Daiichi Sankyo Company, Limited (4568) Earnings Call Transcript & Summary

[Interpreted] I am Manabe. Thank you for joining us today at Daiichi Sankyo's R&D Day. This fiscal year, we have updated our R&D strategy from 3 and Alpha to 5DXd ADCs and Next Wave in line with the strong progress of our pipeline. In particular, the expansion of the ENHERTU indications has progressed very well, and we have also received clinically meaningful clinical trial data for the other 4, 5 DXd ADCs assets, making it a very productive year. We have been accumulating positive data for ENHERTU and Dato-DXd with a view to expanding other indications, or obtaining regulatory approval and under the strong collaboration with AstraZeneca that we have established to date. We will continue to pursue the maximization of product values. For HER3-DXd DS-7300 and DS-6000. The accumulation of favorable data has further enhanced the potential and moved them to the stage. We plan to maximize the product value. In addition to these changes in our internal environment, externally, competition of ADC development has been intensifying which is driving the need to increase capability, resources and the capacity to maximize the DXd ADC franchise. We are always pursuing the best means to deliver innovative drugs to more patients more quickly in line with our company's purpose and mission. In light of the changes in the internal and external environment, we decided that the best means to achieve this was to collaborate with U.S. Merck. We decided and started the partnership in October this year. By leveraging U.S. Merck's extensive experience in oncology, and its development strengths. In terms of capacity, resources and capability, we hope to rapidly deliver a wide range of new treatments to patients in more countries and regions. In addition, by further expanding resources to create a virtuous cycle for sustainable growth. We will accelerate the research and the development of our pipeline in early clinical trial stage, including ADCs after 5DXd ADCs and second-generation ADCs as well as our [ early-stage ] research projects. Together with our strong partners, we will continue to make every effort to achieve the FY 2025 targets of the fifth business plan and realize our goal of contributing to the health and the enrichment of life around the world by providing new treatment options that offer hope to patients as soon as possible. Today, first, Takeshita will give you an overview of our R&D strategy followed by Agatsuma's presentation on the discovery of DXd ADCs and basic technologies for drug discovery. And finally, Mark Rutstein will explain the progress of oncology development and our therapeutic area strategy. I will now hand over to Takeshita.

Manabe, thank you very much for that kind introduction. Next slide, please. And one more slide after that. So let me just first give you a brief introduction about our R&D strategy and a summary of where we stand in terms of clinical development. As many of you know, just until a few years ago, we were talking about 3DXd ADCs. But now today, we have 5DXd ADCs that are really in full development. The original 3 and HER2, Dato-DXd, HER3-DXd now and plus 2 additional DS-7300 directed against the antigen B7-H3 and DS-6000, which is another DXd ADC directed against [ CDH6 ]. So these are the 5 ADCs in active development. And of course, our goal here is to maximize the value of these 5 ADCs. In addition, there is an important component of our clinical development strategy that we call, Next Wave. That's shown in light blue in both in oncology and specialty medicine and vaccines. These are the new drugs, many of them are in research stage or early Phase I stage that will form the pillars for the next generation of Daiichi Sankyo's drugs beyond the era of DXd releases. Next slide. So I think you are now aware that we have 2 major partnerships. I think many of you are familiar with the -- the first partnership with AstraZeneca in HER2 and Dato which has been an incredibly great partnership for us and I think I hope also for AstraZeneca, and we will continue with this partnership for these 2 ADCs. And now as you heard, we have begun a new partnership with Merck on the 3 ADCs that are listed here HER3, 7300 and 6000. We are still in the early days of the partnership, so far this partnership has been very, very good for us. Next slide. So this slide shows in broad terms, what our clinical development program looks like in terms of Expand and Extend. So here's what we mean by Expand. Expand really means to maximize all clinical development possibilities for each of the 5DXd ADCs, we are talking about. And in lung cancer and breast cancer, which are the 2 major indications for us. When we talk about Expand, we're talking really about earlier lines of therapy. And of course, beyond these 2 major cancers, we want to expand the range of cancers to include many other types of cancers besides lung cancer and breast cancer. So that's our Expand strategy. And on the right-hand side, you'll see what we call Extend strategy. This is a very important concept that I want to tell you about. It's largely based on combinations. Combinations of these DXd ADCs plus some of the compounds we have in our early stage pipeline. It is remarkable that we have discovered many synergies with our early-stage compounds plus DXd ADCs. These synergies, we don't always see them but sometimes, when we see them, they are quite remarkable, and we want to pursue this as part of our Extend strategy. Next slide. This is a brief summary of our launch plan for the first 3 ADCs that you're familiar with. This is a long list of indications a long list of current and future approvals for ENHERTU, Dato and HER3. You'll see the many, many breast cancer registration trials, gastric cancer, lung cancer, et cetera, for ENHERTU program. For the Dato program, you see the lung cancer and breast cancer programs and HER3 lung cancer and other types of programs. And so -- and you'll see also that many of these have received major recognition throughout the world from regulatory agencies in terms of breakthrough therapy designations, et cetera. So we're very proud of that. Next slide. So on this slide is a summary of the progress since our last R&D day back in 2022. So in 1 year, this is a summary of I would say the major progress that we have made in our pipeline. It is not the total list, but just a summary. And you'll see that on the ENHERTU program on the far left, we obtained approval for the initial HER2-positive breast cancer in China. We also have HER2 low breast cancer approvals beyond the U.S. and now in Japan, European Union and China. And particularly, we are now pursuing ENHERTU approvals in diseases beyond the 3 cancer types that you are familiar with include [ gland ] cancers and many other cancers that were not part of the original 3 cancer indications, which were lung cancer, breast cancer and gastric cancer. And in fact, based on the clinical data from a clinical trial called [indiscernible], we have received from the FDA a breakthrough therapy designation for HER2-positive solid tumors and HER2-positive colorectal cancer. In the Dato program and in the HER3 program, we have had a major progress in these 2 programs. We have seen the TROPION-Lung01 data. This is a registration study and we have seen the data. And the same thing for the TROPION-Breast01 study. This is another registration study in breast cancer. So between these 2 studies, the data program is proceeding to file for approval using the lung cancer data and the breast cancer data. And of course, for HER3 program, we have obtained the top line results for the HERTHENA-Lung01 study and based on what we think is a very good efficacy and safety profile. We are proceeding to file for approval for this strategy in certain countries. In addition, we have started very important pivotal studies for the [ Hematol ] program that are listed here at the bottom in the middle, the lung study and 2 breast cancer studies. And on the right-hand side, you'll see progress in the DXd ADCs that are in earlier phases of development, the 7300 program and the 6000 program. In both of these programs, we are seeing very good clinical signal and very good efficacy and safety profile, and we are very excited to be pursuing approval by initiating registrations that we can study intended to result in registration studies in certain types of cancers such as small cell lung cancer for 7300 and ovarian cancer for 6000. And finally, on the right corner in the Next Wave category. We have obtained approval for a hematological malignancy with our compound quizartinib in the FLT3-ITD patient population for acute myeloid leukemia. So you can see that we are not just a solid tumor company anymore as we have also a hematology. Next slide. And finally, I want to remind all of you that we have developed a COVID-19 vaccine. This is called DAICHIRONA. This is an RNA-based vaccine. It's the first mRNA vaccine developed in Japan, and it is really intended for the Japanese market and we have a obtained approval for this vaccine. So we're very proud of this software with the Japanese market and regulatory agencies and the government. And we are very interested in using this technology to apply to other types of vaccines, for example, a combination of the flu and COVID vaccine. So that's a very brief summary of what we're doing in R&D. And next, I want to turn it over to Dr. Toshinori Agatsuma. He is the Head of Research and also in generally credited within our company as one of the major inventors of our DXd ADC platform. So Agatsuma, please go ahead.

