presentation. And we'll stop here on the slide and go on to the questions and answer session. The first question is from Mr. Hidemaru Yamaguchi from Citigroup. Please start your question. Can you hear me? This is Yamaguchi from Citi. Yes. Great, thank you. So thank you very much for the presentation. Quick question, first one, firstly on DV3. You talked about the some earlier discussion with the U. S. FDA, which was I think it's called RTOR. So can you remind me, is this the what is the relationship with this event in August and filing? So the August conversation around RTOR was what kind of a review process does the FDA wish to pursue? So real time oncology review is something new to agency where they are willing to review dossier as they become available from the sponsor. It's a way to expedite approval process, and we were granted that. And it's a very fortunate thing for really for patients because they will likely very much likely get access to the drug much earlier than the usual FDA review process. I see. So which I'm kind of confused about it. It is given by the FDA in August, but it doesn't mean you have a meeting in August rather you have this RTOR pathway now. Yes. Well, yes. That's right. Need get it filed? Yes. Well, I do want to make it clear that in August, the FDA did see the preliminary data from And this clinical that really resulted in a decision to grant us the RTOR. Right. So then this RTOR itself can give you approval sometimes? It is one step towards the submission. Yes. But if it but sorry, it's before submission. Submission after Okay. A So the next event yes. Switch we can That's correct. Next event will be the submission. Oh, I see. So when do you think submission to happen? That should be happening sometime this year. Sorry, this year? Yes, this year. Okay. Thank you. That's right. Okay. Thank you. Second question on this one, DV3, is that efficacy is really, really good, I've never seen. But two quick questions. What do you see? It's kind of your opinion, but what do you see? Because given this big difference between the TDM-one and EHA2 or DxD, including bystander effect, which was discussed at ISMA as well. Do you see the chance to get the ROHA2 data or even the first line, which is the earlier stage data, the probability of success within Dai Tsankyo's projection is going to get higher given this better than expected data or it's not really changing? No, it is higher now. The probability of Right. Success is higher, So it's fair to say that probability of success given this data may go up, right? Yes, that's right. Thank you. And finally on the DBC, ILD was also a discussion all the time, but this time there are a few, but probability of happening is getting lower and lower. And especially on the high grade, it's getting lower and there's no grade four and five, condition to go to the ARIA line. So it's also fair to say that given this low risk of higher high grade ILD, which gives you a confidence to go for the earlier line, including once again the LOHA-two and also the FAST line? Yes, I think that's a good interpretation. Okay. Thank you. Quickly on the other two things, the 7,300, you selected three cancers, which as you know, it's an extraordinary or preliminary cancer. But at the same time, there's no overlap with your current other ADCs. So I feel like there are some strategic selection on this one, even though there is a biological selection as well. But are you going to go for these three cancers, so called to get your faster market strategy, including ES or small cell, which is not there are not many drugs available or it's really just a beginning of everything else? Well, so first of all, the cancer that we chose to highlight here was not strategic. It was more data driven. We So by look just see the data and say, oh, this looks good. And as I said that we haven't really fully studied seven thousand three hundred in other cancers like breast cancer for example or other type of the non small cell lung cancers. But having said that the data that we are seeing so far in some of these indications are very intriguing. And I don't think we have actually announced a formal pivotal registration program, but it is of course certainly on our mind. Right. And it's also fair to say that you can as a plan some fast to market meaning norm kind of ORR plus DOR to get the approval type of thing coming out of these three cancers? Yes, absolutely. Sorry for that. Finally, it had to learn. Data is still good, but you are changing your dosage. And this dose change, will this have an impact to your filing process, meaning you're going to file, but the filing time itself, officially announced, was delayed a little bit so far. Can you make a comment on this? Those change may have impact to filing or not? Not really Well, I think the best I can say here is that we're in discussion with the regulatory agencies on how to go about this. Should we file with the current data we have or with the data that we will have in the future? It's the data we have is still good for patients who don't have much other option than ultimately it's a risk benefit analysis. Really a judgment call about that. We are I think suffice it to say that we are discussing