Thank you for waiting. We are now ready to start Daiichi Sankyo's conference call to present ESMO 2021 highlights. Please note that today's call will be recorded, and the language of today's presentation and Q&A is English. Dr. 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 Takeshita, Global Head of R&D at Daiichi Sankyo. Welcome to our conference call to present our ESMO 2021 highlights. I'm going to follow the slide deck that you have in front of you. Slide number two is our usual statements and disclaimers. We'll go on to slide number three, and then four. The three represent our agenda for today. I will give you the introduction, followed by highlights, and the actual ESMO presentation from three clinical trials that we would like to highlight. Then, of course, there is a very lengthy appendix you have in front of you at the end. Slide number four. We want to emphasize here today that this year's ESMO marks a major turning point in Daiichi Sankyo's 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-7300 program, which is the fourth DXd ADC in the clinic. These data really show this growing leadership of Daiichi Sankyo to create transformative medicine, and really also demonstrate the strength of our ADC technology across multiple cancers and also, of course, across multiple ADCs. Now we're going to go to the highlights for ESMO, starting with slide number six. Just a brief summary of these four late-breaking presentations. The first one is the ENHERTU DESTINY-Breast03 clinical trial. This is a phase III randomized clinical trial in the second-line setting for HER2-positive breast cancer. This was the first late-breaking presentation in a presidential symposium, and as such, 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 ENHERTU compared to another ADC called T-DM1. The data show the unprecedented, highly statistically significant, and clinically meaningful improvement in progression-free survival. These data provide definitive data for ENHERTU to become the new standard of care in the second-line HER2-positive breast cancer patients, 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-positive breast cancer. Again, a paradigm shift in the treatment of HER2-positive breast cancer. Next one, on slide number seven, is the ENHERTU clinical trial again, but in a different disease, called DESTINY-Lung01. This is a single-arm phase II clinical trial of patients with non-small cell lung cancer with HER2 gene mutations. We were able to show very good response rates and durable responses in patients with these HER2 gene-mutated non-small cell lung cancer. This is very important because currently, there are no drugs specifically approved for these particular groups of patients. 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. Again, here, ENHERTU has the potential now to transform patient outcomes in these patients with HER2-mutated non-small cell lung cancer. Now this really demonstrates that ENHERTU 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 8. Just want to very briefly mention the two other late-breaking presentations. One was the ENHERTU DESTINY-Gastric02 clinical trial. This was a single-arm phase II trial involving Western patients treated with ENHERTU, which showed very impressive and durable tumor responses, very similar to the original DESTINY-Gastric01 data that was principally conducted in patients who were in Asia. This new study, DESTINY-Gastric02, allowed us to confirm that the activity seen in Asian patients, it also applies to Western patients. Finally, the fourth late-breaking presentation, the Dato-DXd TROPION-PanTumor01. This is not ENHERTU, but the DS-1062 program, in which Trop2 is the target and not HER2. Subgroup analysis of this clinical trial in non-small cell lung cancer patients with actionable genomic alterations, AGA, showed encouraging efficacy, again, gaining a lot of confidence for us in the development of this agent in the AGA population in lung cancer. Finally, in slide nine, we did present very brand-new data in a brand-new ADC called DS-7300. This was a phase I/II study in solid tumors, in which DS-7300 was studied. DS-7300 is directed against an antigen called B7-H3. Currently, there are no B7-H3-directed therapies, and DS-7300 showed very promising clinical data in patients with several types of advanced solid tumors that we'll get to a little bit later, as well as a very good safety profile. We're very hopeful that DS-7300 will follow the footsteps of its older siblings and provide new effective treatment strategy across several types of cancers. This, again, is a demonstration, not just of DS-7300 itself, but really the underlying ADC technology that we have at Daiichi Sankyo in the area of the antibody-drug conjugates. Slide number 10, just to summarize here that we had 18 abstracts that were released at ESMO, and we have included the full slide decks in appendix on all the presentations that we made. 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. ENHERTU DESTINY-Breast03, phase III data, the DESTINY-Lung01 phase II clinical trial data, and finally, the DS-7300 phase I/II clinical data. Now let's now skip on to slide number 12. The first clinical trial that I will present today is DESTINY-Breast03. This is a randomized phase III study in which trastuzumab deruxtecan, T-DXd, is compared against T-DM1, another ADC. T-DM1, as you know, is the 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 left is from Daiichi Sankyo, and of course, one on the right is from Roche/ Genentech, and it is the current standard of care. 