Thank you, Ken. In this session, I'd like to introduce the history of DXd technology that I have been involved in as well as some of our current drug discovery research activities. I joined the company, former Sankyo 32 years ago, and have been engaged in exploratory research and discovery research ever since. In 2004 I started to be in charge of discovery results for biopharmaceuticals. And I was given the opportunity to propose and execute in-house development for ADC technology. In the course of that biotechnology research. I have since been in charge of oncology research function and currently oversees discovery research as a global research head for more than 100 years since its establishment, Daiichi Sankyo has been discovering new drugs from its own research activities. The former Sankyo and former Daiichi Pharmaceutical had research bases in Shinagawa and Kasai, respectively. And at present, as Daiichi Sankyo, we have been active in both sides. The birth of DXd Technology was largely due to the assets and culture that the company has developed over the years. That is how I feel from my own experience. prior to the business integration. Sankyo and Daiichi had developed experience and expertise in antibody technology and Topo I inhibitors, respectively. DXd ADC research launched after the integration. I myself started the ADC research as an extension of antibody research. But since the decision was made to incorporate Topo I inhibitor as a payload, not only antibody drugs, but also Topo I inhibitors experience and know-how have greatly facilitated the progress of the research. Our researchers have a strong desire to save patients and the willingness to take on the challenges of new science and technology. In addition, there is a culture of actively sharing the know-how and results gained by individuals with others, refining the results and striving for perfection. I believe the success of ADC research is largely due to this cultural foundation. Many researchers, leaders are involved in multiple launched products, including ENHERTU. They have been with Daiichi Sankyo for a long time and are not only innovators who embody the culture but also the legacy of that culture, responsible for training their successors and greatly supporting our research. The concept of ADC was first proposed by Paul Ehrlich in Germany in the 1900s. And from the beginning, it was called the magic bullet that efficiently kills cancer cells. However, for a long time, no practical ADC was realized and finally, in 2000, the first ADC drug was approved in the United States. In 2010, when ADC successes was still few, we established an ADC research team. And in 2019, 9 years after its inception, we received approval for ENHERTU. ADCs are often likened to a merger or a marriage between a small molecule drug and an antibody drug. As a metaphor suggests a high level of expertise in both small molecules and antibodies is essential in the development of such technologies. On the other hand, ADC was a blue ocean category with a few successful cases at that time. There was little information available, and it was unclear how to design it. Without being constrained by biased affiliates, we contentiously concluded our own trial and era. In addition, not only efficacy evaluation, but also pharmacokinetics and safety valuations were implemented obtaining multifacility valuation data and apply them to design. That was the strategy we thought we should take. In order to accelerate the activities, ADC specialized cross-functional research working team, consisting of members with different specialties was formed and started its activities in June 2010. This slide shows the 4 challenges of the ADC drug-linker we had at that time. First, back then, only immediate mechanistic payloads, such as tubulin inhibitors and DNA intercalators were used and the patients who are unresponsive or resistant to these ADCs, we don't have an option for ADC therapies. Second, the heterogeneity of the drug binding sites raised concerns regarding the quality assurance of product batches and formulation specifications. Third, the linker was unstable which might reduce the amount of drug reaching to the tumors and increase the free payload in blood, which could cause toxicity issues. In addition, at that time, drug antibody ratio, DAR being [ 324 ] was commonly considered as the upper limit of ADC which limited therapeutic efficacy as an ADC. In order to solve these problems, the team developed the DXd technology. The details of the technology have already been reported in various occasions. So I will not go into those details in today's presentation. This is a research plan the working team had when it started. The column on the right shows ADC products that have been additionally produced as a result of the activities. First, by using an anti-HER2 antibody trastuzumab, we plan to develop a new drug linker, which resulted in the DXd technology ENHERTU. Next, the established linker was applied to antibodies in our in-house oncology projects to create ADC products. This was done with the aim of providing ADC to patients relatively quickly. This first wave efforts produced Dato-DXd, HER3-DXd and DS-7300. In addition, as research progressed, we acquired new knowledge and know-how. We leverage them to identify new ADC targets, such for antibodies over grade ADC from antibody introduction. Those approaches were taken and DS-6000 and DS-3939 were generated from this Wave 2. Let me talk about 3 key points to success in establishing our DXd technology. The first key point is the discovery of potent payload. From an extensive in-house compound library, candidate payloads were selected and screened to evaluate the potential by actually creating ADCs. As a result, we discovered DX-8951, which DXd originated from and found that it was very potent as ADC payload. DX-8951 is a topo I inhibitor, which former Daiichi Pharmaceutical had experience of advancing to Phase III. DE-310 is its polymer conjugate. Unfortunately, these programs were terminated, but researchers in charge, but then joined the working team. They played a major role in accelerating ADC Research. Next page, please. The second key point is the drug linker design. Conventional ADCs are mixtures, although their DAR maybe 2 to 7. As I mentioned before, the average DAR would be up to 3 or 4 according to the technical standard at the time. When an excessive number of drug linkers is bound to an antibody, aggregates would develop, resulting in reduced efficacy. This was a program. One of our targets was to design an ADC with high therapeutic efficacy and uniformity. Specifically, antibody molecule has 8 sustained residues fit for drug linker binding. We aim for a drug linker design with a stable payload binding to all [ ADCs ] residues. We took on a challenge to increase the number of drugs to be loaded and create ADC with high uniformity. This slide shows some of the data when we identified the optimal structure of the linker portion. In the end, we successfully achieved a drug linker design with both high antitumor effect and low aggregation. That's entry #7 in this table. I believe Innovative achievement was realized and by referring to the accumulated data through trials and errors and through the researchers creativity. Next page, please. The third point is the identification of the product value by utilizing the diverse range of animal evaluation models. Let me give you one example. This slide shows the evaluation of antitumor effect of ENHERTU and T-DM1 by building 34 animal models called xenograft models with different HER2 expression levels. This graph shows tumor regression observed in models with downward bars. With T-DM1 tumor regression was observed only in some of the HER3-positive or HER2-positive models. On the other hand, with ENHERTU or T-DXd, tumor regression was observed in all HER2-positive models used in the experiment. Furthermore, tumor regression was observed also in HER2-positive and HER2 drug models as well. Based on these results, even back then, we had hypothesis about the possible efficacy of ENHERTU in HER2-positive patients previously treated with T-DM1 as well as in HER2 low patients. These hypotheses were later approval in DB01, 02 and 04 clinical studies. We were very pleased towards realizing the provision of value to patients. At the same time, this was very encouraging for our continuous challenging activities. Next page, please. As for the future outlook in our ADC research and development, with regards to DXd ADC, we'd like to increase the number of ADCs we can deliver as drugs, expand indications of each product and provide new value by combination with other drugs. Furthermore, by establishing new concept ADC technology, we'd like to further strengthen our position as a global leader in ADC technology. Next page, please. Regarding DXd ADCs, in addition to the 5DXd ADCs DS-3939 entered the clinical stage this year, including that a total of 7 projects are ongoing right now. As for next-generation ADCs, including the DS-9606, which entered the clinical stage last year, multiple projects are in IND-enabling or discovery stage. There are also multiple new concept ADCs. We are proceeding with multiple projects which are now in IND-enabling or discovery stage. Next page, please. I recognize that the strength of Daiichi Sankyo drug discovery is its high level of science and technology and it's craftspersonship enable its unique rollout. Many new colleagues are joining the Daiichi Sankyo Group from Megapharmas, and they are also voicing the same supporting opinion. Next page, please. Our craftspersonship as something in common with Japan's traditional technologies in a sense to craft something unique and precise in my opinion. Also, there is commonality as the established technology is handed down, we're nurturing talent and developing the technology while incorporating new ideas. I would like to maintain and develop it as a strength in developing new standards of care. Next page, please. As one of the measures to strengthen our research capabilities, we are working on initiatives to introduce research processes through DX. Today, I'd like to talk about one of such efforts. Our data-driven drug discovery, which we call D4 initiative. D4 enables us to integrate all the data internally and externally to enhance the probability of success and research speed in our drug discovery research by using AI. In small molecule drug discovery, D4 is being leveraged in all aspects of the drug discovery process. Right now, we are rolling this out to bio-related modalities. Next page, please. Let me give you an example of its utilization in small molecule research. The usual research flow in drug discovery is the DMTA cycle, which we design, make and test the compound and analyze the data by including the Cyber DMTA cycle in the virtual world, using AI in the real DMTA cycle in the real world, we created a new process to realize the design of lead compounds from head compounds or design of development candidate compounds from lead compounds. In this Cyber DMTA cycle, all the integrated data is leveraged to generate a huge number of compounds in the virtual space beyond the imagination of the real space and various properties of the created compounds are calculated. Simulation of binding with targets is also calculated. Based on the calculated numbers, we note down promising compounds. Regarding the short list of compounds, through the review by experienced with experts, we select the candidate compounds, which will go to the next DMTA round. By repeating this cycle, we can create optimal compound speedily. This is a task we started 5 years ago, but this has already been leveraged in many programs. The number of successful cases is increasing in terms of development candidate compounds. By expanding the scope of default utilization in the future, productivity and research can further be enhanced according to our plan. Next page, please. Towards achieving our 2030 vision, we are taking on a challenge to create new post DXd ADC growth drivers. In order to further develop Daiichi Sankyo's drug discovery culture handed down throughout our history, while using the research, the core technology of the foundation with the synergy effect between the pursuit of cutting-edge science and craftspersonship, we will aim to further strengthen our science and technology and realize these goals. That's all from me. The next speaker is Mark Rutstein. Mark, your presentation, please.

