English presentation slides will be shown on the Zoom screen as well as live streaming screen. Both Japanese and English presentation slides have been uploaded to the IR Presentation Material page of Investors section on our corporate website, so please view or download as needed. Our presenters for today are Dr. Ken Takeshita, our Head of Global R&D, Dr. Mark Rutstein, our Head of Global Oncology Clinical Development, Dr. Dale Schuster, our Head of Global Precision Medicine, and Dr. Hiroto Kashiwase, our Head of Global Technology.
We will take questions after the presentation. Dr. Sunao Manabe, our Executive Chairperson and CEO, will open the meeting and will join the Q&A session. Please note that this event will be recorded. With that, let's start the event. Manabe-san, please.
Hello, colleagues. I'm Sunao Manabe, Executive Chairperson and CEO of Daiichi Sankyo. Welcome to our Science and Technology Day. With the growing DXd ADC pipeline, we understand that many stakeholders are very interested in our technology as well as our ADC manufacturing and supply plan. So we have renamed this annual IR event, Science and Technology Day, for this year. When I look back on this year, one of our big accomplishments was the DESTINY-Breast06 study presented at ASCO in June.
Based on the data, we anticipate to further redefine the classification and treatment of metastatic breast cancer with a new use of ENHERTU for patients with unresectable or metastatic hormone receptor positive, HER2- low, and HER2- ultra-low breast cancer. We believe that ENHERTU will continue to change the treatment paradigm for certain patients with breast cancer and broaden the number of people who may be eligible for a HER2-directed medicine.
Recently, we announced that Daiichi Sankyo and AstraZeneca were awarded the Galien Foundation 2024 Prix Galien USA Award for ENHERTU for the best biotechnology product. We are honored to receive this prestigious award in recognition of the science and technology behind ENHERTU, and are thrilled that Dr. Agatsuma was able to accept the award as he was instrumental in the invention of the ADC technology behind ENHERTU. You likely are aware of the sudden passing of Dr. Agatsuma less than two weeks ago. All of us at Daiichi Sankyo are profoundly sad.
Agatsuma-san was a true scientific trailblazer who passionately believed that antibody-based therapies were the future of medicine, which sparked the transformation of Daiichi Sankyo into a global company with competitive advantage in oncology. His legacy will forever be etched into the history of Daiichi Sankyo with its purpose of contributing to the enrichment of quality of life around the world. Now, taking this opportunity, I would like to introduce Dr. Yuki Abe, who will succeed Agatsuma-san and will become our Head of Research effective January 1st.
Abe-san has more than 20 years of work experience in drug discovery research, and in 2010, he joined the ADC research team led by Agatsuma-san, where he made significant contributions as a leader of pharmacological research in discovering our unique DXd ADCs. I strongly believe that Abe-san's leadership will continue to shape the future of Daiichi Sankyo's pipeline with his scientific knowledge. And now, for a word from Abe-san, please.
Hello, colleagues. I'm Yuki Abe. As Manabe-san mentioned, I'm an original member of Agatsuma-san's ADC research team and have worked together with him on ADC research and as research leadership and management for more than 15 years. I will build on our research strategies, enhance our scientific leadership, and contribute to patients and their families' lives. I'm very confident Daiichi Sankyo will continue to create new business opportunities by enhancing our science and technology. Thank you.
Thank you, Abe-san. In addition to the Prix Galien USA Award, we are also honored to receive the World ADC Award for I-DXd and R-DXd, the most promising clinical candidates. This honor for I-DXd and R-DXd means that all five DXd ADCs have received the award in the past five years. Additionally, we received our 12th Breakthrough Therapy designation from the FDA for Dato-DXd based on the TROPION-Lung05 study. We will keep growing with our goal of being a global pharma innovator with a competitive advantage in oncology.
By accelerating value maximization for our ADCs, I'm confident that we will achieve our 2025 goal and keep growing toward our 2030 vision, which is to become an innovative global healthcare company, contributing to the sustainable development of society.