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, the trastuzumab deruxtecan, the T-DXd, has a topoisomerase I inhibitor, compared to T-DM1, which is an anti-microtubule agent as the payload. The antibody-drug ratio is quite different. You also see that with T-DXd, there's an average of eight of these payloads per antibody molecule, compared to 3.5 for T-DM1. T-DXd 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. 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 cell can also be killed by bystander anti-tumor effects, in which the payload is released, passes through the cell membrane to the neighboring tumor cells. These are very important engineering advances that were made in T-DXd. Slide number 14 shows the general study design for DESTINY-Breast03 study. It's a randomized study for patients with metastatic HER2-positive breast cancer, previously treated with a trastuzumab and taxane. The patients are randomized one-to-one to T-DXd or T-DM1. The primary endpoint was progression-free survival, and the key secondary endpoint is overall survival. What we are showing today is the interim analysis for progression-free survival, the data cutoff of May 21, 2021. 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 pre-specified p-value, had to be less than 0.000265. We chose that number because it was an interim analysis. You'll see that the p-value for overall survival did not quite make this boundary. You'll see, of course, that the boundary for progression-free survival far exceeded the p-value boundary set forth in the original statistical analysis. Patient disposition is shown in slide number 15. There were 699 patients screened, of which randomized patients 524, 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 an even split between the two arms, whether it's the region, HER2 status, ECOG performance status, hormone receptor status, et cetera, brain metastases and visceral metastases. In terms of prior therapy, again, the two arms are evenly split between the two. 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. Slide 18 is really the key slide. This is really impressive separation of the two curves for the progression-free survival. You will see that the hazard ratio is 0.28. p-value is zero followed by 22 zeros and 78. It is an incredibly impressive hazard ratio and an equally impressive p-value. You can see that the progression-free survival in the control arm was 6.8 months, has not yet been reached for the experimental arm, the T-DXd arm. Slide 19 shows that progression-free survival analysis in key subgroups. You will see that in every single subgroup analyzed, the hazard ratio is far to the left, indicating a tremendous benefit in every single subgroup category that we have studied and analyzed. Slide 20 is the overall survival data. You can see that the hazard ratio is at 0.56 with a p-value that is quite small, 0.007. As I mentioned, the pre-specified boundary for overall survival was, as listed at the bottom here, 0.000265. 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. Okay. Here are some additional information of interest. The response rates, you can see that the response rate was 79.7% in the T-DXd arm, compared to 34% in the T-DM1 control arm. It's very notable that the CR rate, complete remission rate, was 16.1. These are patients who are really disease-free, no evidence of disease, 16% in the T-DXd arm. Okay. 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. Approximately the same between the two arms. On slide 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 the T-DXd if we look at any grade toxicity. When we look at Grade 3 and worse, I think the numbers are quite acceptable and certainly justifying the risk-benefit for T-DXd in this clinical trial. You'll see that most of the drug-related TEAEs are either gastrointestinal or hematological in nature. Slide 24 shows two adverse events of special interest. One is drug-related ILD, interstitial lung disease. You'll see here that in the T-DXd arm. The incidence was 10.5% for any Grade ILD. More importantly, I think it is very notable that most of the ILDs were Grade 1 and Grade 2, and we did not see any Grade 4 or Grade 5. In contrast, in the T-DM1 arm, the incidence of ILD was 1.9%. In terms of left ventricular ejection fraction decrease, very few patients show the decrease in LVEF, 2.7% in the T-DXd arm and 0.4% in the T-DM1 arm, and none of them were Grade 3 or worse. Only Grade 1 and Grade 2. In conclusion, this is first randomized phase III clinical trial in breast cancer for T-DXd. We demonstrate highly clinically meaningful and statistically significant improvement in PFS compared to the current ADC standard of care, T-DM1. PFS hazard ratio of 0.28 with a very, very small P value, consistent benefits in all patient subgroups. Of course, encouraging overall survival trend. Safety profile that looked quite good, and these data really support T-DXd becoming the standard of care for second-line HER2-positive breast cancer. Slide number 26 shows the next steps for this clinical trial. We were granted the RTOR by the FDA back in