all these things to regulatory agencies. Okay. Thank you. Thank you very much. Congratulations on the data. Thank you. Okay. Thank you. Next question is from Mr. Seiji Wakao at JPMorgan. Please start your question. Hello, this is Wakao from JPMorgan. Can you hear me? Yes, yes. Thank you for taking my questions. I'm surprised that you have presented a mark through exciting data. So my question firstly about DV-thirty three. So especially about PFS. PFS by VLTR was not reached. On the other hand, PFS affected by investigators was twenty five months. Disease results exceed your expectations or they in line with your expectations? Could you comment on this point, Fachi? Are you asking about the difference between the two arms? No. Level of twenty five months, I think it's very tough. Okay. So first of all, there is always some difference between investigator assessed progression free survival and centrally reviewed progression free survival. So it's not a surprise that with, centrally reviewed, it was not yet reached. And, we have a number of twenty five months with investigator assessment. So the fact that, they don't exactly match, perfectly fine. It's often seen in clinical trials. But in terms of the actual number of twenty five months, which is quite long actually compared to the control arm, it's almost a threefold improvement in the progression free survival if we just go by the investigator assessment of the progression free survival. And, I don't know that, I think we all expected that HER2 will be superior to TDM-one, I don't think anyone really expected that the difference would be so large, a threefold increase. Okay. Okay. Thank you. So second about brain metastases. So efficacy was confirmed for patient with brain metastases in DV03. Can we assume that this will lead to its use in clinical practice for patients with brain metastases as well? I'd like to know if the data is competitive against Kaiser in population with brain metastases. Do you think the data to be sufficient to grab the market share from Kaiser among population with brain metastases? Could you comment on Yes. Let me just comment on this. In this clinical trial, the patients who were enrolled, they could have had brain metastases Yes. But they have to have clinically stable treated brain metastases. Mhmm. Okay. So that's very important to note. So those patients who had clinically stable three d brain metastases, for example, with our radiation therapy, you can see that in data set that those patients benefited just as well from the NHER2 as the patients with no gram metastases. Okay. Okay. So next about DB-one. So the efficacy of the drug was confirmed in patient with a PARP expression. What do you think is the mechanism behind this? And I'd love to know if you have any implications for heart load in breast cancer settings. Okay. So the first question I believe was about patients who had HER2 gene mutations, but their HER2 expression was low. Is that correct? Yes. That's right. Okay. So, you know, I think it I'm just going to speculate that for a gene mutation to be an active part of the oncogenesis or the pathogenesis of disease, it's not always necessary that the expression of HER two is high. It's more of that that that mutation confers a signaling advantage, which doesn't always require high levels of protein expression. And I think we can see this in many other examples where protein level expression doesn't always correlate with aggressiveness of the disease or efficacy of agents and drugs and antibodies that are directed against a particular target. So I think that the mutation itself as opposed to the expression is the more important parameter to look at. Okay. Now but I think for these ADCs as a class, what is important also as a kind of a separate matter is to understand that the level of expression of the target could be quite low. Low meaning lower than the currently standard acceptable range of what a HER two positivity is. So so this is the reason why we are very interested in the sub in a category of patients who have low levels of HER two expression but not zero and to see whether or not HER2 is active in patients with low levels of HER2 expression. And in fact, we are conducting a clinical trial of breast cancer patients with this HER2 low expression. And we hope to be able to report that data to you in the future. Okay. Okay, I understand. So last about DS-seven 100. So verified ILDs at sixty milligram per kilogram have been identified. Do you think this is simply those issue or is it due to the mechanism? Could you comment on this point? Okay. Well, I think my guess and this is just a guess is that it's a dose related issue. Okay. Thank you. I understand. Thank you. That is from my side. Thank you. Thank you for taking my question. Okay. Thank you very much for your questions. The next question is from Mr. Katsuaki Hashiguchi at Daiwa Securities. Please start your question. Hello, I'm Katsuaki Hashiguchi from Daiwa. Thank you for taking my questions. I have two questions. My first question is on NHEART or NSCLC with the HAT2 mutation. It's encouraging data, I think, but in the previous presentation, asked for twenty twenty for cohort two before expansion in the same