I'd like to start Daiichi Sankyo's R&D Day. I'm Asakura from Corporate Communications Department. I will serve as emcee today. Let me explain the language for this meeting. We are going to use Japanese and English in this meeting. Simultaneous interpretation is available. Please click interpretation icon at the bottom of the Zoom screen. Select the language of your preference, Japanese, English, or off. If you select off, you will hear the original sound. On the Zoom screen, English presentation materials will be displayed, while in the live streaming, presentation materials in Japanese will be shown. Presentation materials in Japanese and English are posted on our corporate website under the IR Presentation Materials section in the IR Library. You can download the files if necessary. Four members are participating, as is shown on page three. President and CEO, Sunao Manabe. Head of Global R&D, Ken Takeshita. Head of Japan R&D, Wataru Takasaki. Mark Rutstein, who assumed the post of the Head of Global Oncology Development in October this year. Please provide a brief introduction of yourself to the audience. Hello, my name is Mark Rutstein. It's very nice to meet everybody. I've been at Daiichi Sankyo for less than two months. I have come from Bristol Myers Squibb, where I was leading the late-stage immuno-oncology program. I have nearly 20 years of oncology clinical development experience across the Amgen, Eli Lilly, Bayer, and Bristol Myers. It is my true pleasure to be here, and I look forward to working with many of you going forward. Thank you. Thank you, Mark. You can find today's agenda on page four. First, Manabe will give you opening remarks. Ken Takeshita will explain the clinical progress and R&D strategy. We will take your questions at the end. Please note that we are recording this meeting. Thank you for your understanding. Now we'd like to begin. Manabe-san, please. Manabe speaking. Thank you for joining Daiichi Sankyo's R&D Day today. I will talk about the progress of the five-year business plan, where we are now in its second year. Please turn to page five. This page shows the positioning of our group's five-year business plan for sustainable growth. During the course of this five-year business plan from FY 2021 through FY 2025, we will achieve our 2025 goal. Global pharma innovator with competitive advantage in oncology, and we'll shift to further growth towards our 2030 vision. Page six shows our strategic pillars for our five-year business plan. Our R&D capabilities are important in the first and the third strategic pillars. Firstly, to maximize 3 ADCs. We have been maximizing ENHERTU and Dato-DXd through strategic alliance with AstraZeneca and maximizing HER3-DXd without a partner. We will continue to expand workforce and supply capacity flexibly depending on changes around product potential. Secondly, to identify and build pillars for further growth. To promote sustainable growth during the course of the 5-year business plan, we will identify new growth drivers following 3 ADCs and select and advance promising post-DXd ADC modalities. Our initiatives planned for each strategy are making steady progress. We are very satisfied with the achievements so far. From page 7 and onwards, you can find the major progress since R&D Day 2021. First, about ENHERTU. We have been making steady progress in maximizing product value of ENHERTU. Based on the approval of new indications and strong market penetration, I'd like to mention three major achievements we have made since the R&D Day last year. The first point is the approval for HER2-positive breast cancer second-line. Based on DESTINY-Breast03 study, which showed unparalleled improvement in PSS compared to standard of care, Kadcyla T-DM1. HER2-positive breast cancer second-line was approved in May this year in the United States. We started promotion accordingly. ENHERTU has already established leadership in HER2-positive breast cancer in the second-line settings and beyond in the United States and expanding market to other countries and regions. Secondly, ENHERTU has pioneered HER2-low breast cancer as a new clinically meaningful patient segment. Based on DESTINY-Breast04 study-Which showed potential to transform treatment for HER2-low breast cancer patients. We obtained the approval for HER2-low breast cancer previously treated with chemotherapy in the United States. We started promotion in August 2022. In November, DESTINY-Breast04 study was selected as the Clinical Advance of the Year. A script award given to a clinical study which made the greatest contribution to the advance of healthcare. Previously, untargetable HER2-low breast cancer patients are known to account for approximately half of all breast cancer patients. In other words, the number is twice as much compared to that of HER2-positive breast cancer patients. We have been able to provide a new treatment option to more breast cancer patients, which is one of the major achievements in the current fiscal year. Right now, in the United States, there has been a rapid uptake for HER2-low breast cancer in the United States. We are aiming to accelerate market expansion to other countries and regions as well. Thirdly, our initiatives to expand leadership across other HER2 targetable tumors are also making steady progress. In August, ENHERTU was approved for HER2-mutant NSCLC second line and beyond based on DESTINY-Lung01 and DESTINY-Lung02 studies. We started promotion in August. ENHERTU was approved for the third cancer type, following breast cancer and gastric cancer. We will continue to aim for getting approval for earlier lines of therapy in these three tumor types. At the same time, we will aim to expand the indications other than those three so that we can maximize the product value of ENHERTU. Page eight shows the progress of Dato-DXd, HER3-DXd and Alpha. We are making steady progress in the development of growth drivers after ENHERTU. Regarding Dato-DXd and HER3-DXd, pivotal studies are on track, respectively. To further enhance product value, we also started three new phase III studies in the patient populations where we obtained promising data in phase I. We positioned two DXd ADCs, DS-7300 and DS-6000, as rising stars, as growth drivers following 3 ADCs. Development here is also making steady progress. We obtained data which showed early efficacy signals in multiple cancer types such as small cell lung cancer and ovarian cancer. For DS-7300, we started phase II study in extensive stage small cell lung cancer. Post-DXd ADC modalities are also making steady progress. For DS-5670 COVID-19 messenger RNA vaccine, primary endpoint was achieved in phase I, II, III study to evaluate the efficacy and safety of the booster vaccination in November. We are now preparing to file our submission. Development of other new modality is also making progress. Due to strategic reasons, we cannot disclose the details right now. We started phase I clinical study for the next generation ADC, DS-9606. Please turn to page nine. The value of 3 ADCs, including ENHERTU and the growth drivers following them, has been greatly enhanced over the past year. We are becoming more confident that we can achieve FY 2025 goal in the 5-year business plan. We will continue to take challenges so that we can provide our products to patients who need new treatment options earlier. That's all from me. I am handing over to Takeshita. Manabe-san, thank you very much. Let's