Thank you very much, Agatsuma. My name is Mark Rutstein, and I lead Oncology Clinical Development at Daiichi Sankyo. I'm excited to be here. What I'm going to do is review the clinical progress that we've had, which has been substantial. I hope you'll recognize the breadth and depth of our pipeline as I review the data. And I want to underscore the commitment that we have to patients to address -- continually address unmet medical needs for all patients who are in need. Next slide. So Takeshita showed this slide earlier, I won't spend too much time, but I will tell you, I will frame my presentation against this slide. So we will talk first about expand strategy on the left, and we will show how we strengthen our lung and breast cancer clinical program and then expand into additional indications and earlier lines of therapy. I will then talk about the extend strategy extension, where we look at rational combinations, including our DXd ADCs and sequences in addition, we think about different formulations. And of course, as Agatsuma mentioned, we have new concept ADCs. And so we'll talk about some of that next-generation Next Wave technology which is already in the clinic. So with that, next slide, So first, we will talk about expand and within expand, we will talk about first breast cancer. Next slide. So our overarching breast cancer strategy is as follows: we would like to expand our leadership in breast cancer. We want to deliver novel options to improve outcomes across a broad set of distinct patient segments. We would like to establish foundational treatments across stages of disease from early to metastatic who would like to explore novel combinations and sequences and of course, we would like to understand the underlying biology of breast cancer. Next slide, please. So the first data that I'd like to show in breast cancer is from TROPION-Breast01. We presented this data at ESMO 2023. This is a positive Phase III trial of Dato-DXd monotherapy in hormone receptor positive HER2 low or negative breast cancer. As you can see, it met its primary PFS endpoint, that's a dual endpoint, it showed a clinically meaningful improvement in progression-free survival, hazard ratio 0.63. Now very fortunately, we saw a tolerable safety profile, demonstrating an overall favorable benefit risk profile because, indeed, the rate of the Grade 3 and higher adverse events in the Dato Group was less than half of that in the chemotherapy control arm and the rate of ILD in this study was low. Based on this data set in a recognition of a positive benefit risk profile, we do plan to file in the -- we do plan to file in the U.S. based on this study within 2023. Next slide. So the next is BEGONIA, which we also showed in ESMO 2023. This time, again, with Dato-DXd but this time in triple-negative breast cancer with a Phase II study and in combination with immunotherapy. This is a very important data set because it demonstrates the ability to combine the DXd technology, in this case, our TROP2 DXd ADC with immunotherapy, durvalumab, a PD-L1 inhibitor. And what we saw in 62 patients, front-line triple-negative breast cancer, we saw a 79% response rate, very encouraging, and interestingly, the majority of patients here, close to 90% were low PD-1 -- PD-L1 expressing. An encouraging signal in PD-L1 largely low PD-L1 expressing population and durability as well with a median duration of response of 15.5 months and a median PFS of 13.8 months. Overall, a well-tolerated regimen with the ILD of Grade 1 and Grade 2 only. And we will continue in this BEGONIA study to study this combination in PD-L1 high-expressing patients. And later on, when we give an overview of the pivotal trial program for Dato-DXd and breast cancer, will show that the combination of immunotherapy, including durvalumab and Dato-DXd is important under study already in some of our pivotal trials. Next slide. So the next from ESMO 2023 was a pooled analysis in HER2-positive metastatic breast cancer with a HER2 in patients with bone metastases or intracranial disease. What this pooled analysis showed is that in HER2 is effective treatment option for patients with HER2-positive metastatic breast cancer with either treated stable intracranial metastases or untreated and active brain metastases. And you can see the data down below for both subpopulations of treated stable and untreated active brain metastases. You can see there was evidence of a robust intracranial response relative to the control group, 45% versus 27% in for patients with treated and stable brain mets and then 45% versus 12% for patients with the untreated active brain mets. Importantly, the safety profile in this population was manageable and consistent with what we know about in HER2's tolerability. So this is an important data set to underscore the capability of the DXd technology to demonstrate efficacy in patients with brain metastases or generally a poor prognosis population. Next slide. Now at the recent San Antonio Breast Cancer meeting, we showed data from DESTINY-Breast08. This is an early phase study to look at ENHERTU in combination with various other agents. And in this case, we show data from the cohorts with endocrine therapy, demonstrating that when an ENHERTU is combined with either anastrozole or fulvestrant, there's tolerability and activity in chemotherapy-naive patients with HER2 low metastatic breast cancer. Overall, from the standpoint of safety on the left. There were no new safety signals apparent, and there was a general ability to combine these 2 combinations of ENHERTU with endocrine therapy. From an efficacy standpoint, there was a 71% response rate in the 21 patients where T-DXd was combined with anastrozole and a 40% response rate in combination with fulvestrant. The safety profile was consistent with what we would expect when combining these agents and of course, you can tell by the subgroup numbers of 21 patients and 21 patients, respectively, it is difficult to chalk conclusions from efficacy from these data sets but we can see that there is feasibility of the combination, and we will continue to further investigate. I think this data is important because it demonstrates our commitment to assess our DXd assets in combinations with other MOAs mechanisms of actions and drugs. Next slide. So this is an overview of our breast cancer program. And it is indeed very robust. So if you look at an HER2 in orange, of course, there are the approvals in HER2-positive breast cancer in HER2 low metastatic breast cancer. But as we look at HER2-positive breast cancer, we can anticipate some interesting readouts as we move in HER2 into earlier stages of breast cancer. The frontline with DB09 the high-risk adjuvant setting with DB05 and the neoadjuvant setting with DB11. In addition to that, in the HER2 low setting, we await soon the readout of DB06 in that earlier set earlier line of therapy in HER2 low patients. Then for Dato-DXd, we did just -- we did just present the positive results in hormone receptor positive disease for DB01. We discussed those today briefly. And you can see we have a broad program up above in triple-negative breast cancer pivotal trials in the frontline setting in CPS less than 10 in CPS greater than 10 population. Pivotal trial DB03 in the high-risk adjuvant setting and then also recently launched in the perisurgical setting, neoadjuvant and adjuvant. And some of these trials are using a combination of immunotherapy with Dato-DXd, as mentioned previously. And when we think of BEGONIA and the possibility because we