study. Median PFS was fourteen months and ORR was 62%. The data in the expansion cohort is really worse. What do you think about the reason? Well, the reason is that the prior data that we showed was what I would call immature data with a smaller sample size. And typically in a clinical trial as the data matures, these numbers, the progression free survival, for example, it will move around quite a bit. And so it is expected that oftentimes that progression free survival numbers, duration of response numbers will vary over time over the course of the clinical trial. Thank you. My second question is on DS-seven thousand three hundred. Which dose is tested in dose expansion part? I think we are still discussing that. So I don't know that we have anything to disclose to you today. But we can see that what we can see is that in the Phase I trial, we went to a very high dose of sixteen milligrams. And I'm not really sure that sixteen milligrams is really necessary because we can see activity of the drug get much lower doses. So we have a fairly wide range of doses to examine. Okay. Thank you. That's all. Thank you very much. Okay. Thank you for your questions. The next question is from Mr. Shinichiro Muraoka Please start your question. Hi, this is Shinichiro Muraoka of Morgan Stanley. Can you hear me? Yes. Great. Thank you. Congratulations for your great, great achievement of So my question first question is about DP-three. So twenty five months PFS is as you showed, so much longer than the clear particular first line data of project class asset in the past. So my question is about future Parzata, actually DB-nine study. According to clinicaltrials.gov, the study is ENHER2 combination with projector such a dosing design. So what's the dosage of NHAR2 in the DB-nine study? I think for first line real world use, so dose reduction or so less frequency would be I think necessary. So what's those are you you adopt? And what's the rationale behind? Could you share your view Yes. On We did conduct some early safety studies of the combination. And so we're using the dose based on that data and it is the standard dose. I'm sorry. So can you comment about that dosage is high lower than the So we are using the standard dose. Standard, so five point five, five point four mg. Yes, five point four mg. So you think the ILD risk is manageable with first line study, right? Well, yes, I mean we don't we have not seen the data yet. We can only speculate based on the data from the DB03 study which is the second line. I got it. And why don't you in the DB059 study why don't you incorporate the monotherapy of Enhert2 in the study? I think it's not included. Well, I think it really has to do with the study design and whether or not each arm contributes significantly to how we can interpret the clinical data. And at some point, having too many arms complicates things. And I think when the original study was designed, it was felt that having a single arm I mean a single agent arm, it may not be in the best interest of the patient, first of all. And second, that the key comparisons were the ones that are really what we're using now in 2021. Okay. I got it. And I know it looks it's a bad question about commercial sort of the results. So I know that it's not appropriate for you, but so given this impressive DVD03 data, I think the price of Enhedu can be raised or should be raised compared to the current start of Tandem therapy. You think it's worth ranging the price in The U. S. Or not? Well, I am the clinical development person, but I will certainly relay your comments to the commercial people. Great. Thank you. And finally about the study, so the data is quite impressive. But I want to I'm not sure whether physicians take hard to test or whether it will be penetrated into the long distance area. Now as you know, AGI test, PD L1 test, many ALK tests, many gene test is required for lung cancer area. So adding part two test for just for one percent or three percent, one or two percent of patients. Do you think it will take time for educating physicians or is it once after the approval, it will be to become the standard of care soon? Could you say that Okay. That's a good question. So it's it's always difficult to predict the behaviors of prescribing physicians. But, in lung cancer, this is one disease area where mutational analysis is essential part of clinical practice. Because we know now that, the few percent of the patients who have actionable genomic alterations or mutations that their treatments are substantially altered and affected by the results of the DNA analysis. And so analysis of HER2 mutations for lung cancer patients, I think that it's probably, very easily adopted as standard practice because that's what lung cancer doctors do these days, look for many other genes besides just HER2 mutations. Okay. Great. Thank you very much. That's all. The next question is from Mr. Homi Shisakai at Credit Suisse. Please state your question. Good morning or good evening wherever you are. This is Himeyoshi from Credit Suisse. First of all, congratulations for great data setting and probably setting the new standard of therapy as far as PB3 is concerned. I have three follow-up questions. One is the