go to the next slide here. We're going to go through the progress that we have made in various cancers. First, with breast cancer progress. Next slide, please. Probably one of the most important accomplishments from 2022 is shown on this slide. This photograph that you see on the upper right is the moment when the DESTINY-Breast04 data was presented at the ASCO 2022 plenary session. We received a standing ovation for our trial data because... receiving a standing ovation is rather unusual, even at ASCO, where many breakthroughs are being presented. I think personally, I have seen one of those standing ovations one or twice in my career. The reasons are, why was this so monumental accomplishment? It's because we created, with this clinical trial, a new patient segment which we call HER2-low. In these patients who are neither HER2 completely negative and neither also, HER2- positive. We studied ENHERTU in these patients with a low level expression of HER2, regardless of their hormone receptor status. You can see here that both progression-free survival and overall survival are quite positive in terms of hazard ratio and statistical significance. This was really probably for us, our number one accomplishment for 2022. The next slide shows you how this fits into the treatment paradigm. You'll see here that on the left-hand side, the old treatment thinking, in which the breast cancer patients were divided into HER2- positive, hormone receptor positive but HER2- negative, and both hormone receptor negative and HER2- negative, namely the triple-n egative breast cancer. What we have done here is that, among the patients who are hormone receptor positive and HER2- negative, this gray box, we have taken about 50% of the patients in that category and created a new category. Those patients are eligible now to receive ENHERTU because of the DESTINY-Breast04 data that we just talked about. This is first ever approval for HER2-low patient population, remarkably, we received approval within 11 days of filing acceptance under the FDA RTOR program. To give you an update on the regulatory submission status, we have filed in both Japan and Europe and in China, and we are awaiting regulatory action in those countries. Next slide. More recently, as recently as last week, we updated the field at the San Antonio Breast Cancer Conference. We presented 30 abstracts, including three oral presentations. Here are some highlights of our presentations at the San Antonio Conference. We presented overall survival data in DESTINY-Breast03 study. You're familiar with this as the one of our original DESTINY-Breast studies. In a new updated data, we show that the overall survival benefit is quite substantial and significant compared to control arm. Next, we showed brand-new data from a clinical trial called DESTINY-Breast02. This was a confirmatory study for our original registration trial, which was a single-arm phase II trial called DESTINY-Breast01. We also reported data on DXd breast cancer data from the TROPION-PanTumor01 trial, in which we reported the patients with hormone receptor positive, HER2-negative metastatic breast cancer. We also presented data on the durvalumab combination as part of the AstraZeneca-sponsored BEGONIA study. We'll get to these a little bit later, and some of the details here. Next slide. First, I'd like to go over with you the data from the DESTINY-Breast03 clinical trial. You'll remember that this was a clinical trial comparing T-DXd ENHERTU versus the old standard T-DM1. We updated the progression-free survival and overall survival, and these remain quite clinically meaningful, both progression-free survival and overall survival. For an statistically significant improvement in overall survival, compared to T-DM1. Next slide. In terms of safety, the mean and treatment duration was much longer in the T-DXd arm compared to the T-DM1 arm. The rates of grade 3 TEAEs were similar between the two arms. In terms of the most common drug-related TEAEs, in the T-DXd arm, it was pneumonitis and ILD. In the T-DM1 arm, it was cytopenias and pneumonitis. Specifically in terms of pneumonitis, we want to mention that the incidence of the pneumonitis and ILD were similar to other breast cancer trials with ENHERTU. With longer treatment exposure and follow-up, the ILD and pneumonitis rate increased from 10.5% in the PFS interim analysis to 15.2%. The overall incidence of grade 3 events was 0.8%, which was the same as the initial PFS interim analysis. There were no grade 3 or grade 4 or grade 5 drug-related events as per central blinded adjudication. Therefore, the updated results from DESTINY-Breast03 with longer follow-up further support the use of ENHERTU as the preferred second-line standard of care in patients who have HER2-positive breast cancer. Finally, I want to mention that the results of this study, this particular DB03 study, was published on the same day as at the San Antonio in the journal access. Next study is the DESTINY-Breast02 trial. This, as I mentioned earlier, this is a confirmatory study for our original DESTINY-Breast01 study, which was conducted in patients with relapsed metastatic HER2-positive breast cancer. Unlike the DESTINY-Breast01 study, which was the original breast registration study, DESTINY-Breast02 study is a randomized study comparing ENHERTU versus the control arm, which was investigator's choice. Here again, you'll see the substantial improvement and superiority of PFS and overall survival for the ENHERTU with a very good hazard ratio and the P value that are highly statistically significant. In terms of safety, there are no new safety signals. The safety was really consistent with what we already know about the safety of ENHERTU. The incidence of ILD in this study was 10.4% overall, and in terms of Grade 5 ILD events, it was 0.5% compared to our original DESTINY-Breast01 of 2.7%. We believe, of course, that this reduction in the incidence of grade 5 represents our improved understanding of how to detect ILD early and how to manage ILD early, so that these ILD events do not progress to grade 5, but they're caught early on at earlier stage at grade 1 or grade 2. Next slide. In, as a summary, in terms of breast cancer, we have a new standard of care in HER2-positive metastatic breast cancer, with breast cancer DESTINY-Breast03 study data and DESTINY-Breast02 data as well. Of course, at the San Antonio Conference, if you attended it, there was a lot of discussion about this new category of patients, HER2-low. As I mentioned earlier, this HER2-low patient population was really truly pioneered by DESTINY-Breast04 study. As of today, ENHERTU is the only drug that is indicated for this particular type of breast cancer, HER2-low metastatic breast cancer. Next slide. Okay, now we're gonna switch over to our Dato program. Dato is the ADC that is targeting TROP2. We reported at the San Antonio some results from TROPION-PanTumor01. Now, this is a multi-cohort clinical trial, at the San Antonio Conference, we presented data on one cohort of patients who were hormone receptor-positive and HER2-negative. You see there, based on this waterfall plot and the spider plots, you see the very encouraging and durable efficacy in patients with hormone receptor-positive, HER2-negative breast cancer patients. These are patients who previously received a median of five lines of treatment for metastatic disease. These are patients who are highly refractory