Today, Ken Takeshita will first provide an R&D update, followed by Mark Rutstein and Dale Schuster to discuss the progress of clinical development and translational research. Finally, Hiroto Kashiwase will explain our plan to expand our ADC manufacturing capabilities and the establishment of a global supply platform. Now, I'll hand the reins over to Ken Takeshita. Ken-san, you are up, please.
Manabe-san, thank you very much. And it's a pleasure for me to give you first an overview of where we stand within our research and development organization and the progress we have made so far this year. Next slide. This is our basic strategy on what we are trying to accomplish in oncology. Within the DXd ADC programs, we are very interested in, first, in the two major indications, lung cancer and breast cancer, and expanding those indications into earlier lines of therapy. In addition, we also want to expand the range of DXd ADC usage into diseases other than lung cancer and breast cancer.
So this is part of the left-hand side of the slide. Now, on the right-hand side, you will see yet another component of our R&D strategy, which is to address unmet medical needs after HER2, identify combinations of unique combinations of our DXd ADCs with other compounds, particularly those within our own pipeline, and also to grow the earlier pipeline in terms of second, third, and other next-generation ADCs. And that's part of our extended strategy. Next slide. First, let me touch on our breast cancer program.
And our vision really is to deliver transformative therapies that improve the lives of patients with breast cancer. And I think all of you will probably agree with us that HER2 has pretty much delivered these types of transformative therapies, initially in the relapse refractory metastatic setting. And as we move forward into earlier lines of therapy, HER2 continues to demonstrate exceptional clinical trial data. Next slide.
This is our summary of our major progress in our breast cancer since last year. In terms of our ENHERTU program, the clinical trial DESTINY-Breast06 showed that ENHERTU was active not just in HER2-positive patients, but also HER2-low and, moreover, HER2-ultra-low breast cancer patients, in patients who are all hormone receptor positive. I think you're aware that we have submitted the data from this DESTINY-Breast06 trial for regulatory approval in various parts of the world.
In terms of going into earlier lines of therapy, there are a number of very important clinical trial readouts that are coming up in terms of both the Dato program and the ENHERTU program. Top-line results are anticipated for TROPION-Breast02 in triple-negative breast cancer and also DESTINY-Breast11 and DESTINY-Breast05 and DESTINY-Breast09. These are all coming up in the next one-year period or so.
In terms of hormone receptor positive or HER2-negative breast cancer, we are proceeding with our submission plan for TB-01, and as you may remember, the PDUFA date on that submission is January 29, 2025, which is about a month away from now. Of course, we are continuing to study in-house assets, valemetostat being a combination partner for DXd ADCs in breast cancer, and also ENHERTU and DS-1103. This is a SIRP alpha program, again, a combination particularly focused on breast cancer. Next slide. This is our disease map.
This is a depiction of the world of breast cancer in multiple lines of therapy, lines of therapy depicted in the vertical columns, and on the left-hand side, in the rows are the various subtypes or subsegments of breast cancer. You'll see that in every segment of breast cancer, we have a clinical trial going on. In many of the segments, particularly triple-negative breast cancer and HER2-positive patients, we have multiple clinical trials in earlier lines of therapy, including the first-line, adjuvant, and neoadjuvant.
I think it's very important to note that we have not just ENHERTU, but also the Dato program in blue in many of these patient groups. Of course, in green are some earlier phase clinical programs in HER3, DXd ADC, 1103, and valemetostat. These are in earlier lines of earlier part of development. We're very hopeful that they will all bear fruit in the way that Dato and ENHERTU has. Next slide. We continue also to be very interested and focused on lung cancer, particularly with respect to ENHERTU. These are the HER2-positive and HER2-mutated patients with lung cancer.