AstraZeneca was highly praised of Daiichi Sankyo ADC technology. So do you think that this DB3 data driven by overwhelming efficacy from ADC technology. Is that your observation as well? That's my first question. Well, I think the answer is absolutely yes. A technology that's important. Right. So that could apply to other, obviously, ADC technologies. That's why Daiichi Sankyo is heavily invested right now. Yes. I mean we're using the basic the same basic technology for other ADCs besides Enhertu. Right. So I think it's very important to know for that. Yes. You updated the technology in your presentation. Thank you very much. The second question is more like a translational research side. Could you say highly expressing HER2 cells in HER2 low tumor? That could probably drive or getting benefit for some patient in HER2 low expression tumors. I'm not talking about just a breast or lung or you know tumors in general. So the question is whether or not in HER2 low patients that there may be some Yes, HER2 low patients having CAR T2, highly expressed CAR T2 among CAR T2 row patient that can be found. And if it can be found, Yes. Then that could drive the benefit for at least could apply probably DB3 data. Yes. Think that's a possibility. You know, I don't think we have looked into this in great detail. But as you know, as you point out, patients with HER2 low disease, if you actually look at the microscope, there is some heterogeneity in the level of expression of HER two. It's not it's not uniformly low or the tongue. There are patients who have these scattered cells that are very highly positive for HER2 as you mentioned. And perhaps it's those patients that have derived greater benefit. I don't think we have enough data to notice. Think once you complete the trial of the HER2 low patient then I think we're in a better position to understand. Okay. So that's next year, right? Yes, next year. Yes. Third question, the safety side. I know that IRD may not be as big issue as it used to be, but still I think you're having the IRD management protocol mediocre side probably. Can you lower this protocol given this dataset from DB3, Ramzi one? And my question is what about the early setting or not really early setting question from Bakkor, the adjuvant use. Can you see any prospect from this safety data? Well, others have pointed out the safety data for the DESTINY Breast three study is better than the what we have been reporting previously. Why is that? And I think they're really and we can only speculate, but the one reason, of course, could be that it's earlier launch of therapy. It also could be that we know much more about how to manage interstitial lung disease. And we have been able to incorporate the ILD management, details into our clinical trial protocols. So, whatever the reason, we know that, the IOD incidence is much less. And, of course, that is very important, as Jim pointed out, for earlier lines of therapy, adjuvant therapy, etcetera. So, yes, it's really our hope that in these earlier lines of therapy, ILD incidents will remain well. Okay. Very clear. Thank you very much. The next question is from Mr. Arai at B. O. B. Securities. Please state your question. Hi, this is Tatsuyuki speaking from B. O. B. Securities. Can you hear me? Yes. Thank you. My question is about your thought on the market side, how the market size could change in HER2 positive breast cancer? Second, why? Given the strong response rate and longer progression free survival duration, I think more patients will stay on the treatment in second line setting under Enhertu rather than it is now under Kadcyla. So could you share your thoughts on how the market size in second line could change after the approval of Enhertu? That is my first question. I can only speculate on what's going to happen in terms of physician prescribing behaviors. But because the data is so compelling, I think it's very likely that NHERT2 will become the standard of care in the second line patient population and replace TDM-one as a standard NK. I think you're also suggesting that for each patient, the duration of therapy is going to be longer with Enhertu than the TDM-one. And I think that's the correct observation. Okay. Could you give a number like the duration of like a treatment on average and in this new breast cancer suite? So I don't think we reported in our data set the duration of therapy. But what we did show was that the progression free survival was almost threefold increased compared to kidney and more. Okay. Thank you. Great. My second question is about the DS-ten sixty two ARPAN2 MOR-one study results for lung cancer with actionable gene mutation. It has shown a strong response rate for EGFR mutated lung cancer, although it has like the higher dose eight milligram per kilogram has some safety concerns related to ILD. So could you share your expectation on the development strategy of this drug in this EGFR mutant lung cancer? You have a U3-fourteen zero 2 in this indication and I think you need to see data more closely in middle dose sixty milligram per kilogram in the future in order to see like risk benefit profile of the drug. But yes, anyway, could you share your Yes. Think your observation is