to standard of care treatments. Response rate of 27% here is quite good. With a median progression-free survival measured at 8.3 months. In terms of safety, the, in this 41 patient data set, grade 3 and worse adverse events were seen in 41% of the patients. Most common adverse events were stomatitis and nausea. There were two patients who had pneumonitis, grade 1 in one patient and grade 3 in one patient. One patient was adjudicated as having grade 3 drug-related interstitial lung disease. Therefore, we concluded from these data that the Dato-DXd demonstrates encouraging efficacy and manageable safety profile to support its further development in breast cancer, including this clinical trial called TROPION-Breast01. This is a phase III randomized study being conducted in a second-line setting for hormone receptor-positive, HER2-negative breast cancer. Next slide. We previously reported on the Dato-DXd data in triple-negative breast cancer. This data here that was presented at San Antonio represents an update on that dataset. Again, we can see continued efficacy of data in this patient population. These are patients who had three prior metal ions for the treatment of their triple- negative breast cancer. Therefore, highly refractory patient population. In this patient population, the overall response rate was 32%. The median progression-free survival, 4.4 months. Overall survival, 13.5 months. The safety was quite good. Very similar pattern to the prior slide. The most common AEs being stomatitis, nausea, vomiting. At least in this patient cohort of 44 patients, there were no cases of ILD reported. Again, in a triple negative breast cancer, in this TROPION-PanTumor01 study, data continues to show good efficacy and safety profile. These data really support our ongoing phase III study of TROPION-Breast02 in the frontline setting for triple negative breast cancer. Next slide. Okay, this is the BEGONIA study. This is a clinical trial being conducted by AstraZeneca as a sponsor. This is a very interesting trial. It's a multi-cohort trial in which various combinations of drugs are tested in triple negative cancer, triple negative breast cancer. These are previously untreated or resectable metastatic patients. This is a very interesting cohort of patients who were treated with a combination of Dato-DXd and durvalumab. There's a confirmed response rate of 73.6%, including four patients who achieved a complete response. You'll see, based on the spider plots here, that responses appear to be quite durable in this patient population being treated with Dato-DXd and durvalumab. The most common AEs were nausea, stomatitis, and alopecia. There are patients who had the various grade 3 and worse treatment-related AEs, but including grade 1 adjudicated ILD and/or pneumonitis in two of these patients out of the total of 61 patients. On this data, we concluded that this combination of Dato-DXd plus durvalumab shows a compelling high response rate and a quite manageable safety profile in the frontline setting for TNBC, and that we're very interested in exploring this combination further in triple negative breast cancer. Next slide. What are we doing with this combination data? The durvalumab plus Dato-DXd. This is a new study that we're talking about here. This is called a TROPION-Breast03 study. This is a study being sponsored by AstraZeneca. This is a study in which patients who have residual disease after neoadjuvant chemotherapy is enrolled. It's a three-arm study, sample size a little bit over 1,000 patients. Here are the three arms. The control arm is investigator's choice of therapy. The second arm is Dato-DXd single agent. The third arm, of course, is our, the most interesting experimental arm here, which is the Dato-DXd plus durvalumab. You'll see the endpoints here, the primary endpoint being disease-free survival, secondary endpoint being disease-free survival, overall survival, et cetera, in the various comparisons of the three arms. This is, this was just posted on ClinicalTrials.gov about less than a few weeks ago. We are very interested in seeing this study enroll and, of course, seeing the results from this study. Okay, next slide. Just to summarize here, in terms of the Dato-DXd breast cancer program, we've seen that this drug is active in hormone receptor-positive, HER2-negative metastatic breast cancer. That really gives us more further confidence in the currently ongoing TROPION-Breast01 clinical trial. We continue to see durable anti-tumor activity in patients with previously treated triple-negative breast cancer. As you know, we have already been conducting a clinical trial, phase III trial of TROPION-Breast02 in triple-negative breast cancer. Finally, based on the BEGONIA data, this is a durvalumab plus a Dato-DXd combination for early triple-negative breast cancer. We have initiated a new trial, phase III trial called TROPION-Breast03. Next slide. In the next several slides, I'm going to be reviewing with you our progress in lung cancer. Next slide. First of all, I think you're aware already that ENHERTU has activity in lung cancer. ENHERTU mutated non-small cell lung cancer that has already been reported at ESMO and also in various journals. You'll see here the remarkable waterfall plot here showing a response rate that's quite remarkable, around 58%. The duration of the response was 8.7 months. The safety of this drug in lung cancer patients with this ENHERTU mutated non-small cell lung cancer was quite good and consistent with what we know about the safety profile of ENHERTU in breast cancer patients, in terms of things like the incidence of ILD and other adverse events. The next slide. Okay, in terms of what we, what we have accomplished in terms of for the lung cancer program, many of you are aware that we received previously a Breakthrough Therapy Designation from the FDA for ENHERTU in ENHERTU mutated non-small cell lung cancer. We've received already approval for ENHERTU at this dose that's mentioned here, 5.4 mg per kg dose. At the same time, we also received a FDA approval for new companion diagnostics, both tissue and liquid biopsy tests for ENHERTU mutated non-small cell lung cancer. We have also. This is a U.S. status. We have also submitted the same dataset to other agencies, notably in Japan and we also plan to do a submission in Europe. In addition, I want to mention here that we have additional clinical trials going on, DESTINY-Lung04 and 05 in HER2 mutated non-small cell lung cancer in the front line setting for the 04 study and the second line setting for the 05 study going on in China. This is a very important study and a very important program for ENHERTU, particularly because it's a brand-new indication beyond the gastric cancer and breast cancer that we already have indications for. Okay, next slide. Now we're going to switch over to the Dato-DXd program in lung cancer. This we presented earlier this year at the World Conference on Lung Cancer, the data from TROPION-Lung02 study. In this interim analysis, you'll see a good activity of both a doublet and a triplet in these patients within the front line setting. By doublet here, we're talking about the Dato plus pembro combination. Triplet here refers to the Dato plus pembro, pembrolizumab plus a platinum. Both seem to be quite active. The response rate was 62% with the doublet and 50% with the triplet. These are, of course, our sample size is quite small, so the confidence