August of this year. Of course, we have much more confidence now in our other clinical trials in which ENHERTU is being studied in HER2-positive breast cancer. Breast-09 study and the Breast-05 study. These are ongoing study, which we hope to report sometime in the future. The next clinical trial that we want to highlight is DESTINY-Lung01 study. This is a phase II trial of T-DXd again, but in a different disease, HER2-mutated metastatic non-small cell lung cancer. Okay. The HER2 mutations are seen in about 3% of non-squamous non-small cell lung cancer. Currently, there are no approved HER2-targeted therapies for patients with this disease. Because T-DXd is a HER2 targeting agent, we were very interested, of course, in studying ENHERTU in patients with HER2-mutated non-small cell lung cancer. These are the data that we are about to see. DESTINY-Lung01 study has several different cohorts. There were the HER2 overexpressing Cohort 1 and Cohort 1A, and the HER2-mutated cohorts, which are called Cohort 2 and Cohort 3 expansion. Cohort 2 studied a dose of 6.4 mg, two, three weeks, whereas the Cohort 1 studied two different doses of 6.4 mg and 5.4 mg every three weeks. The primary endpoint was response rate. Now we're going to focus really on the Cohort 2, which are the HER2-mutated cohorts. There were a total of 91 patients, as you can see on slide number 30 now. 91 patients, 34% were Asian, 44% were Caucasian, and this was a clinical trial conducted in Asia, Europe, and North America. You can see this, the majority of the patients had a kinase domain mutation. In terms of prior therapies, the median number of prior therapy was two, so these are really third-line patients. Most of the patients had been treated with a platinum agent and a checkpoint inhibitor, namely an anti-PD-1 or PD-L1 agent. Okay. Slide number 32 shows the overall response rate of 54.9%, which is, of course, a very high number, including 1.1% of the patients who had a complete remission, 63.8% with a partial remission. The median duration of response was 9.3 months. Slide number 33 shows the classical waterfall plot. You can see that the majority of the patients had the tumor shrinkage experienced. Down below on the lower half are the details of the kind of mutation that the patients had. There's a lot of detail in here, really a take-home message here is that ENHERTU appears to be quite effective in any kind of mutation, whether it's an exon mutations or gene amplifications, which is very encouraging for these patients with many different types of gene alterations of the HER2 gene. Okay. You can see here again that in terms of efficacy analysis by subgroup, you'll see that the brain metastasis 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 53.5% response rate. Those who had the platinum plus an anti-PD-L1 still had a very high response rate, about 64.9%. Those patients who had asymptomatic CNS metastases at baseline did just as well as those who had no CNS metastases. 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 now. These are really amazingly durable responses. Okay, slide number 36 shows the progression-free survival curve and overall survival curve. You can see the median progression-free survival of eight months and median overall survival of 17.8 months. These are quite encouraging because these are really third-line patients who had exhausted standard of care treatment for their disease. 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 TEAE, 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 3 adverse events, the most frequent Grade 3 adverse event was neutropenia. In terms of the drug-related interstitial lung disease, what was reported in this clinical trial was that 26.4% of the patients experienced drug-related ILD. Some of the details are shown here in terms of the time to onset of 141 days, median duration of 43 days. 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. Finally, the conclusion for this slide is in slide number 40. T-DXd demonstrated robust and durable anti-cancer activity in patients with previously treated HER2 gene-mutated non-small cell lung cancer. The efficacy of about 50% was consistently observed in every subtype of patients, including those patients with stable CNS metastases. 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. Most of the ILD cases were of low grade. Just a reminder that this data was generated with a 6.4 mg dose, and currently, the 5.4 mg dose is being explored in future studies to evaluate the optimal dosing regimen for these patients with HER2-mutated non-small cell lung cancer. For now, I think we can conclude that DESTINY-Lung01 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 cell lung cancer with the various health authorities. I would also like to note that we have a new study called the DESTINY-Lung01 study in the frontline setting for previously untreated patients with locally advanced or metastatic non-small cell lung cancer with the HER2 mutation. This is a randomized study against standard of care, which we just initiated, I believe it was last month. The next few slides are just a summary of the entire clinical development program for ENHERTU. I think this you have seen previously. There's really no change, really, in the breast cancer program. In the gastric cancer program, in the lung cancer