But more importantly, very important program of Dato-DXd in non-small cell lung cancer, as well as some new assets that we have in small cell lung cancer, the Harpoon asset, T-cell engager, and our own DS-7300 B7-H3 DXd ADC. So let me just go over some of the details of our lung cancer strategy. Next slide. So this is a summary of the major progress we have made since the last R&D data we had about a year ago. And I think you're aware that we obtained clinical trial data on TROPION-Lung01. We submitted the data for FDA.
Unfortunately, based on the FDA interpretation of the data and our discussions with the FDA, we have withdrawn the submission for TROPION-Lung01, but instead replaced it with a new submission for accelerated approval in a new patient population, EGFR-mutated patient population, based on TROPION-Lung05, which was a focused clinical trial in EGFR-mutated patient population, as well as supplementary data from TROPION-Lung01. In fact, we are very strongly positive on the data we're seeing in EGFR-mutated patient population.
We did receive the breakthrough therapy designation from the FDA for this patient population based on the data that we submitted. In addition, we remain very interested in exploring HER3-DXd as a potential new treatment for EGFR-mutated non-small cell lung cancer. We did, however, receive a complete response letter for our DESTINY-Lung01 submission due to some manufacturing issues, which we can discuss later at this meeting.
We have very interesting new combination studies going on with our alliance partners. And these may represent new future standards of care. And these are the clinical trials TL10, TL12, TL14, and TL15. In addition, in small cell lung cancer, as I mentioned to you earlier, we have started a collaboration with our Merck pharma counterpart in a compound known as MK-6070, also known as the Harpoon asset, which is a DLL3 targeting T-cell engager.
So this compound has generated a lot of interest due to high response rates that have been reported already in clinical trials of relapsed refractory small cell lung cancer. And so it's a very natural combination partner for our I-DXd, this DS-7300 program, because I-DXd also has demonstrated high response rates in relapsed refractory small cell lung cancer. In addition, we have initiated pivotal studies in lung cancer, focusing again on the small cell lung cancer with our I-DXd program. And this will be right now a monotherapy study.
But as I mentioned, we are also studying in combination with the Harpoon asset. We remain very interested in earlier lines of therapy for lung cancer. And as you know, we have multiple clinical trials going on in frontline lung cancer with Dato-DXd program in non-small cell lung cancer. Next slide. This is our disease map, the lung cancer disease map. And here again, we have lines of therapy in the vertical and the patient segments depicted on the horizontal.
You'll see here again that we have many, or maybe most of the patient segments covered by all of our assets, a major one being in blue our Dato program, but also to mention that in orange is our ENHERTU program. Yellow is our I-DXd program, DS-7300, and HER3-DXd in green. Not shown here, but very much on our mind, of course, is our Harpoon asset, the DLL3 engager, also in small cell lung cancer. Next slide. This is a listing of our major progress in indications other than breast cancer and lung cancer.
Just to reiterate that we have multiple clinical trials going on in these other cancers, such as, for example, with ENHERTU, we received a pan-tumor approval based on the pan-tumor study for HER2-positive solid tumors. We also have a clinical trial going on now in BTC, biliary tract cancer, in the front-line setting in the form of BTC01 clinical trial. In terms of other DXd ADCs, we have pan-tumor studies with the HER3 program, the I-DXd program, and also the R-DXd program, really to explore with all these ADCs the range of potential indications for these three ADCs.
In ovarian cancer, we have initiated a pivotal study called the REJOICE-Ovarian01. The first subject dose was back in April of 2024. We also have next-generation therapeutics in the form of DS-9606. This is a new one, a next-generation ADC with a different payload. And we also have received approval for valemetostat, an EZH2 inhibitor in PTCL in Japan, but more and more interestingly, perhaps, is that it's a potential combination partner for all of our DXd ADCs.
And finally, we are working on a new formulation for patient convenience as a subcutaneous formulation of ENHERTU. Next slide. And I spent a lot of time on clinical trial update, but I do want to make sure to mention that we are also making a lot of progress in bringing more innovation to our research programs. And this slide shows you what we're doing in terms of promoting external collaborations. We have created what we call research innovation hubs in key cities around the world.