in interval is quite large. You'll see that probably, perhaps approximately the doublet and triplet response rates are quite similar. In terms of treatment-related AEs, we saw a grade 3 and worse AEs in about 35% of the patients receiving a doublet and 54% of the patients receiving a triplet. Of course, because we do expect to see more adverse events in patients getting a triplet due to the addition of the platinum agent. Most frequent AEs were stomatitis and nausea. This is very encouraging data for us because it really tells us that this combination of Dato-DXd plus a checkpoint inhibitor, namely pembrolizumab, it is quite active and the responses appear to be quite durable. Next slide. Based on these data, we have initiated the two very important large clinical trials. These are both intended to be registration trials. The first one is the TROPION-Lung07 trial. This is a patient population who have non-small cell lung cancer, whose PD-L1 status is less than 50% by staining. In those patients, as you are aware, the standard of care treatment currently is a pembrolizumab plus multi-agent chemotherapy, typically pemetrexed and a platinum. In TROPION-Lung07, that is the control arm C. There are two experimental arms. Representing the two types of combinations that we studied earlier in the previous slide. Arm B is the doublet and arm A is the triplet. Arm B is a doublet of the Dato-DXd plus pembrolizumab, and arm A is the triplet that adds a platinum to the pembrolizumab Dato-DXd doublet. The second trial is the other half of the patient population not covered by the upper study, the Lung-07 study. In TROPION-Lung08, we are studying patients whose PD-L1 status is 50% or greater. In those patients, currently, the standard of care is pembrolizumab monotherapy. In this study, in TROPION-Lung08, the experimental arm is pembrolizumab plus Dato-DXd. Both of these studies are ongoing now, and we are very excited about both of these studies, and we anticipate seeing the data in the near future. Next slide. I just want to summarize here our, the status of our lung cancer program. We have approval for ENHERTU in the HER2-mutated non-small cell lung cancer in the second line and worse. We have now initiated a randomized phase III study of DESTINY-Lung04. This is an ENHERTU program in the front-line setting in patients who have HER2-mutated non-small cell lung cancer. Our Dato program remains one of the most important clinical trial program for lung cancer. We have two important clinical trials, TROPION-Lung07 and 08. In addition, we are still continuing with the TROPION-Lung01 randomized phase III study. This is in the second and third-line setting, unlike the TROPION-Lung07 and 08, which are in the front-line settings. Finally, we did not give any recent data updates on our HER3 program, but we did initiate a new phase III trial of HER3-DXd, the phase III trial, HERTHENA-Lung02, in August of this year. These are for patients who have EGFR-mutated non-small cell lung cancer. Next slide. Okay, now in the next few slides, I'm going to go over with you some new ADCs that you may not have heard about. The rising stars. These represent the new DXd ADCs, and we also have some hematology data to show you. Next slide. First one is DS-7300. The target here is an antigen called B7-H3. This is a rather ubiquitously expressed tumor antigen. We initiated quite a while, some time ago, phase III, phase I and II clinical trial of DS-7300. Most recently at ESMO, we reported on some data on SCLC, which I will go over with you a little bit later. On the right-hand side of the slide here, DS-6000. This is yet another DXd ADC program. The target is CDH6, Cadherin-6. Unlike B7-H3, which is, as I said, is widely expressed in many cancer types, Cadherin-6 is restricted mostly to ovarian cancer and renal cell cancer, so we are focusing our efforts initially on those cancers. Next slide. In terms of 7300, here's some data and across all different cancers that we studied and at various different doses that we studied. You'll see all kinds of the study, all kinds of indications, all kinds of patients who are enrolled in this study. At least looking at the waterfall plot, you can see that this drug is quite active in this patient population of various refractory cancers. Response rate was 28%. Most common AEs were cytopenias and some GI symptoms. There was some drug-related ILD and pneumonitis reported. Next slide. This slide shows a close-up of the data in some interesting patient populations indications. First is SCLC, small cell lung cancer. You'll see here that as of today, in this slide, the response rate here is 53% in this patient population with refractory small cell lung cancer. The duration of response is 5.5 months. We think that this is a very good data so far, and we are pursuing further development of DS-7300 in small cell lung cancer. Next is metastatic castration-resistant prostate cancer. Here you see a response rate of 28%. You'll see in the earlier slide, sorry, that in addition, although not shown in this slide, we are seeing an additional activity of DS-7300 in esophageal squamous cell cancer as well as the squamous type non-small cell lung cancer. These are very encouraging data for DS-7300 program, we are accelerating our development of this drug in small cell lung cancer as well as other cancer types. Next slide. For the DS-6000 program, as I mentioned, we're focusing on ovarian cancer and renal cell carcinoma. So far we are still, you know, we're still in the early stage of the phase I program, but we are starting to see already a definite signal in ovarian cancer. Even if we take into account the lower doses, you can see that about five out of 15 patients with ovarian cancer showed a response. Very encouraging, particularly at these higher doses, the response rate and also CA-125 reduction is quite high. We think that we can pursue ovarian cancer further in this program. Of course, we are still waiting to have enough renal cell carcinoma patients to make a decision there. You can see that with these two new DXd ADCs, there's quite promising clinical activity and we are pursuing a registration path for those two new DXd ADCs. Next slide. We're going to now switch over to our hematologic malignancy program. The first one is quizartinib and the second one is EZH program. This slide shows our quizartinib program. We just, this data was presented at the Presidential Symposium of the European Hematology Association. As you'll see that in this clinical trial, the randomized study of chemotherapy plus or minus quizartinib, there's a clear difference in the overall survival curve with hazard ratio as shown there of 0.77 and a P value of 0.03. We're very excited about this data. The data, the overall survival improvement is clinically meaningful. We have submitted an NDA based on this data to both FDA, EMA and the Japan regulatory agencies. Next slide. This slide shows that we achieved our first approval for this drug called valemetostat, also known as EZHARMIA. This is EZH1 and EZH2 dual inhibitor, and we received in Japan an approval for adult T-cell leukemia/lymphoma. There is remarkable activity here, with a high response rate of 48%, including 20% response rate in this patient population, which is generally considered to be quite refractory. In addition to this ATLL program, we have ongoing clinical trials in other T-cell lymphomas and other B-cell lymphomas, as well