program, there are two new studies that are shown with the white bars. One is called the Gastric06-China phase II study. This is really for registration in China. The DESTINY-Lung01 study I just mentioned, this is the randomized study comparing ENHERTU versus standard of care chemotherapy for patients with previously untreated HER2-gene mutated non-small cell lung cancer. We just initiated that very recently. Just to complete the picture, we do have other cancer indications that are being studied, colorectal cancer and other tumors. I don't have any new studies to report to you for today compared to our last update from ASCO. Okay. Finally, I would like to go over with you data from a brand-new ADC called DS-7300. This is the ADC directed against an antigen called B7-H3. Okay. Slide number 46 shows the background and rationale. B7-H3, also known as CD276, is a transmembrane protein that's overexpressed in various cancers, including lung cancer, prostate cancer, esophageal cancer, breast cancer, head neck cancer, et cetera. 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. 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. Data slide number 47, just a little bit on the background and the scientific rationale. It is an IgG1 directed against the B7-H3 with the standard payload of deruxtecan. The drug to antibody ratio is four drugs to one molecule of antibody. As with the ENHERTU and other ADCs, it has some of the features that we have engineered into the ADC, such as the stable linker payload, tumor selective cleavable linker, and the bystander anti-tumor effect. Slide number 48 is a schematic of our phase I study design. It was a dose escalation study studying various doses. You can see that we started at the 0.8 mg per kg, and we actually reached a very high dose of 16 mg per kg. Okay. We're really going to be reporting to you some of the early data from this clinical trial. Okay. 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 mg all the way up to 16 mg. You can see that so far, we have studied a total of 70 patients at various doses that are listed here with various different types of cancers. Slide number 50 is a summary of the overall safety divided by dose. You can see that, in general, there is a suggestion of a dose-dependent increase in the incidence of Grade 3 AEs, including couple of cases of ILD at the two highest doses, at the 12 mg and the 16 mg doses. The most common AEs are listed here. They were typically gastrointestinal, nausea, vomiting, decreased appetite, et cetera. These were really low grade, at Grade 1 or Grade 2. In terms of Grade 3 toxicities, the most frequent was anemia. Okay. Let's get to the sort of interesting part. The efficacy is shown on slide number 53. Of the 70 patients enrolled, there were 15 partial responders, which is quite encouraging, as well as, of course, the 32 patients with stable disease. Slide number 54 is a waterfall plot again showing activity of this agent in patients with really quite refractory cancers. We think that there is a very interesting pattern of responses in patients with small cell lung cancer and possibly prostate cancer. 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 the activity of this ADC will have in these other cancers besides small cell lung cancer and prostate cancer. Yes, conclusion for slide number 55. This is the first in-human trial of a single agent DS-7300, a novel ADC directed against B7-H3. We observed, of course, very encouraging partial responders, 15 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. Of course, we're not anywhere close to having a good look at other cancers either, such as the non-small cell lung cancer, breast cancer, et cetera. A lot of high hopes for this ADC. Okay. In conclusion, what I'd like to show here on slide 56 is that these are really evidence of a further maturation of Daiichi Sankyo's ADC program and really growing leadership in creating transformative medicines for patients with cancer. What is important here? First of all, we can see that the DESTINY-Breast03 study was a direct comparison, head-to-head against another ADC. 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 Daiichi Sankyo research labs, that really paid off. It's a confirmation of the technology we have here in Daiichi Sankyo to create new ADCs. I think that the second significance of this is that we're 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, B7-H3. It really, it's again a testament to the robust technology capabilities we have to create new ADCs beyond just the HER2 ADC. As noted on this slide, our entire R&D portfolio will be updated at the R&D Day on December 14th. Okay. That concludes my slide presentation. We'll stop here on the slides and go on to the questions and answer session. We will now start the Q&A session. When the operator calls your name, please give your name under your company name, then start your question. The first question is from Mr. Hidemaru Yamaguchi from Citigroup. Please start your question. Hi. Can you hear me? This is Yamaguchi from Citi. Yes. Great. Thank you. Thank you very much for your presentation. Quick question, first one, firstly on DB-03. You talk about some earlier discussion with the U.S. FDA, which was, I think it is called RTOR. Yeah. Can you remind me, what is the relationship with this event in August