have in DB04, DB03 and DB05, such a combination. And that's not all because in green, we have here HER3-DXd and we are absolutely planning to build on the clear signals of efficacy that we have seen with HER3-DXd across segments of breast cancer. So more to come. Next slide. So now we'll talk about lung cancer. Next slide. So in terms of our lung cancer strategy indeed here as well, we look to deliver practice-changing medicines to meet evolving unmet needs in a broad set of distinct patient types. We want to provide superior second-line plus treatments and differentiated combinations in metastatic non-small cell lung cancer with DXd as the foundation. We want to move into earlier stage disease, and we also want to identify novel therapeutic approaches not only for non-small cell lung cancer, but also small cell lung cancer, particularly with our I-DXd B7-H3 agent. Next slide. So this is data from DESTINY-Lung02. This is the Phase II data set that we presented at World Lung cancer in 2023. This is ENHERTU mutation positive non-small cell lung cancer. This is a Phase II study that led to registration. And indeed, ENHERTU, which was already approved in this setting in the United States, has extended approval in Japan in August as well as in the EU in October. And what you can see at 5.4 milligrams per kilogram of ENHERTU monotherapy. You can see very clear evidence of efficacy with a response rate of 49% and a duration of response of 16.8 months. And this was activity regardless of HER2 mutation type HER2 amplification status or prior therapy with a generally manageable safety profile and a positive benefit risk profile. And based on this data ENHERTU is approved at 5.4 milligrams per kilogram. Next slide. So this is TROPION-Lung01. Of course, we showed this data at ESMO 2023. This is another positive Phase III trial for Dato-DXd, but this time in non-small cell lung cancer. This is Dato-DXd versus docetaxel in the second-line plus setting. It met its dual primary endpoint of progression-free survival, which we can see on the left, hazard ratio of 0.75, response rate also favored Dato-DXd and overall survival at the interim favored Dato-DXd but was not significant and the trial is continuing to the final analysis. On the right side, we can see some key subgroup analyses. And what we could see is differential activity according to histology, nonsquamous 0.3 hazard ratio for PFS and then squamous had a hazard ratio greater than 1, which suggests no clear benefit in the squamous subpopulation. There was also a difference in efficacy by AGA status with better efficacy in the subgroup of patients who had these actionable genomic alterations. Next slide. So here, the progression-free survival KM curves for those histology subgroups. On the left, as you can see, hazard ratio of 0.3 and with a separation in the KM curves. Importantly, in the box in the bottom of the left KM curve, the PFS hazard ratio for non-squamous patients without actionable genomic alterations was 0.71. What this suggests is that Dato-DXd is active in the non-squamous patients regardless of AGA status, which is important. And then on the right side, as we explained, we do not see evidence of efficacy in the squamous subset. Now based on these findings, we plan to file in the United States for this data within 2023. We also plan to amend the TL08 study, the frontline study of Dato-DXd plus pembrolizumab in PD-L1 50% entire populations to cap the squamous population. Next slide. This is the safety profile in TL01. Indeed, on the left, what we see is in most categories of adverse event there was favorability towards Dato-DXd. There were fewer grade 3 and above treatment-emergent adverse events with Dato-DXd as well as fewer adverse events leading to a reduction or discontinuation compared to docetaxel. That said, on the right side, there were adverse events of special interest. We recognize based on this data set, where 3% of patients in the Dato-DXd arm had Grade 3 or higher adjudicated drug-related ILD that ILD requires careful monitoring and management. There were 7 Grade 5 ILD events in the Dato-DXd arm. The primary cause of death in 4 out of 7 was attributed to disease progression by the investigator. And notably, the rate of fatal ILD was higher in the squamous population than a non-squamous population. This does underscore a favorable benefit risk profile in the non-squamous population. The other adverse events of special interest, ocular toxicity and stomatitis are represented there and very rarely led to discontinuation of treatment. Next slide. So now I'll briefly mention TROPION-Lung05. This was presented at ESMO 2023. This is a supportive study to TL01. TL01 enrolled patients who had actionable genomic alteration, but only about 15% of that Phase III population fell into such subgroup. So this is an additional Phase II study of 137 patients with AGA actionable genomic alteration, heavily pretreated non-small cell lung cancer with Dato-DXd monotherapy treatment. And what we can see is that the ORR was 35.8% with a PFS of close to 5.5 months in patients -- in the subset of patients with EGFR mutation, the overall response rate was nearly 44%, an adjudicated drug-related ILD rate was 4%. Overall, this provides more evidence for the efficacy of Dato-DXd in patients with AGA. Next slide. Now we turn to HER3-DXd and this is the HERTHENA-Lung01 study. This is a Phase II study with pivotal intent. And what we showed at world lung cancer was that as a monotherapy, this HER3-ADC demonstrated clinically meaningful and durable efficacy in patients with EGFR mutation-positive non-small cell lung cancer in patients who had progressed after EGFR TKI and platinum chemotherapy. On the left, you can see the efficacy data. And indeed, in the overall population, the confirmed response rate was nearly 30% with a median duration of response of 6.4 months and efficacy was observed across diverse mechanisms of EGFR TKI resistance and a broad spectrum of pretreatment HER3 membrane expression. This is a high unmet medical need indication. These patients had received a median of 3 prior treatments. Overall, the drug was well tolerated was an ILD rate of about 5%. And this data set is the basis of an ongoing regulatory submission planned for 2023. The confirmatory study, HERTHENA-Lung02 is ongoing and HER3-DXd received breakthrough designation in this setting in 2021. Next slide. So like ENHERTU in HER2-positive metastatic breast cancer, HER3-DXd demonstrates activity in patients with brain metastasis in EGFR mutation-positive non-small cell lung cancer. This is a subgroup analysis of patients in the Phase II study. Metastasis in EGFR mutation-positive non-small cell lung cancer, HERTHENA-Lung01, you can see particularly on the right with a subgroup of 30 patients who had not been irradiated at baseline, so untreated brain metastasis is a 33% CNS BICR response rate by CNS Bicker interim response, you can see that 30% of those patients had a complete response, and there's durability as well with a CNS duration of response of over 8 months. It was also activity on the left side of the table in the broader population of 95 patients. And on the right, you can see an example of radiograph where you can see the reduction in the magnitude of the lesions of the intracranial lesions in a patient with a partial response. So again, high prognosis -- poor prognosis population, another DXd-ADC showing the activity to treat those brain mets. Next slide, please. So this is DS-7300. This is our B7-H3 ADC at World Lung