as in solid tumors. We are very excited about this drug. What's shown here really represents only our very first step in what we hope will be many steps and many approvals in many different indications for this drug. Next slide. The summary for these rising stars, the next generation ADCs, DXd ADCs and our hematology program, we want to accelerate the development of DS-7300, in particularly with respect to small cell lung cancer. We're very interested in the 6000 program in ovarian cancer right now, especially. We are waiting for the regulatory approval of quizartinib for the frontline setting for acute myelogenous leukemia. We hope to see that sometime in the first half of next year. In terms of the valemetostat program, we received already one approval for a small indication in Japan, and we're continuing to develop this further in other broader indications. Next slide. Okay, now, in terms of the next few slides, I'm going to go over with you how we think about the remainder of the pipeline. Next slide. Currently, as you just heard, we have five DXd ADCs that are very active in lung cancer, breast cancer and many other solid tumors. What is our plan for the future for the next five, 10+ years? That's what I'm going to go over with you in the next few slides. Basically, here's what we want to do. In addition to breast cancer and lung cancer, we want to study many other cancers with unmet medical needs. Really expansion of indications beyond lung and breast. In lung cancer and breast cancer, we want to expand our indications in those diseases into earlier lines of therapy. In terms of extending the use of ENHERTU, Dato and others, you'll see that, as illustrated on this slide on the right-hand side, we have other ADCs coming later on. Not just the DS-7300 and DS-6000, but DS-3939 and other next generation ADCs. These will contribute to the extension of our DXd ADC program for the next many years to come. We are also quite interested in having a good look at our existing research pipeline assets to see how we may combine them with existing DXd ADCs. Thereby, again, also giving us an opportunity to extend our presence in lung cancer, breast cancer and other solid tumors. Okay, next slide. In summary, here's our breast cancer strategy. We want to build on our leadership in breast cancer. You can see here now that ENHERTU is going to become a very important drug for many patients with breast cancer. We see that as an opportunity to provide not just a foundational treatment, not only in the refractory setting, but in earlier lines of therapy. Also as the base to study combinations of ENHERTU with other compounds that we have in our pipeline. Because we have been conducting a lot of clinical trials, we are starting to really understand the biology of these HER2-low and HER2-negative breast cancers and how they respond to various DXd ADCs we have. We can start to understand how to rationally develop and design new drugs in patients who are no longer benefiting from DXd ADCs. Next slide. Next slide is a summary of how we think about the entire picture of breast cancer. You see that currently we have two major drugs, ENHERTU, and that's also illustrated here in orange color, and also DXd ADC, that's illustrated in blue. Between the blue and the orange colors, you can see that most patient populations in breast cancers are covered by the existing clinical trials and also some thinking about earlier stage clinical trials that are under discussion. Finally, I want very much to also mention here that to the far right here, where it says p ost ENHERTU space. This is a very important strategic patient population, patients who are no longer benefiting from ENHERTU or Dato. How can we help them? As I mentioned to you, we have many next generation ADCs and other assets that we can use to test whether or not they have activity in this post ENHERTU patient population. Next slide. Here's a summary of our lung cancer strategy. Currently, we have already one approval for ENHERTU in the HER2 mutated patient population. We are working on the HER3 ADC by focusing on the EGFR mutated non-small cell lung cancer patient population. Most importantly, the Dato-DXd program. This is our major program in lung cancer for both the PD-L1 positive and PD-L1 negative patient populations. The TROPION-Lung07 and TROPION-Lung08, these two studies cover the majority of patients with non-small cell lung cancer, and we're very excited about seeing the data on those two clinical trials in the near future. Finally, I want to remember to mention that we think we now have a drug that we can develop in small cell lung cancer, namely DS-7300. Next slide. Next slide shows how we think about the entire world of lung cancer. In terms of non-small cell lung cancer, those patients with actionable genomic mutations. If they have a HER2 mutation, then ENHERTU is going to be our drug to develop. If they have an EGFR mutation, then it's going to be HER3-DXd that we will further develop in these patients with EGFR mutated lung cancer. For the non-actionable genomic mutation patients, Dato-DXd represents our thinking about how we can help these patients. TROPION-Lung07 and TROPION-Lung08 are the two trials addressing this patient population. As indicated here, we are of course thinking about earlier stage lung cancer, stage 1 through 3, and how to position Dato-DXd and HER2 and HER3-DXd in these patient populations. Finally, I want to mention the DS-7300 program in small cell lung cancer. Next slide. Now I want to go over with you some of these combinations that I mentioned to you earlier. You already heard about some checkpoint inhibitor combinations, which is starting to yield very interesting data. We have ongoing clinical trials in targeted therapies that are listed there, such as tucatinib and other osimertinib and other clinical trials. I also want to mention that it's very important from an internal research and development strategy to mention here that at the bottom we have a number of internal assets that are, we are very interested in combining because these combinations of DXd ADCs plus an internal asset appear to be quite interesting and promising based on animal data. Of these combinations, we are very much interested in conducting an ENHERTU plus vemurafenib in HER2-low breast cancer. This is a clinical trial being done in collaboration with MD Anderson Cancer Center Breast Cancer Group. We have many more combinations with novel assets with undisclosed mechanisms of action. We hope to be able to mention more details on these combinations with novel assets that are perhaps at our next investor relations meeting. Next slide. Finally, I want to mention that patients who have become resistant to ADCs, particularly DXd ADCs such as ENHERTU. This is an emerging new unmet medical need in the cancer community, particularly breast cancer and possibly in the future, lung cancer as well. We're spending a lot of time and effort now to try to understand the mechanism of resistance of cancer cells to these ADCs. By understanding the mechanism, we can develop better treatments for these patients who don't no longer respond to one DXd ADC or another. You can possibly combine with other ADCs to overcome these resistance mechanisms. We can hypothetically theorize that these resistance mechanisms could be due to target-mediated resistance, such as loss of antigen or payload, such as the loss of a sensitivity to