and the filing? The August conversation around RTOR was. Yeah What kind of a review process does the FDA wish to pursue? Real-Time Oncology Review is something new to the agency where they are willing to review dossiers as they become available from the sponsor. Right. It's a way to expedite the approval process, and we were granted that. It is a very fortunate thing, really for patients because they will very much likely get access to the drug much earlier than the usual FDA review process. Oh, I see. I'm kind of confused about it. It is given by the FDA in August, but then it doesn't mean you have a meeting in August. Rather, you have this RTOR pathway now. Yes. Well, yes, that's correct. Yeah, right. But [crosstalk]. It is filed? Yeah. I do want to make it clear that in August, the FDA did see the preliminary data. Right. From this clinical trial. That really resulted in a decision to grant us the RTOR. Right. This RTOR itself can give you approval. Yes. Some time? Yeah. Well, it is one step towards the submission. Yes. Sorry, it's before submission. Submission may happen. It is before submission. After RTOR [crosstalk]. Okay. Yes. The next event. Yes. Yes, that's correct. Next event will be the submission. Oh, I see. When do you think the 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, DB-03, is that its efficacy is really good. I've never seen. Two quick questions. What do you see? It's kind of your opinion, what do you see? Given this big difference between the T-DM1 and HER2 or T-DXd, including bystander effect, which was discussed at ESMO as well, do you see the chance to get the [adjuvant] data or even the first line, which is the earlier stage data, the probability of success within Daiichi Sankyo's projection is going to get higher given this better-than-expected data or it's not really changing? Oh, no, it is higher now. It's higher. of success is higher. Yes. Right. It's fair to say that the probability of success given this data may go up, right? Yes, that's right. Thank you. Finally, on the DB-03, ILD was also a discussion all the time, but this time there's a few, but the probability of happening is getting lower and lower, and especially on the high-grade, is getting low and there's no Grade 4 and Grade 5, which may be a good condition to go to the earlier line. It is also fair to say that, given this low risk of higher high-grade ILD, which gives you confidence to go for the earlier line, including, once again, the robust and also the first line. Yes, I think that's a good interpretation as well. Okay. Thank you. Quickly on the other two things. DS-7300, you selected three cancers, which, as we know, it's extraordinary or a preliminary cancer. At the same time, there's no overlap with your current other ADCs. I feel like there are some strategic selection on this one, even though there is a biological selection as well. Are you going to go for these three cancers, so-called to get your first market strategy, including ES or small cell, which there are not many drugs available, or it's really just a view of everything else? Well, first of all, the cancer that we chose to highlight here was not strategic. It was more data-driven. Right. biological. We just see the data and say, "Oh, this looks good. Right. As I said that we haven't really fully studied DS-7300 in other cancers like breast cancer, for example. Right. Other types of the non-small cell lung cancers. Right. Having said that, the data that we are seeing so far in some of these indications are very intriguing. Right. I don't think we have actually announced a formal pivotal registration program, but it is of course, certainly, on our mind. Right. It's also fair to say that you can plan some faster market, meaning no kind of ORR plus DOR to get the approval type of thing. Yes. coming out of these three cancers. Yes, absolutely. Okay. Sorry for that. Finally, ENHERTU lung, the data is still good, but you are changing your dosage. 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 dose change may have impact to filing or not, or not really, no? 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? Right. With the data that we will have in the future? Right. The data we have is still good for patients who don't have much other option than ultimately it's a risk-benefit analysis. It's really a judgment call about that. I think suffice it to say that we're discussing all these things through the regulatory agencies. Okay. Thank you. Thank you very much. Congratulations on the data. Thank you. Okay. Thank you. The next question is from Mr. Seiji Wakao at JP Morgan. Please start your question. Hello. This is Wakao from JP Morgan. Can you hear me? Yes. Thank you for taking my questions. I'm surprised that you have presented much through exciting data. My question, firstly, about DB-03. Especially about PFS. PFS by BICR was not reached. On the other hand, PFS assessed by investigators was 25 months. Did these results exceed your expectations, or were they in line with your expectations? Could you comment on this point, [Takeshita]? Are you asking about the difference between the two arms? No, the level of 25 months. I think it's very top line. First of all, there is always some difference between investigator-assessed progression-free survival and centrally reviewed progression-free survival. It's not a surprise that with centrally reviewed, it was not yet reached, and we have a number of 25 months with the investigator assessment. The fact that they don't exactly match, it's perfectly fine. It's often seen in clinical trials. In terms of the actual number of 25 months, which is quite long actually compared to the control arm, it's almost a three-fold improvement in the progression-free survival, if we just go by the investigator assessment of the progression-free survival. I think we all expected that ENHERTU would be superior to T-DM1, but I don't think anyone really expected that the difference would be so large in a three-fold increase. Okay. Thank you. Second about brain metastases. Efficacy was confirmed for patients with brain metastases in DB-03. 