And so far this year, we have established and opened our offices in Cambridge, Massachusetts, and in Munich as places where we gather information from various biotech companies and academia in those regions and establish collaborations or partnerships. We are remaining, of course, very much interested in promoting innovation in not just the clinical area, but also, as you can see here, in the research area also. With that, let me just turn it over to Mark Rutstein, who will give you the details of our clinical trial update.
Great. Thank you so much, Ken, for setting the stage and providing an overview of where we stand in terms of our R&D strategy, so if we could go to the next slide, please. Yes, and my name is Mark Rutstein. I lead oncology clinical development at Daiichi Sankyo. So a true pleasure to be here, and we'll be covering a number of topics, and we'll try to be efficient. We'll talk about recent clinical data from medical congresses.
We'll talk about the activity of the DXd ADCs in brain metastasis. We'll also profile some of the pivotal trials for HER2 that are ongoing in early-stage disease frontline and adjuvant and neoadjuvant that we'll read out in the coming year, and we'll look at ILD analysis, as well as a few of our new assets to profile, demonstrating the robustness of our pipeline, its breadth and depth, so next slide, please.
In terms of Congress highlights, this is a snapshot of DB06 PFS exploratory subgroup analysis. We've heard from Manabe-san and Takeshita-san on this dataset. And we know in the intent to treat population, it was a significant clinically meaningful PFS benefit in the HER2- low population and the ITT population, which encompassed ultra-low patients as well. Here we look at PFS in subgroups of time to progression on frontline endocrine therapy and CDK4/6 inhibition.
You can see the 3KMs, whether or not time to progression had occurred in less than six months, six to 12 months, or greater than 12 months, and HER2 demonstrated a clinically meaningful efficacy benefit. And this included patients with rapid progression on frontline ET and CDK4/6. Next slide, please. Continuing on this trend of DESTINY-Breast06 efficacy subgroup analyses, we look here at the PFS benefit in HER2 being observed regardless of disease burden.
So if we look to the left side of the slide in the two Kaplan-Meier's, in the subgroup of patients with less than three local or metastatic sites at baseline versus those in the bottom with greater than three, equal to three local or metastatic sites at baseline, we can see robust efficacy regardless in terms of PFS. And then on the right side in the table, a couple more measures of disease burden, baseline tumor size, and visceral disease status. So regardless of these subgroups, the baseline tumor magnitude or whether or not patients had visceral disease, we can see there is consistent benefit of ENHERTU in this study.
If we move to the next slide, please. So this is just a complement and look at the safety as well. So here we have safety, overall safety in those subgroups which we discussed, subgroup of the time to progression on the frontline endocrine therapy and CDK4/6, or the subgroups according to disease burden. And we can see that the safety profile of ENHERTU in these subgroups is consistent with the overall safety profile that we saw in DESTINY-Breast06, whether we look at grade 3 related AEs, serious AEs, AEs leading to discontinuation, or occurrence of ILD.
Next slide, please. So now we shift to another dataset presented at the San Antonio meeting just about a week ago. And this is DESTINY-Breast08. So of course, in our development plan, we look to understand what are optimal combination partner drugs for ENHERTU. So here in a HER2-low metastatic breast cancer patient population, a phase I-B study looking at the combination of ENHERTU with either capecitabine or capivasertib. So on the top, what we see when ENHERTU is combined with capecitabine in a 20-patient subset, there's a 60% response rate.
On the bottom, with ENHERTU is combined with capivasertib, which is an AKT-inhibiting drug from our partner AstraZeneca, the response rate is also in the 60% range. And when we look at the subgroups of patients that were treated with ENHERTU and capivasertib, whether or not they had PIK3CA, AKT, or PTEN altered tumors, we saw evidence of efficacy. And then from a safety standpoint, the safety in these combinations was generally consistent with what we know about the agents that are included in the combination. Next slide, please.