the deruxtecan payload. I think we have now a rational way to develop new drugs in these patients who are no longer responding to ENHERTU. Next slide. Okay. Finally, in the next few slides, I'd like to go over with you what we are doing here from the R&D organizational standpoint, not the clinical trial data, but really what we're doing internally. Next slide. We are creating a single global R&D group to deliver our strong pipeline. We are creating a global R&D organization because, specifically because of our pipeline being so rich, with a lot of great drugs to develop. We're creating an organization, R&D organization that can do justice to these great drugs we have. A lot of this you don't really see when you're looking at clinical trial data, but here's a list of things we're doing here, within our R&D group. We've streamlined the governance. We organized our R&D organization. We created a new function called clinical science. We also created a new function of global team leaders who are cross-functional team leaders. We also created a new function called therapeutic area strategies function to specifically develop disease-based strategies as opposed to asset-based strategies. We're very much interested in integrating research and clinical development, you know, much closer relationship between research and development. One example of that would be these mechanistic studies of resistance mechanisms that can lead to new drugs that can be studied in a clinical setting. Next slide. We are also enhancing our clinical development capabilities. Many of you are aware that we have been outsourcing many of our functions in clinical trials. We are going to start to do some insourcing of some of the functions to really streamline and accelerate our clinical trial program. You'll see this enhanced phase one engine and enhanced preclinical early clinical correlation. This is kind of the same thing that we want to create much closer relationship and interaction between our great research programs and our phase one team. Also, at the same time, create phase I center of excellence that can do high quality and high throughput trials more efficiently at the selected phase I centers. Next slide. Here is a summary of what we all hope to be achieving with these new programs beyond the current 3 ADCs that you're aware of. By 2025, we will have started eight new phase I novel assets, including new ADCs and next generation ADCs. By 2025, of these eight, we will have established proof of concept or early signals from these new assets, including these next generation ADCs. Of course, we will continue with our submission activities for ENHERTU, Dato, HER3, and many other programs. By 2025, we will have submitted 12 new BLAs and NDAs. Next slide. I think we are going to stop here with our presentation of R&D and get ready for Q&A. You can see here our purpose and vision. We really want to be using our great research capabilities to serve patients globally by using our strength, which is really our research, science, and technology. Thank you very much, and we are going to be ready for some questions and answers. Now we'd like to start taking questions. I'd like to explain how you can speak up. At the bottom of the Zoom screen, you have raise hand button. Please press it and I will appoint you. When your name is called upon, please unmute yourself and ask your questions. After you completed asking questions, please disable the raise hand button and mute yourself. Please start. The first question is from Muraoka-san from Morgan Stanley Securities. Go ahead, please. Good afternoon. I am Muraoka from Morgan Stanley. Do you hear me okay? Yes. We hear you okay. Thank you. In the presentation, you didn't really mention HER3-DXd. You didn't talk about HER3-DXd so much. On page 53, and that's appendix. If I take a look at page 53 and page 54, between January to March, HER3, [HERSNAR], LAM-0 01 study results are going to come out. This is, very much brought forward in terms of the timings. The results are going to come out earlier than expected. What is the background of that? What are your expectations? If the results are positive, I'm sure you are going to go ahead with the approval application. Are you going to promote this on your own? As you know, currently this HER3 program is being run by ourselves only without a partner. Yes, as you have mentioned, we do have a registration trial going on. It's, we expect to see the data readouts from, on the initial one, in the second half of 2022. It's a very exciting program, for EGFR mutated patients who have previously been treated with EGFR mutation agents such as osimertinib. Thank you very much. I have other questions on HER3. TAGRISSO combination first line treatment clinical trial is ongoing right now. If I take a look at the ClinicalTrials.gov, January 2024 is the timing for the results to come out of this study. Compared to the official schedule you are announcing, this can be brought forward much earlier. Can I have that expectation for that as well? We are still conducting our phase I trial, the combination of the TAGRISSO plus the HER3 DXd ADC. We don't think we have actually announced when we will be initiating the phase III program. I think we want to make some decisions based on what we see with the combination data first, the phase I trial. Thank you very much. My last question. This question goes to Manabe-san. Manabe-san, the clinical trial results are very good. R&D expense is JPY 1.5 trillion for five years. Of course, this is affected by Forex rates. This is going to increase. That's what I think. To what extent do you think? Yes. Manabe would like to answer that question. Because of the depreciation of the yen, and that has to be factored in, but the results are very positive out of those clinical trials. Yes, we are expecting that R&D expenses may go up. That's not incorporated into the budget yet. We are going to be flexible. We are still keeping the budget that's being already planned. You're talking about slight increase. Is that the range you are thinking of? Well, we are still reviewing. We'll probably have some opportunity in the future. I would say at this moment, a slight increase is expected. Thank you very much. Next, JP Morgan. Mr. Wakao, please. Hi. JP Morgan, Wakao. Wakao from JP Morgan. Thank you. Page 43, I have a question on that. Because of the TROPION- Lung 03 study, 07, 08, you're very confident about it. I was able to understand it clearly. You are aiming for earlier stages. Regarding the earlier stages, you will perform phase I study, and then phase III will be performed after that. Early stage development strategy is something I'd like to know more. Also, TROPION-Lung01 study, how confident are you? 07 and 08, you're very confident about those studies. Monotherapy Lung01 data will become available soon. How confident are you the study a success is already taken for granted? That's my first question. I think you had a couple of different questions in your first question. I think your first part of the question was about early-stage lung cancer, if I remember correctly. So we haven't made, announced any plans to do stage 1 through 3 lung cancer as of yet. At the moment, we are still focused on, metastatic lung cancer, stage 4, and the TROPION programs are listed there. I think you asked about our confidence level in TROPION- Lung 01. This is a clinical trial in patients with relapsed disease. Based