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 Pfizer in population with brain metastases. Do you think the data will be sufficient to grab the market share from Pfizer among population with brain metastases? Could you comment on this point? Yes. Let me just comment on this. In this clinical trial, the patients who were enrolled, they could have had brain metastases. Yeah. They had to have clinically stable, treated brain metastases. Okay, that's very important to note. Those patients who had clinical stable, treated brain metastases, for example, with a radiation therapy. You can see that in our data set, that those patients benefited just as well from the ENHERTU as the patients with no brain metastases. Okay. Next about DB-01. The efficacy of the drug was confirmed in patients with HER2 expression. What do you think is the mechanism behind this? I'd like to know if you have any implications for high load in breast cancer settings. Okay. The first question, I believe, was about patients who had HER2 gene mutations, but their HER2 expression was low. Is that correct? Yeah, that's right. Okay. 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 HER2 is high. It's more of that the mutation confers a signaling advantage, which doesn't always require high levels of protein expression. Okay. 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 like drugs, antibodies that are directed against a particular target. I think that the mutation itself, as opposed to the expression, is the more important parameter to look at. Okay. Okay. Now, 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 HER2 positivity is. This is the reason why we are very interested in a category of patients who have low levels of HER2 expression, but not zero, and to see whether or not ENHERTU is active in patients with low levels of HER2 expression. 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 near future. Okay. I understand. Last about DS-7300. Grade 5 ILDs at 16 mg per kg have been identified. Do you think this is simply a dose 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 it from my side. Thank you. Thank you for taking my question. Okay. Thank you very much for your questions. Thank you. The next question is from Mr. Kazuaki Hashiguchi at Daiwa Securities. Please start the question. Hello, I'm Kazuaki Hashiguchi from Daiwa. Thank you for taking my question. I have two questions. My first question is on ENHERTU for NSCLC with ERBB2 mutation. It's encouraging data, I think, but in the previous presentation in ASCO 2020 for Cohort 2, before expansion in the same study, median PFS was 14 months and the ORR was 62%. The data in the expansion cohort is a real loss. What do you think about the reason? The reason is that the prior data that we showed was what I would call immature data with a smaller sample size. Typically, in a clinical trial, as the data matures, these numbers, the progression-free survival, for example, it will move around quite a bit. It is expected that oftentimes, 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-7300. Which dose is tested in dose expansion part? I think we are still discussing that. I don't know that we have anything to disclose to you today. What we can say is that in the phase I trial, we went to a very high dose of 16 mg, and I'm not really sure that 16 mg is really necessary because we can see activity of the drug at much lower doses. 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 at Morgan Stanley. Please start your question. Hi, this is Shinichiro Muraoka of Morgan Stanley. Can you hear me? Yes. Oh, great. Thank you. Congratulations for your great achievement of DB-03. My first question is about DB-03. 25 months PFS is, as you showed, much longer than the CLEOPATRA first-line data of pertuzumab plus trastuzumab in the past. My question is about future first-line, actually DB-09 study. According to ClinicalTrials.gov, the study is ENHERTU combination with pertuzumab, such a dosing design. What's the dosage of ENHERTU in the DB-09 study? I think for first lines, real world use, so dose reduction or less frequency would be, I think, necessary. What dose do you adopt, and what's the rationale behind? Could you share your view? Oh, yes. We did conduct some early safety studies of the combination. We're using the dose based on that data, and it is the standard dose. I'm sorry. Can you comment about that dosage is lower than the. Oh, no. We are using the standard dose. Standard. So, 5.5mg, 5.4 mg? Yeah. Totally up. 5.4. Yeah. Do you think the ILD risk is manageable