Cancer in 2023, we were very excited to show this robust and durable efficacy in a heavily pretreated small cell lung cancer population. These are patients treated at, at least 6.4 milligram per kilogram dose. It's a cohort of about 20 patients. The response rate here is 52.4%. And the median PFS, 5.6 months. So this is a very nice signal in a high unmet medical need heavily pretreated population and generally well-tolerated monotherapy agent in this setting. If we move to the next slide. So this is the Phase II study IDeate-1, which is a dose optimization study in small cell lung cancer. We know that before we enter pivotal trials, it's important to get the right dose for the patients, randomized 8-milligram per kilogram or 12-milligram per kilogram randomized patients to either one of those two doses. Indeed, dose optimization was completed, and now we're preparing to extend enrollment. And as Takeshita [indiscernible] mentioned, we will now plan for a pivotal program, and we will initiate a Phase III trial in fiscal year 2024. Next slide. Okay. So this is the overall picture of non-small cell lung cancer. As we mentioned, based on DESTINY-Lung01 and 02 in HER2 is approved in the HER2 mutation positive second line plus setting, we have an ongoing study for HER2 in orange there in the front line within HER2 monotherapy in DESTINY-Lung01 in HER2 mutation positive patients. We showed the data, and we mentioned here in blue, from TROPION-Lung01, we have submission underway. And in addition to that, we have ongoing frontline trials in PD-L1 greater than 50% population and PD-L1 less than 50% population in TL07 and TL08, respectively. And as we explained, DS-7300, our B7-H3 ADC is on route to pivotal trials. So we believe we have a very robust lung cancer program and a growing lung cancer program. Next slide. So now I want to talk about the new disease area. So with EXPAND, we talk about movement into new diseases. And if we could have the next slide. So the idea here is to build on the success of what we've seen so far with the DXd platform and move into gynecology -- gynecological tumors, general urinary tumors in gastrointestinal tumors. Next slide. And so we did present at ASCO 2023 data from CRC02. This is HER2 in advanced HER2-positive metastatic colorectal cancer at 5.4 milligrams per kilogram, which was a better tolerated dose than 6.4 milligrams per kilogram. We saw a robust efficacy signal with a response rate of nearly 38%, median duration, 5.5 months. This is activity irrespective of -- status. Overall, the drug was well tolerated, particularly at 5.4 milligrams per kilogram with no grade 3 or higher ILD. And these results are important for us in extending beyond breast and lung cancer into additional indications. Next slide, please. Of course, we had data from PAN-TumoR02 at ESMO 2023. This is data for an HER2 monotherapy in a broad range of HER2-expressing advanced solid tumors. You can see them there, endometrial, cervical, ovarian, bladder, BTC and pancreatic. Overall response rate, 37.1%, durability 11.3 months, and in the subset of patients with IHC3+, a 61.3% response rate and median DOR of 22 months. We also showed at the ESMO meeting some PFS and OS data that was clinically meaningful, the safety profile, well tolerated. Overall, 1% create 5 ILD rate. And importantly, we plan to file this data within 2023 for a potential -- as a potential tumor-agnostic therapy in previously treated patients with HER2-expressing solid tumors in the U.S. Next slide. So our B7-H3 ADC with a lead indication of small cell lung cancer, has also shown activity in multiple other solid tumors, including esophageal cancer that's squamous esophageal metastatic castrate-resistant prostate cancer and squamous non-small cell lung cancer. So here on this slide, we can see in a cohort of 28 esophageal cancer patients a response rate of 21% castrate-resistant prostate cancer above 25%. That's a cohort of 59 patients. And then on the right, with a smaller group of 13 patients an early signal in swamous non-small cell lung cancer nearly 31%, observed safety profile, manageable and tolerable. And I think that speaks to the breadth of the capability of this B7-H3 ADC to address unmet needs across tumors. The incidence of ILD was 5.7%, and the one grade 5 event occurred at a dose of 16 milligrams per kilogram, which is higher than we will likely see in advancing this drug forward into next stage of trials. Next slide, please. So DS-6000 is our CDH6 ADC, and we presented data at ESMO as well of this agent in platinum-resistant ovarian cancer. And very excited by this data with a strong clinical activity in this patient population, very high unmet medical need with a median of four prior treatment regimens, response rate of 46%. And median duration of response 11.2 months and overall, a tolerable safety profile. You can see by the color coding on the waterfall plot, there were responses at multiple doses. And in the safety, what we observed was there were two Grade 5 ILD events at the 8-milligram per kilogram dose. We're not going to move forward with that dose. And indeed, we're exploring continue to explore 4.8, 5.6 and 6.4 milligrams per kilogram. And at these doses, from what we can see is a very encouraging benefit risk profile evolving. And we will prepare for a Phase II/III study currently, and we're excited to move this asset into pivotal trials. Next slide, please. Okay. So overall, we're making steady progress across these DXd-ADCs. The two drugs and HER2 and Dato-DXd, we have partnered with AstraZeneca. For in HER2, we have built a foundation in breast, gastric and HER2 mutation positive non-small cell lung cancer. We will go earlier as I explained in both Preston lung cancer in multiple studies, and we will go wider, as mentioned with DESTINY-PanTumor02. And in Dato-DXd, we presented these two positive Phase III trial results TL01 and. We will go Breast01 earlier, as I explained, in multiple pivotal breast and lung cancer trials. And we also will go wider, where we are exploring in the PanTumor01, 02 and 03 trials, multiple additional indications in GI, GU in existing and additional tumors. Now for the three assets that we have partnered with our new partner, Merck, HER3-DXd, we will build the foundation with the -- an EGFR mutation-positive non-small cell lung cancer with filing underway with HL01, an ongoing pivotal trial Lung02, we'll go earlier by evaluating combinations, including with osimertinib, and we will go wider. We're just not ready to share those plans yet. For DS-7300, we have our strong signal in small cell lung cancer. We will go earlier, and we look forward to showing you those plans in the future, and we will go wider as explained on the previous slide and the multiple additional indications. And for R-DXd, we see a strong signal in ovarian cancer. And as mentioned, we plan pivotal trial, and we have additional plans to show you in the future going earlier and wider. Next slide, please. So combinations are critical, and we're going to discuss a few of those and combinations are critical for that expansion of R-DXd strategy, and that includes either with our partner, AstraZeneca, with durvalumab, osimertinib or the immunotherapy bispecifics or with our partner, Merck with pembrolizumab and other potential agents. And indeed, that could include also our internal assets such as DS-1103, our SIRPa antibody or our EZH1/2 inhibitor Valemetostat or other external assets. Next slide. So in summary, for these 5 DXd ADCs, a lot of progress made, very