So now we turn to the dataset that was alluded to by Takeshita-san that looks at EGFR mutation-positive non-small cell lung cancer with Dato-DXd. This is the dataset which supports the recently disclosed submission in the November timeframe for EGFR mutation-positive non-small cell lung cancer for accelerated approval. So here what we see is a pooled analysis of EGFR mutation-positive non-small cell lung cancer patients in TROPION-Lung01 and TROPION-Lung05. And this was presented at the ESMO Asia meeting in 2024.
People will remember that TROPION-Lung05 serves as the basis of the submission that we've made with supporting evidence from TROPION-Lung01 and PanTumor01. But this dataset pools the Lung01 and the Lung05 data. You can see the eligibility criteria on the left, fairly similar eligibility criteria overall. There was in TROPION-Lung05 a dedicated phase II study to AGA non-small cell lung cancer population, most of whom were EGFR mutation-positive. They had to have at least one line of prior therapy and also one to two prior cytotoxic agent-containing therapies in the metastatic setting.
In TROPION-Lung01, again, here a little bit different, but again, we'll see in the demographics, it's a similar population, one to two prior approved targeted therapies and also may have received immunotherapy. And the patients were 137 patients from TROPION-Lung05 phase II and then Dato-DXd in TROPION-Lung01. Excuse me, 137 patients EGFR mutation-positive in TROPION-Lung05 in the pool. And then from TROPION-Lung05, there were 78 and then Lung01 39 patients, and they were looked at for efficacy. So a total EGFR mutation-positive pool of 117. Next slide, please.
So here are the demographics and baseline characteristics. And what you can see here, I would maybe focus on the median lines of systemic therapy, second from the bottom. And you can see in the pool of 117 patients, you can see there's a median of three prior lines of therapy. If you look to the right, you can see that the TROPION-Lung01 EGFR mutation subpopulation of that phase III trial, they were a little bit less heavily pretreated at a median of two lines. But overall, this is a heavily pretreated patient population.
And on the bottom row, you can see that a large percentage of these patients have received prior osimertinib, both in the frontline and in the second line. If you move to the right, you can see the EGFR mutational profile. The majority of patients had exon 19 deletions, but the aberrations ran the spectrum in terms of EGFR mutation profile. Next slide, please. So here is the efficacy data of the pooled analysis in EGFR mutation-positive non-small cell lung cancer.
You can see in the pool, the confirmed response rate was nearly 43% with a median duration of response of seven months, median PFS of 5.8 months, median overall survival in this pool, 15.6 months. Now, patients who received prior osimertinib have had similar efficacy. And so on the basis of what we see here, we believe this is robust clinical activity in a high unmet medical need patient population, very advanced and heavily pretreated EGFR mutation-positive non-small cell lung cancer.
So overall, very promising efficacy and formed the basis for the disclosed regulatory accelerated approval submission in the U.S. Next slide, please. So to complement, we discussed the safety. Overall, we can see there were low rates in this pool of 117 patients, low rates of serious treatment-related AEs, leading to discontinuation. Grade greater than or equal to two stomatitis, which is a known adverse event of interest for Dato-DXd, our TROP2 DXd ADC, was seen in about a third of patients but was effectively managed with dose reductions and delays.
And in fact, there were no treatment discontinuations due to stomatitis. In addition, no grade 4 or 5 ILD events in this pool of patients. So overall, considering both the safety and the efficacy, we believe there's a positive benefit-risk profile here for the patients and that this may be a potential treatment option for them in the second line and later setting. Next slide, please. So now I'm going to shift gears to hematology. Of course, we do spend a good amount of time talking about our solid tumor portfolio and our DXd assets. But we are certainly very enthusiastic about Vanflyta or quizartinib.