with first line study, right? Well, yes. I mean, we have not seen the data yet. We can only speculate based on the data from the DB-03 study, which is the second one. I got it. Why don't you, in the DB-09 first line study, why don't you incorporate the monotherapy of ENHERTU 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. At some point, having too many arms complicates things. I think when the original study was designed, it was felt that having a single-agent arm, it may not be in the best interest of the patients, first of all. Second, that the key comparisons were the ones that are really what we're using now in the phase III trial. Okay. I got it. It's about a question about the commercial side of it. I know that it's not appropriate for you. Given this impressive DB-03 data, I think the price of ENHERTU can be raised or should be raised compared to the current standard of therapy. Don't you think it's worth raising 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. Finally, about the DL-01 DESTINY-Lung01 study. The data is quite impressive. I'm not sure whether physicians take the ENHERTU test or whether it will be penetrated into the lung cancer area. Now, as you know, EGFR test, PD-L1 test, many ALK tests, many gene tests are required for lung cancer area. Adding ENHERTU test for just for 1% or 2% of patients, do you think it will take time for educating the physicians, or once after the approval, it will become the standard of care soon? Could you share your view? That's a good question. It's always difficult to predict the behaviors of prescribing physicians. In lung cancer, this is one disease area where mutational analysis is essential part of clinical practice. We know now that those few% of the patients who have actionable genomic alterations or mutations, that their treatments are substantially altered and affected by the results of these DNA analysis. 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. Fumiyoshi Sakai at Credit Suisse. Please start your question. Good morning or good evening, wherever you are. This is Fumiyoshi Sakai from Credit Suisse. First of all, congratulations for great data setting and probably setting a new standard of therapy as far as DB-03 is concerned. I have three follow-up questions. One is the AstraZeneca was highly praised of Daiichi Sankyo ADC technology. Do you think that this DB-03 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. It's the technology that's important. Right. That could apply to other, obviously, ADC technologies. That's where Daiichi Sankyo is heavily invested right now. Yes. We're using the same basic technology for other ADCs besides ENHERTU. Right. I think very important 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 tumors, that could probably drive or getting benefit for some patient in HER2 low expression tumors? I'm not talking about just breast or lung or tumors in general. The question is whether or not in HER2 low patients, there may be. Yes. HER2 low patients who are having highly expressing HER2 among. Yes. HER2 low patient. That can be found. Yes. Yes, that could drive the benefit for at least probably DB-03 data. Yes, I think that's a possibility. 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 HER2. It's not uniformly low all the time. 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 a greater benefit. I don't think we have enough data to notice. I think [crosstalk]. Yeah Once we complete the trial of the HER2-low patients, then I think we're in a better position to understand. Okay. That's next year, correct? Yes, next year. Yes. Third question, the safety side. I know the ILD may not be as big issue as it used to be, but still, I think you're having the ILD management protocol, mitigation side, probably. Can you lower this protocol given this data set from DB-03, ramucirumab? My question is, what about the early setting or not really early setting question from Buckhorn, the adjuvant use. Can you see any prospect from this safety data? Well, I think as others have pointed out, the safety data for the DESTINY-Breast03 study is better than what we have been reporting previously one year ago. I think, and we can only speculate, but the one reason, of course, could be that it's earlier lines of therapy. It also could be that we know much more about how to manage Interstitial Lung Disease. We have been able to incorporate the ILD management details into our clinical trial protocols. Whatever the reason, we know that the ILD incidence is much less, and of course, that is very important, as you point out, for earlier lines of therapy, adjuvant therapy, et cetera. Yes, it's really our hope that in these earlier lines of therapy, ILD incidence will remain low. Okay. Very clear. Thank you very much. The next question is from Mr. Tatsuyuki Arai at BofA Securities. Please start your question. Hi, this is Tatsuyuki speaking from BofA Securities. Can you hear me? Yes. Thank you. My question is about your thought on the market size, how the market size could change in HER2-positive breast cancer second line. 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. 