exciting in breast cancer within HER2, solidifying position as standard of care in HER2-positive and HER2 breast cancer with Dato-DXd hormone receptor positive breast cancer with a pivotal -- positive pivotal trial TB-01 and then expanding into triple-negative disease with lung cancer in HER2 representing a new targeted therapy in the mutation -- HER2 mutation positive setting, and with HER3-DXd and Dato-DXd establishing foundations in subtypes of non-small cell lung cancer, and with DS-7300 being positioned in small cell lung cancer. In addition to that, we talked about multiple new disease areas, including within HER2 in multiple HER2-expressing solid tumors based on -- and then DS-7300 in multiple indications that are potential and DS 6000 in ovarian cancer. Next slide. So I want to touch briefly on the next wave. And if this is part of our extension strategy that we talked about. So if we go to the next slide. We'll first talk about a sixth DXd-ADC. So this ADC has entered the clinic. We're very interested in this one. This is DS-3939, Its target is MUC1. MUC1 is expressed on a broad range of tumors, including lung cancer, breast cancer, urothelial cancer, ovarian cancer and other tumors, so broad potential. It has a DAR of 8, and this is a Phase I dose escalation study that's ongoing. So we now have 6 DXd-ADCs in the clinic with a robust DXd-ADC pipeline. Next slide. I want to talk a little bit about combinations with our DXd-ADCs. Next slide. So we showed this slide earlier. And indeed, what I want to profile are two of our ongoing combinations with Daiichi Sankyo internal assets, that is Valemetostat and DS-1103. So if we go to the next slide, please. So there is a rationale for combining Valemetostat with a DXd-ADC. Valemetostat is an EZH1/2 inhibitor. The hypothesis on the left is that when Valemetostat inhibits EZH1/2, mechanistically, this decreases the trimethylation of lysine 27 of histone 3. And this will result in an increase in schlafen 11 expression. When schlafen 11 expression goes up, this increases sensitivity to the DXD payload. Indeed, schlafen 11 is a determinant of sensitivity to DNA damaging agents. So we do have a very clear scientific rationale for the combination of this EZH1/2 inhibitor with DXd-ADC. Next slide, please. This is an ongoing study of valametostat with HER2. This is a collaboration study with MD Anderson Cancer Center, and that's in metastatic breast cancer that's HER2 low, ultra-low or IHCs 0 -- I'm sorry, HER2 IHC 0. So interestingly, beyond this combination where we have multiple doses of -- with HER2, you can see on the bottom, another combination company-sponsored trial is under preparation to look at Valemetostat with other DXd-ADCs. Next slide. So this is turning now to our SIRPa antibody DS-1103. And indeed, there is a scientific rationale for combining the SIRPa antibody with HER2. And SIRPa antibody blocks what's called the don't eat me signal or the anti-phagocytotic signal in cancer cells. And you can see on the left, when we combine this SIRPa antibody DS-1103 within HER2, we significantly enhance the antibody-dependent cellular phagocytosis. So demonstrating that mechanism to overcome that don't eat me signal. And then on the right, you can see an in vivo preclinical experiment with an anti-mouse [ SIRP-alpha surrogate ] antibody with in HER2, what you see is that the combination improves survival in these animals. And you can see the red line of survival being higher than the other lines, red line being combination, other lines being the monotherapies of enhertu in the SIRPa antibody. Next slide. So with that, we do have an ongoing Phase I trial of our SIRPa antibody DS-1103 in HER2 expressing solid tumors. In this case, dose expansion is planned in HER2 low metastatic breast cancer within HER2 and further studies in combinations are underway with DS-1103. Next slide. And then we want to close with our unique and innovative assets. Next slide, please. So we did present at this ASH just a few days ago, Valemetostat that same EZH1 and 2 inhibitor, we talked about in solid tumors has the breadth and range to cover potentially not only the solid tumors, but has shown benefit in the hematologic malignancy. Valemetostat as a monotherapy demonstrates clinically meaningful benefit in patients with relapsed/refractory peripheral T cell lymphoma. And here, you can see the results of a Phase II single-arm study, 130 patients with a response rate of nearly 44%, complete response rate of 14.3% and good durability for the medium DOR of 11.9 months with an acceptable safety profile, mostly cytopenias seen. So very good data to address a very high unmet clinical need and including across different PTCL subtypes as shown on this slide. Next slide. So then quizartinib, as mentioned by Takeshita-san, this is an approved FLT3-ITD small molecule in newly diagnosed FLT3-ITD-positive acute myelogenous leukemia based on a randomized Phase III trial, now approved in Japan, the United States and the European Union based on the overall survival benefit on the right side of the slide with a hazard ratio of 0.77. Interestingly, if we move to the next slide. So we showed the positive Phase III trial in FLT3-ITD-positive AML. But what we've seen with an investigator-initiated sponsored study here on this slide, its preliminary evidence of efficacy of quizartinib when added to frontline chemotherapy regimen with newly diagnosed FLT3 negative AML. This is a collaboration study with the PETHEMA Group. Importantly, roughly 70% to 80% of -- AML patients are FLT3 wild type. So most of the patients are FLT3 wild type. In this Phase II study with 273 patients. Even though event-free survival did not reach significance, there was a clear trend of benefit. Hazard ratio for EFS 0.74, hazard ratio for PFS, 0.56. Although not statistically significant on the right side, you can see that KM curve showing a clear trend in favor of quizartinib versus placebo in this frontline FLT3 wild-type population. So we're very excited about the possibilities of quizartinib in this additional larger population FLT3-ITD negative AML. Next slide. And lastly, a potential first-in-class anti-CD147 antibody, a monoclonal antibody targeting CD147, first-in-human trial is ongoing. This target is a potential prognostic biomarker in several solid tumor diseases, including HCC, hepatocellular cancer and CRC. And this CD147 complex has reported to play a role in pathogenesis of cancer, including survival, invasion and metastasis, unique MOA ongoing Phase I study, and we look forward to showing you the results when available. Next slide, please. So the next wave summary is as follows [indiscernible] 5 DXd-ADCs that we're very proud of, we look to the future and to expand. And indeed, that's combinations with next-wave assets with DXd-ADCs, that's accelerating new therapies as quickly as possible with a broad pipeline of greater than 20 candidates in IND-enabling stage across therapeutic areas, including oncology. The next slide. So with our 5 DXd-ADCs, we established the foundation go earlier and wider. And with our next wave pipeline, we continue to grow following these DXd-ADCs based on an EXPAND and EXTEND strategy. Next slide. Okay. So I think I've given you a very thorough overview of our clinical progress. We're excited by the potential to continue to advance this pipeline to meet the goal of our central mission, which is to address unmet medical need, and we will never stop as long as there are patients waiting and need these drugs. Thank you for your time.