So what we see with the arrow here on the left is quizartinib or Vanflyta, which is a small molecule FLT3-ITD inhibitor, had actually been tested in relapse refractory AML in FLT3-ITD mutation setting. This had actually led to approval in Japan. And then more recently, the newly diagnosed AML study called QuANTUM-First was conducted. And we've disclosed that that led to global regulatory approval in many regions for quizartinib in combination with standard cytotoxic chemotherapy in frontline FLT3-ITD mutation-positive AML.
But now more recently, we have announced the start of a study in FLT3-ITD negative or wild-type AML. And this is called the QuANTUM-Wild Study. We'll show the design on one of the next slides. This study was brought forth based on an investigator-initiated phase II study called QUIWI. Now, before we transition to the next slide, I want to point you to the pie graph on the upper left because the approval of Vanflyta in FLT3-ITD frontline AML was important for patients. This only represents about 30% of the patient population. Indeed, a much larger portion, 70%, is FLT3-ITD negative.
Next slide, please. As background, it is not only FLT3-ITD mutation that may drive survival and proliferation of leukemic cells. Indeed, elevated expression of the FLT3 receptor, including the wild-type receptor, is observed. High levels of FLT3 gene expression are detected in a high percentage of the AML blasts independent of FLT3 mutation. And therefore, we believe this is the basis by which this small molecule FLT3-ITD inhibitor could drive utility in patients who do not express, whose disease is not associated with the ITD mutation.
So the clinical utility of Vanflyta in patients with FLT3-ITD negative AML is supported by clear evidence. That is preclinical studies, including ex vivo plasma inhibitory assays showing suppression of the FLT3 phosphorylation in cells expressing the wild-type FLT3, but also clinical data. And indeed, there was some phase I data and also phase II data. So if we move to the next slide, this is the phase II investigator-initiated dataset called QUIWI that supports indication expansion for Vanflyta to that newly diagnosed FLT3-ITD negative AML setting.
So these are descriptive efficacy results, but they provide a clear trend in efficacy. If you look on the left with the primary EFS endpoint, clear separation of the curves with a hazard ratio of 0.72. If you look on the right, overall survival, hazard ratio 0.63. And again, although not achieving statistical significance, a very clear trend in efficacy with the separation of the KM curves. So we're very excited for the potential of this drug to address a further and broader AML population. Next slide, please. Here is the new phase III study design, QuANTUM-Wild. So this is a randomized trial in frontline FLT3-ITD negative AML.
It is newly diagnosed AML. And the patients receive induction cytotoxic therapy. Then they're randomized two to two to one to Arm A, which has quizartinib in induction plus quizartinib and standard therapy in consolidation, and then quizartinib monotherapy versus Arm B, which is placebo throughout, no quizartinib in all three phases of treatment, versus Arm C, which has quizartinib in induction, quizartinib and standard therapy in consolidation, and then placebo. Arm C is intended to help us understand the contribution of quizartinib to that maintenance phase.
The primary endpoint is overall survival. Secondary endpoints include event-free survival. We're excited to say that this study is starting. Next slide, please. Now we'll talk about DXd ADCs in brain metastasis. Next slide. Brain metastasis in breast and lung cancer is described here. Brain metastases occur in nearly a third of patients with HER2-positive breast cancer or TNBC. 10%-20% of these non-small cell lung cancer patients have brain mets at the time of diagnosis. We also know small cell lung cancer patients are even twice as likely compared to non-small cell to develop brain mets.
Of course, brain metastases have a significant impact on prognosis and quality of life. Next slide, please. A key dataset from ESMO 2024 addressing HER2 in brain mets was the DESTINY-Breast12 study. This is a phase III-B study in patients with HER2-positive advanced breast cancer having received two or fewer prior lines of therapy. Two cohorts are enrolled into this study, patients with brain mets, that's above in the dark blue, and that's either stable brain mets or active brain mets. Then we look at the PFS. Then patients with no brain mets for which we look at overall response rate.