on... I mean, we know quite a bit about how data works in patients with, non-small cell lung cancer, relapsed disease. I think we're pretty confident that we will be better in the control arm in this clinical trial, which is a taxane. Mark, do you want to have any additional comments on this, Mark? Yeah, sure, Ken. I think the confidence comes from, you know, data we previously presented with our Trop2-ADC, Dato-DXd in a very advanced non-small cell lung cancer population with a response rate of 26% and an immediate duration of response that was between 10, 11 months. With this, and considering the activity we've seen in the earlier trial and considering in the control group here is a cytotoxic chemotherapy agent that we know well, we do have confidence in this. Thank you. Thank you very much. Next, page 41. HER2 IHC 0. In terms of the number of patients, that's about 20%, 30% HER2 pure, HER2- negative neoadjuvant first-line therapy. What is the target you're going to develop here? No possibility of development here or to do with this phase? Okay. Yes. I think you're asking about HER2 IHC 0 adjuvant, neoadjuvant setting. Is that correct? Yes, you're right. Okay. This is a patient population where patients are typically not responsive very much to chemotherapy. They are. These are the mostly patients who receive a hormonal manipulation. At the moment, we are interested in explore, of course, exploring the use of data, for example, in this HER2 IHC 0 patient population. I think we need to see some data before we really dive into a big program in this patient population. I don't know. Mark, any more comments? Yeah. Ken, I can just second what you say, that I think with the IHC 0 population, it's a place where we've seen Basically in a fully triple negative breast cancer population, and as Ken presented, we've seen very clear proof of concept. We've seen that with Dato-DXd, not only as a monotherapy, but also in combination with immunotherapy, as we showed the BEGONIA data. I do think we don't have yet any, uh, let's say, a very early plan for a trial with Dato-DXd. You did see that Ken did mention in this triple negative population, we've just launched a new trial in the post neoadjuvant setting with... or high risk adjuvant setting. phase III trial, TROPION-Breast03. This is an example of where we could use our pipeline to address a population of patients that is triple negative that does include the IHC 0 population. Thank you very much. DESTINY-Breast07 was not presented, but you presented at the symposium. First-line patients are the target population. As for the abstract CLEOPATRA study, ORR was not so different. In the poster presentation, there was an update and further improvement, I think. As of now, the number of patients is still small, so just with this data, it may be difficult to say anything definitive. Based on these results for the first-line in HER, how confident are you? If monotherapy data is better, monotherapy and combination, which is better? Do you have any comment on that? You know, I think we're still waiting for more data, in that patient population before we make any major decisions here. We understood. Thank you. Next is Yamaguchi -san from Citigroup Securities. Hi, can you hear me? Yes, we can. Thank you very much for the presentation. The first quick question at Yamaguchi for Citi. First quick question is that, I just learn about more background of Dato, TROPION-Lung01 on the chemo arm. You said that you understand those, the treatment very well. Can you give me as a background, what is the typical PFS for those, the arm which you trying to compare? Thank you. Okay. This is the question about TL 01. Yes. Yes. As you are aware, this is the control arm has been studied in many different clinical trials including most recently new trial data that was re-report, I think it was at ESMO. Some new trial with the same control arm. We are aware of these many different numbers that are floating out there, and we have taken that into account in our clinical trial. Mark? You know, Ken, thanks. I think you've said it. Certainly what we've seen over time is we've seen with the report of the clinical trials with docetaxel on the control arm, we've seen some increase in the PFS. Certainly, historically had been less than 4 months, now has creeped up over four months. As stated by Ken, we're taking consideration of this data as it evolves. Thank you. Thank you. The second question, quickly on you talk about the DS-7300, and which you're very excited about it, I guess. Just a nuance, but you seem to be excited more on the SCLC at the moment because you have more data, rather than the prostate cancer. Is that correct? If that correct, is that any way to accelerate the pathway of the development of DS-7300 after you're gonna see some early data in a few weeks? Yes. Yeah, next year, maybe. Yeah. DS-7300 is a so rather than unusual drug in that B7-H3 is widely expressed. The phase one trial is enrolling all comers cancers. What we're doing is really to look at individual cancer patients that enroll. As soon as we see a signal in a particular type of cancer, we start to do some work in that particular cancer setting. By coincidence, as there are large numbers of small cell lung cancer patients who enrolled in this trial, we were able to get a good signal in this cancer type. It also means as we go along with this program, we'll probably see more signals in more cancer types. Prostate cancer certainly looks like it's going to be a good one. There's going to be other ones too, I suspect. Squamous cell lung, non-small cell lung cancer looks very interesting. There's gonna be more as time progresses, is my guess. Okay. Finally, quick comment please on the [DS-7300]. You presented the PFS last year, and you upgrade OS this year and updated the PFS as well. Of course, due to the nature of PFS and OS, the hazards ratio for PFS is really strong. Where, hazard ratio in OS is very, still strong, but numerically it's lower. That happen all the time, but is it kind of in line with your expectation from a scientific standpoint? Or is better or less than you expected on the OS, hazard ratio concern? Thank you. Yes. yes. The observation that you just made, that hazard ratio is much smaller with PFS compared to OS. That's a typical observation that's seen in almost every single phase III clinical trial. Why is that? I think it's because, you know, with overall survival, these patients who relapse after receiving one of the two drugs in the treatment, they have the opportunity to receive many other treatments. Right. This is the reason why, the overall survival is a reflection not only about the two drugs that are being studied Right. All the other subsequent drugs that these patients received at the time of progression. It's, in a sense that given the current status of the treatment, it's not really that surprising because of this difference? Yeah. This is what we expected typically. Okay. Yeah. The hazard ratio is smaller with the overall survival. Right. Right. Okay. Thank you. Do you agree, Mark, on this one? Thank you. Mark? Yeah. Yes, I agree. Thank you. Thank you. That's it from me. Thank you. Next. Daiwa Securities, Mr. Hashiguchi, please. Hashiguchi speaking. Thank you very much. Page 44. HER2-low breast cancer, ENHERTU and EZHARMIA development could occur. I'd like to know the theoretical background for this combination. Why the valemetostat? There