We'll now take questions. And the first question is from Yamaguchi-san from Citi.

Can you hear me?

Yes.

This is Yamaguchi from Citi. Three quick questions. The first question goes to Page 38 of the [indiscernible] 08. And regarding this 08, can you give me the rationale why there is so wider difference on ORR between two agent, which is more of the action is a little bit different, one is aromatase, one is Estrogen [indiscernible]. But can you give me the reason. And also can you give me what is the difference between the standard PFS, which I think is like 13, 14 months of standard PFS. So I don't see [indiscernible] benefit of adding a DXd at the moment But can you confirm those two things on this one?

Thank you very much for that question. I think I will ask Mark to answer to address this question.

Yes, sure. So it's a good question. I think the sample sizes are very small. And so I think it's hard to determine any conclusions of efficacy there. I think when we look at the results, they can be easily influenced by a small number of patients, including the fact in the fulvestrant arm, there were a few patients who did withdraw consent prior to disease assessment. So I don't think it's possible to make any clear comparison of efficacy at this point, and we will need to continue to collect further data of combination of endocrine therapy with HER2 to be able to understand further.

Okay. The second question goes to Page 51, regarding lung cancer strategy. This is a bit odd one. So it needs to be upgraded where squamous space will be white in a short period of time, maybe. So can you give me the new strategy of the DS-7300 maybe getting into this NSCLC schemas portion where it's going to be vacant coming maybe from the dato product?

That's really another great question. Yes, because we are seeing some emergent data of promising data in the squamous type non-small cell lung cancer in DS-7300. So I think your expectation is actually a reasonable one that we may have at the DS-7300 our major strategy into the squamous. Yes.

[Interpreted] Okay. I'd like to ask one last question Agatsuma-san. You mentioned various next direction and next-generation products. But I believe that up to 9606, you attached sugar chains and change in the payloads and these are disclosed as patents. I would appreciate if you could give us an idea of the concept of the next generation beyond that.

[Interpreted] Agatsuma speaking, I would like to answer. At the moment regarding the details, our policy is not to disclose yet. But whether or not we use sugar chains, we have several options. And we are in a position to select the optimum one in terms of the concept. And of course, we may try both and select a better one. As a payload, we do have multiple technologies. And as a result, we'll be able to try wide variations. And of those will be selecting the superior one. And we have been preparing for the next new concept ADCs in this way .

The next question is from Hashiguchi-san from Daiwa Securities.

[Interpreted] Hashiguchi from Daiwa Securities. My question is how to leverage DB08 study. Many patients who are pretreated with endocrine therapy, their data as well represented in this data set. But in the market, endocrine therapy naive patients may have a bigger potential in my view. So in the next development, regardless of the prior therapy histories, are you going to target both populations or those who are previously treated with endocrine therapy going to be the focus? You still need to assess further that's mentioned a few times. Do you need a little more time to study optimal dosing and administration? Do you have to consider the potential cannibalization with Dato or in the near future, can you move on to the pivotal study quickly? Are you considering such a possibility as well? I'd like to hear your current view.

Okay. Thank you very much for that question. This is really regarding -- strategy in patients with Hormone Receptor Positive Breast Cancers. Again, here, I will ask Mark Rutstein to address this question.

Yes. Thank you for the question. So indeed, we already have a strong focus in patients who have failed or are resistant to endocrine therapy. And fairly soon, we'll have the readout of DBO6 for HER2 in this HER2 low population where patients would have previously received endocrine therapy. In terms of next potential steps, we don't have anything specific to disclose, but we indeed are interested not only in patients who have failed endocrine therapy or resistant, but also potentially moving into the earlier lines where patients could receive endocrine therapy even potentially for the first time, depending on how early we could take the clinical development. So I would say that we have broad interest clearly we establish a foundation in patients who have received the endocrine therapy. But in hormone receptor positive disease, we absolutely are interested and consider to look at earlier lines of therapy, including potentially patients who are in a more endocrine-naive setting or an earlier setting. And yes, in terms of combinations with hormonal therapies such as anastrozole and fulvestrant, we would absolutely need to collect more data because I mentioned the data sets that we have to date are very limited only about 20 patients in each subgroup so more research to consider.

The next question is from Wakao-san from JPMorgan.

[Interpreted] This is Wakao, JPMorgan. My first question is about partnering. I understand that you partnered with Merck due to changes in the external environment that's highlighted. But I think the external environment will continue to get tougher. Given that, is it correct to understand that you are basically aiming for partnerships with respect to ADCs in the future as well? On the other hand, mega pharma, including AstraZeneca, I think, are also promoting the internal development of ADCs, including this situation. If you aim for partnering in the future, do you think mega pharma will continuously be a partner in the future?

Yes, that's a really good question about our future partnering strategy based on what's happening in external environment. And also in terms -- but also in part -- your question about what kind of pipeline we have with [indiscernible]. But perhaps I can ask Manabe-san to address [indiscernible] on the business side about how you feel about the partnering question.

[Interpreted] First, Daiichi Sankyo partnered with AstraZeneca and experienced a lot. We also wanted to partner with Merck. We reviewed if we could do it ourselves, we wanted to do it alone. But as I mentioned before, we concluded that the partnership would be better than doing it on our own in order to deliver the product to patients quickly. However, I believe that through these two partnerships, Daiichi Sankyo's own marketing sales and the development capabilities will also be strengthened. So we'd like to do the next -- our product on our own. I believe that Daiichi Sankyo has proven ADC's superiority in various ways. And probably because of that, many companies, including MegaPharma have been refocusing on ADCs. We are very confident in our ADC technology. And although many companies, including MegaPharma are also working on it, we think ours is superior. As for which to choose, if there is a good product, we want to develop it quickly and deliver to patients. We believe it is data-driven. And currently, we are superior to others. I think our product will be chosen. I think that we should make the next ADC with confidence. As a result, better ADC will be selected based upon the balance between efficacy and safety.

[Interpreted] Understood. Thank you very much. Second, I'd like to ask a question to Agatsuma-san. You presented the challenges of ADCs and your company's efforts in this area. Various -- companies developing ADCs, mainly in China and mega pharma companies are also involved. In this environment, could you tell us about the specific factors that enable your company to remain a leading player in ADCs? For example, are you overwhelmingly superior to other companies in terms of technology? Or can you give us some more specific points of differentiation.

[Interpreted] Thank you for your question. I myself am honestly surprised by the large investment in the ADC area over the past few years. I feel that ADC has become a major item. On the other hand, we have been steadily expanding for the past 10 years by building a team specializing in ADCs. In our experience, we have worked on antibodies and small molecules. It takes time and effort to optimize the process. We have created DXd-ADCs in our activities up to 2010 to '12. We have also created new technologies that we have yet to introduce to you as we have been refining the process based upon our experience with DXd-ADC. I think we have the big advantage in this area. However, the amount we have invested is very large in the society. And we are aware that competitors are doing this. I mentioned the uniqueness of our concept, craftsmanship and culture by creating a new science and technology, creating it inside of the company and incorporating it and that we refine it as present as possible for perfection. This way, we'd like to differentiate ours.

[Interpreted] Finally, regarding TROPION-Lung01, is my understanding correct that you have already started the filing or you are still preparing for filing?

You're asking about the submission status of TL01. I don't think we have need any announcements yet. But Mark, perhaps you can update us on that.

Yes. No announcement just yet. We're still in the stage of filing planning, but we do indeed plan to file, yes, just not have made any specifics about the time line. Thank you.

Okay. Thank you. I understand. [Foreign Language]

The next question is from Muraoka-san from Morgan Stanley.