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. Because the data is so compelling, I think it's very likely that ENHERTU will become the standard of care in the second-line patient population and replace T-DM1 as the standard of care. I think you're also suggesting that for each patient, the duration of therapy is going to be longer with ENHERTU than with T-DM1, and I think that's the correct observation. Okay. Could you give a number of the duration of a treatment on average and ENHERTU in this new DESTINY-Breast03 therapy? I don't think we reported in our data set the duration of therapy. What we did show was that the progression-free survival was almost threefold increased compared to T-DM1. Okay. Thank you. Yes. Great. My second question is about the DS-1062 TROPION-PanTumor01 study results for lung cancer with actionable gene mutation. It had shown a strong response rate for EGFR-mutated lung cancer. Although, like the higher dose, 8 mg per kg, has some safety concerns related to ILD. Could you share your expectation on the development strategy of this drug in this EGFR-mutated lung cancer? You have a U3-1402 in this indication, and I think you need to see data more closely in middle dose, 60 mg per kg in the future in order to see like the risk-benefit profile of the drug. Yeah, anyway, could you share your- Yes. Development strategy [crosstalk]. I think that's correct. Yeah. Yeah, I think your observation is correct. We're very encouraged by the activity of our Dato-DXd in EGFR mutated patients, but we just need to do a little bit more work on it. Okay, good. Thank you. The next question is from Mr. Naoya Miura at Jefferies Japan. Please start your question. Hi, good morning. This is Naoya Miura from Jefferies, Tokyo. Thank you very much for taking my questions. I have one question on page 34 for the ENHERTU for breast-adjusted 0.0. In the prior treatment received, a sub-analysis group, targeted therapy and anti-PD-1/L1 therapy had shown better ORR than other cases. From the scientific perspective, what do you think this is any benefit with using with PD-1/L1 therapy for HER2-mutant disease? Or is it possible to be shown in the other tumor types, like breast cancers or gastric cancers? I think you're referring to the fact that the response rate was a little bit higher in patients who had the anti-PD-1 therapy. Correct? Yes. Okay. These are kind of small patient numbers, I'm not completely sure that this is a true increase in the response rate. The 95% confidence interval, there's quite a bit of overlap between 64.9 and 53.5. Is there a true difference or not? I don't know. If there is indeed a difference and that the response rate is higher, it could be certainly that the prior PD-L1 or PD-1 therapy has resulted in a better immune environment, such that when the patient is treated with an ADC like T-DXd, there is a release of some tumor antigens, resulting in eliciting of some anti-tumor immune response. Maybe that is the reason why the response rate is higher. It's a little bit too early to speculate definitively on these sorts of matters. We just need a little bit more patient numbers to know for sure if prior treatment with a PD-1 agent makes a difference. Okay. Thank you very much. The next question is from Mr. Hidemaru Yamaguchi at Citigroup. Please start your question. Hi, once again from Yamaguchi. Can I add one more additional question, if I may? Hello? Yes. Okay, great. Thank you. It's a little bit different question, but I'll just ask because of so-called the NCCN guidelines on the metastatic breast cancer. Category of evidence-wise, as of today, ENHERTU is the 2A grade, where tucatinib had a 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 your first indication. It's fair to say that you can change this category evidence from Grade 2A to Grade 1, 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. 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 timeline for both FDA and the NCCN. Okay. It moves in a different way, right? Well, of course, it's a different group of people reviewing the data. Yeah. 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 as a guideline. Is that the way how it works? Yes. Sometimes they do ask the sponsor to provide some data. for them to review. Yes. Yes. Right That's what happens quite frequently. Okay. Thank you. The next question is from Mr. Stephen Barker at Jefferies Japan. Please start your question. Yes, Steve Barker 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. Thank you. Okay. I don't think I can comment on this, on 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. There's going to be some heterogeneity for sure. Do you think that's going to be a factor in how ENHERTU performs across different tumor types? I guess the possibility does exist. We can see with these waterfall plots that the majority of patients do benefit with a tumor shrinkage from just the drug. For example, in this breast cancer study, the DB-03 study, the response rate was about 88%. Does that really mean that the microenvironment was the same, or was it heterogeneous but still good enough for the drug to get in there and do its job? It's kind of a speculation. Understood. Thank you. As there are no more questions, we will close the Q&A session. Okay. Well, thank you very much. We'd like to close today's conference call. Ladies and gentlemen, thank you very much again for your interest and participation. Stay safe and healthy, everyone. Goodbye. This is the end of the call. Thank you for your participation.