are so many candidates for combinations, but out of them, why valemetostat? This combination is promising why in HER2-low breast cancer? Please explain the scientific background. In the second half of this year, first subject dosed. Dosing is scheduled in the second half. This is for you. Is this going to be an exploratory phase or a study? From the beginning, is it going to be a confirmatory like study you're planning? For treatment-wise, what is going to be the population of patients, in what stages? Okay. In terms of the scientific rationale for this combination, I have to say that, I can only say, we've studied ENHERTU combination with various combination partners. Interestingly, valemetostat turned out to be a very good partner for ENHERTU in this kind of breast cancer in animal models. The reason why it's a synergistic combination with ENHERTU, I don't think we yet fully know. I think one could certainly hypothesize that valemetostat being an epigenetic agent, is able to upregulate certain genes that sensitize breast cancer cells to the action of the deruxtecan. I think that's a possibility. In turn, this is really intended to be an exploratory signal seeking study. We'll do a dose escalation phase one study first, followed by an expansion phase. Okay, understood. Thank you. That's all from me. Next f rom Mitsubishi UFJ Morgan Stanley, Kumagai -san, please. Kumagai speaking. Do you hear me okay? Yes. Thank you. This is extension on the Muraoka-s an's question. It's about midterm management plan. I think assets potentials are going up because of the good results. Are you going to think about updating your numbers, management numbers? Manabe would like to answer your questions. Including R&D expenses and also revenues, we are right now reviewing these numbers. Once we fix the numbers, in the fiscal year, next year, if everything goes well, we'll be able to update those numbers. Thank you very much. That, TROPION-PanTumor01 study, there is a high incidence of stomatitis. Is it manageable? I'd like to know. Yes. The stomatitis appears to be unique to Dato-DXd and not typically seen with other DXd ADCs. Yes, it is manageable. Mark, any comments from you there? You know, thanks. Just to add that it typically occurs at a lower grade. We do have a dose modification protocol dedicated to this. We're also looking to understand what is the optimum treatment strategy in terms of an oral agents that can support this. So far, we found that the stomatitis does not have much impact on the conduct of trials and is manageable. Last question. Page 48, phase I center of excellence is the term you use. Comprehensive cost-effective phase I trial conduct that is being mentioned, how is it different from the past model? That's all from me. What we want to be doing here is to start phase I clinical trials quickly and at centers that can specialize in phase I programs. Why are we doing this? The reason is that as you just heard previously, we have a lot of things in our resource pipeline that is coming up into clinical stage in the next few years. We think that this is a very important for the future of our oncology program beyond the DXd ADC programs that you heard. For this reason, we're putting a lot of emphasis on our phase I centers. These are going to be selected centers that have done phase I trials, and as you know, phase I trials are very different in operational conduct compared to a typical phase II or phase III trial. We want to open them quickly because as I said, we are very interested in getting a clinical signal. We want to be able to ensure that we obtain appropriate biopsies for pharmacodynamic measurements and the biomarker analysis. Not every center is able to do those things. Mark, any more comments to add on this? Ken, I think you've largely covered it. I would just add that. I think, Ken, you alluded to that in the initial presentation, that what we seek to do is also bring more of our, let's say, medical modeling and conduct in-house as opposed to relying on contract research organization or CRO. That's also part of it. Thank you very much. This is going to be the last question. Credit Suisse Securities, Mr. Sakai, please. Hi. Credit Suisse, Sakai. Sakai from Credit Suisse. I have two questions. The first question I'm gonna ask in English because I'm referring to a comment from U.S. oncologist. I don't know if this is the consensus, but his comment that following the DESTINY-Breast04 result, my practice is now being placed a greater emphasis on the patient with IHC 0 or 1 and HER2-positive breast cancer. Is this common? I mean, what's the logic behind this practice? Can you elaborate? Okay. I want to make sure I understand your question. I think you asked about patients with breast cancer whose HER2 status is IHC 0 or 01. Is that correct? Yeah. I think the, that's the, slide 41. I think that I'm referring, or he's referring to this slide. You know, HER2 positive, IHC 0 or + 1. This category of the patient. Okay. The concern from the doctors is that there's Not concern. His practice is now putting great emphasis on this category of the patient a fter the success of [Breast 404] result. That's a positive comment. That's a positive move. Okay. Now I understand. Okay. Yes. We have received a lot of comments similar to what you heard from oncologists. The reason is that we now have a whole new category of patients who are HER2 low. There is a very good treatment for these patients, namely ENHERTU. What's very tricky here is that HER2 low represents a pathological diagnosis that previously wasn't a major concern when treatment selection was being made by the physician. I do want to mention that, for example, there's a How do you, for example, make a difference between or distinction between HER2- low and HER2 -zero? HER2- low, the lower limit is very faint staining of the tumor cells in 10% of the cells. If you are at 9% faint staining, that's not HER2- low anymore. That's a HER2, It's in that category on this slide here where it says, HER2 IHC greater than 0 but less than +1. Right. Kind of a very subtle and possibly an artificial borderline between HER2-low and less than HER2- low. Yes, there's a tremendous interest among the physicians to treat these fairly large numbers of patients with HER2-low, but they have to be remembering that there is a nuance between HER2-low, which wasn't really reported previously on pathology reports. There's a, you know, the difference between HER2-low and HER2 less than low. I guess that's how I might describe it. All right. Did I answer your question? Yeah. I think you are saying that subtropical analysis could be very important going forward. Well, I think the, you know, the DB04 data is very clear that in the HER2-low patient population, ENHERTU is superior to our study in the control. I think what is going to be the important nuance for the physician is to be able to understand the pathology reports. He may need to get assistance from the pathologist himself because previously, the pathology reports mostly reported that patients were HER2-positive or negative because the HER2-low category did not exist previously. Cool. Right. That's very clear. Yeah, I don't have any more question. Let's, let's wrap up my question. Thank you very much. Okay. Thank you so much. We are past time, so we'd like to conclude the Daiichi Sankyo R&D Day. Thank you very much. Thank you very much, everyone. Thank you very much. Thank you.