correct. We're very encouraged by the activity of data DXT in EGFR mutated patients, but we just need to feel a little bit more work on it. Okay. Good. Thank you. The next question is from Mr. Please start your question. Hi, good morning. This is Naveen Mura from Jefferies Tokyo. Thank you very much for taking my questions. I have one question on the Page 34 for the Enhance Group read adjusted 91. In the prior treatment received, sub analysis group, total base therapy and anti PD-one hundred eighty one therapy has shown better or out other cases. So from the scientific perspective, what do think this is the kind of the any benefit with using with PD-one hundred one service for how to mutate this disease or this is possible to be shown in the other tumor types like breast cancers or gastric cancers. Okay. So I think you're referring to the fact that the response rate was a little bit higher in patients who had the anti PD-one therapy, correct? Yes. Okay. These are kind of small patient numbers and I'm not completely sure that this is a true increase in the response rate. You know, the 95% confidence interval, there's quite a bit of overlap between 64.953.5%. And so is there a true difference or not? I don't know. But if there is indeed a difference and that response rate is higher, I mean, could be certainly that the prior PD L1 or PD-one therapy has resulted in a better immune environment such that when the patient is treated with an ADC like TDXD, there is a release of some tumor antigens resulting in, eliciting of some antitumor immune response. Maybe that is the reason why the response rate is higher. I think it's a little bit too early to speculate definitively on these sorts of matters. Just we just need a little bit more patient numbers to know for sure if prior treatment with the PD-one agent makes a difference. Okay. Thank you very much. The next question is from Mr. Hidemaru Yamaguchi at Citigroup. Start your question. Once again from Yamaguchi. Can I add one more additional question, if I may? Hello? Yes. Okay. Great. Thank you. So it's a little bit different question, but I just asked because of so called the NCCN guidelines on the metastatic breast cancer, so called category of evidence wise. As of today, EHA2 is the 2A grade or tucatinib had one at this moment. Given this Phase III study, which is the second line, but it did show a very robust data rather than our data where you get the first indication. Is it fair to say that you get changes in structural evidence from 02/2021 or even before filing or getting approval, is there any chance this regimen will be categorized as the second line? Two questions at the same time. Thank you. I don't want to make any statements on behalf of the NCCN. It is really up to them to review any clinical data and make their own judgment. But as you know, sometimes they can make a decision before the FDA does or sometimes around the same time or sometimes later. I know it's a very different time line for both FDA and NCCN. Okay. So it's moving a different way, right? Well, of course, it's a different group of people reviewing the data. Yes, yes, yes. So in a sense that it's nearly nothing up to you to communicate with them rather they're trying to explore the data and decide by themselves other guideline. Is that the way how it works? Yes. Sometimes they do ask the sponsor to provide some data for Yes. Them to That's what happens quite frequently. Okay. Thank you. The next question is from Mr. Steven at Jefferies. Please state your question. Yes, Steve Bajka from Jefferies. Thanks for taking my question. My question is about the performance of the linker in the tumor microenvironment. It seems that that's one of the key reasons why Enhertu works so well. You get the disassociation between the toxic compound and the antibody. I was just wondering if the microenvironment is the same across different tumor types from breast to lung? Any comments on that would be appreciated. Okay. So I don't think I can comment on this as in the biochemistry of the tumor microenvironment. I don't think I'm the right person. I think you're probably correct also, however, that the microenvironment is not the same in every patient. So there's going to be some heterogeneity for sure. Do you think that's going to have a be a factor in how, ANTO-two performs across different tumor types? You know, I guess the possibility does exist, although we can see with these waterfall blocks that the majority of patients do benefit with a tumor shrinkage from distant drug. I mean, for example, in this breast cancer study, the three study, the response rate was about eighty percent. So does that really mean that the microenvironment was the same? Or was it heterogeneous but but still good enough for the drug to get in there and do its job. It's kind of a speculation. Understood. Thank you. If you have a question, please press As there are no more questions, we will close the Q and A session. Okay. Well, thank you very much. And we'd like to close today's conference call. So ladies and gentlemen, thank you very much again for your interest and participation. Stay safe and healthy everyone. Good bye. This is the end of the call. Thank you for your participation.