[Interpreted] Muraoka [indiscernible] I have a question on 7300 on Page 50. Regarding IDH1 study results timing, will be available around 2025 or it will take a little more time, what will be the timing? And on the same side, Phase III, this Phase III that is starting. Can it be a registrational study as pivotal by evaluating, for example, ORR or will you look at it until survival data becoming available? And is the target going to be an extensive stage [indiscernible]

Okay. This is a question about the small cell lung cancer program for 7300. And in the initial study of [ 1981 ] which was a dose-finding study, and we have the results of that. And based on the results, we are now able to initiate a Phase III study using the dose that we selected. The dose selection was actually put quite clear based on the risk benefit profile that we saw with the 2 doses. Mark, you perhaps want to add some additional comments?

Thank you, Takeshita-san. And so we haven't disclosed exactly what the design of our study would be. We also have not disclosed a registrational strategy. I think you asked about accelerated approval versus waiting for the overall survival. So more information to come, but we're not yet prepared to share such detail. And yes, the target indication is extensive stage small cell lung cancer to confirm your question. And in terms of the publication from the Phase II dose finding study, we have not yet announced a data publication, but we'll provide that data as soon as possible.

[Interpreted] I just want to reconfirm regarding this IDH1 results. For example, at ASCO or ESMO in 2024, can we expect that you'll be presenting or publishing the data?

I don't know the actual publication plans for the [indiscernible] clinical trial. Mark, are you aware of the details of that plan, [indiscernible] next year?

Yes. So we haven't announced exactly at which Congress will bring the data. There's a good chance it could be in 2024, but we don't have a publication strategy to share, including which Congress .

[Interpreted] Understood. Thank you very much. That's all.

The next question is from Mamegano-san from BoA.

[Interpreted] Mamegano from BofA Securities speaking. I have a question about DB08 study. I think the data is quite good. I want to know about the competitive environment. CDK4/6 inhibitors and more recently, AKT inhibitors are becoming available. If you are to proceed with the study in HR positive cancer, I think you will need to impair against these competitors, and you can win in terms of efficacy, including safety. Could you please comment on your competitive edge compared to endocrine therapy for breast cancer?

Mark, I want to ask you to comment on this question again about DB08 and the competitive landscape for the Hormone receptor-positive breast cancer.

Yes, I'm glad to comment. So indeed, I mean the standard of care in the frontline setting is endocrine therapy in a CDK4/6 inhibitor, and there's a clear benefit in standard of care. In addition to that, as you mentioned, there are KT inhibitor. And there are multiple trials ongoing to improve upon the existing standard of care. So it's a very active and dynamic space. So we are looking at that earlier stage of HER2 low breast cancer, and there are multiple strategies we can pursue. But at current, we're not disclosing exactly how we would approach this. I would say, though, we are fairly confident in the tolerability that we've seen from HER2 with very favorable benefit risk profile, right, in DB04.We will soon show and have the data for the DB06. And based on what we know today, we believe that it would be possible to build a tolerable regimen to study earlier stages of HER2 low metastatic breast cancer using in HER2. So multiple potential strategies, nothing that we can disclose today and confident in the tolerability of ENHERTU in this setting.

The next question is from Sogi-san from Sanford Bernstein.

Thank you very much for taking my question. I'd like to have views both from the research and development on two points. First of all, it is great that you continue to advance the improvement of ADC platform. But also, I think when we look at the ADC, we questioned that it is a really ADC platform. Obviously, you have made a tremendous progress comparing to the previous versions. But I think at this stage, we also question about the targets because obviously, HER2 was an excellent target for monoclonal antibody as well as the ADC, that's sure really evolving, the efficacy. But we also sort of feeling that HER2 is actually a little bit exceptional, and we may not be able to replicate such efficacy in other targets. So I'd like to have -- I'd like to hear from both research and the development on this point. And -- but at the same time, we also understand that -- ADC really opened the kind of different prospects, which is that the ADC doesn't have to really target driver of the over expression of the target that is present on the cancer cell, but rather even the presence of kind of smaller amount, which was demonstrated in HER2 low the situation, as long as you can deliver the drug to those cancer cells that actually that brings the efficacy. So a little bit of a complicated question, but I really like to see what is the potential target you are seeing? What is the difference from the HER2 and the future of ADC? That is first question. And the second question is the expense strategy and particularly, you mentioned about the combination with a -- and this sounds like this is a strategy to sensitize the cancer cell to your payload. But it looks like your payload is the potency is quite high already. But I think the really challenge seems to be more the target driven, which I alluded to earlier. So I'd like to have the -- your peers on these points.

Thank you very much for those 2 questions. I would try to address the questions and then I hand it over to [indiscernible]. And I think your first question was about the future of ADCs and how we think about this. And in addition to the target on antibody portion, there are 2 other components to ADCs, the linker and the payload. And I hope to understand that based on a lot of research, but it's possible to vary, not just the target but also the linker and the payload to give rise to ADCs with many different properties different from the original DXd series of ADCs. So it's possible to create the new drugs, very different from the original we experience the ADC series. So I don't know [indiscernible] comments and from a research standpoint [indiscernible].

[Interpreted] research would like to comment. Thank you very much indeed for your insightful question. We have engaged in research activities by keeping on mind the selection of targets as well as the antibodies, which bind to the target. One thing I can say here is that ADC is an area which has just started in research and development, how to bind to cancer cells, how to go inside the cells, what kind of behavior is considered good for ADCs. There are still many unknowns. I think that is the correct understanding. We rigorously chose parameters, we could set back then. And what we selected based on them is the current DXd-ADC. With substantially high efficiency, I think we have been able to provide benefit above a certain level. Of course, we are continuing our research. We are pursuing something like ADC specific pharmacology. While studying, what kind of things consider superior, we'd like to leverage the knowledge to the next program. I cannot disclose the details, but the payload is different for new concept ADCs. Potency is different and the mechanism is different. The target appropriate for each ADC may be different from the target for DXd-ADC. We spotlighting these factors and selecting targets and antibodies. That's all for me.

Okay. Thank you very much. Mark, any comments from a clinical development standpoint on future of DXd beyond HER2?

Yes, I think I got Agatsuma-san and Takeshita-san have covered it. I would just say from a clinical standpoint, I'm excited by the potential of innovation, looking at multiple structural aspects of ADCs. And of course, targets, linkers, payloads. But in addition to that, the potential for even bispecific ADCs. Or I mean, many ways that we can look -- that we can look to optimize both the benefits side of the antibody drug conjugate, but also minimize the toxicity. So nothing more to add, but excited for all that's possible in these new concept ADCs. I think there was also a question on the mechanism of action by which development that would potentially drive additive or a combination effect within HER2. In HER2 is a targeted agent, of course, but Valemetostat has a very different mechanism of action indeed based on the literature, there's evidence that Valemetostat could absolutely sensitize cancer cells to DNA damaging agents based on this upregulation of schlafen 11. But anything further I could clarify on the hypothesis and the reason for the combination, I'm happy to do that.

Thank you very much. Very helpful.

We've ran over the scheduled time, and we would now conclude Daiichi Sankyo's R&D Day. Thank you very much for joining today. [Portions of this transcript that are marked [Interpreted] were spoken by an interpreter present on the live call.]