This is the largest study, a prospective study of ENHERTU in HER2 in patients with brain mets. Next slide, please. Here is the key efficacy data in patients with baseline brain mets. There were 263 patients with baseline brain mets, some stable, some active. You can see the 12-month PFS rates, 12 months overall survival rates, and 12 months CNS PFS rates, that's progression-free survival in CNS lesions, was pretty similar and consistent between patients with active and stable brain metastasis.
Then on the right, on the bottom bullet, what's not shown is there was consistent 12 months overall survival in patients with brain mets and those without brain mets. You can see that's quite high at more than 90%. Next slide, please. Here is the central nervous system overall response rate in baseline brain met patients. These are patients with measurable CNS disease at baseline, which is a post-hoc analysis. What you can see is that ENHERTU showed substantial CNS response. This is CNS overall response rate.
CNS response in the overall patient population, including the subgroup of patients with stable and active brain mets. Next slide, please. Here is the safety. Here's an overall summary in DESTINY-Breast12 of AEs occurring in 20% or greater patients in either cohort. When we look at the types of events of nausea, fatigue, constipation, neutropenia, etc., this is very much consistent with the previous reports of ENHERTU with no new safety signals identified. Next slide, please.
Though we will not have time to present all the other datasets demonstrating DXd efficacy in non-small cell lung cancer patients with brain mets, we wanted to provide a summary of what has previously been disclosed, including in HER2 in DESTINY-Lung01 and DESTINY-Lung02, demonstrating monotherapy in intracranial activity in patients without prior treatment of bone mets, including Dato-DXd, our TROP2 DXd ADC, showing activity and efficacy in TROPION-Lung05, which we discussed moments ago in terms of the pooled analysis, and then also TROPION-Lung01 as wel.
The pivotal trial in the second line setting demonstrating activity in patients with and without baseline bone mets, and then lastly, as we had previously presented, our HER3-DXd demonstrating durable intracranial response in patients EGFR mutated who had baseline brain mets and no prior radiotherapy in HL01. Next slide, please. We want to close out the discussion of brain mets with I-DXd. This is our B7-H3 DXd ADC. This is an ongoing and important program in small cell lung cancer.
We had presented at the ESMO IDeate-Lung01 subset analysis demonstrating the efficacy, particularly of 12 mg/kg with a 54% overall response rate in second line plus small cell lung cancer. Here we look further into that subset in the patients with brain mets. What you can see is that in the 37 patients with brain mets in this small cell lung cancer population, the CNS confirmed overall response rate was nearly 38%. CNS duration of response was 6.2 months.
And then in the subset of 16 patients with brain target lesions at baseline, the CNS confirmed overall response rate was about 53% with a CNS duration of response of 4.4 months. And the safety in this population was similar in patients with and without brain mets. Next slide, please. So overall, there's accumulating evidence across assets and datasets establishing the DXd ADCs are effective in brain mets and breast and lung cancer. And this continues to show the benefits of the DXd platform and its ability to address high unmet need patient populations and high unmet clinical need patient subgroups.
Next slide, please. So now we'll quickly talk about the early line pivotal trials for ENHERTU in HER2 that are ongoing. Next slide, please. So Takeshita-san had showed this scheme of our breast cancer clinical trials. What we're going to do now is just briefly have a quick reminder on the design of DESTINY-Breast09 in HER2-positive frontline disease, DESTINY-Breast05 in the adjuvant setting, and then DESTINY-Breast11 in the neoadjuvant setting as these trials will be reading out in the 2025 timeframe.
Of course, we have other trials that are going to read out, but we're not going to talk about the designs here today. We mentioned earlier TROPION-Breast02 in frontline triple negative breast cancer. More to come, of course, but we're going to talk a little bit about in HER2 now. Next slide, please. This is DESTINY-Breast11. This is a neoadjuvant study. As we think about these studies, in HER2 has provided transformative clinical benefits to patients with advanced breast cancer in different patient segments.
So now there's an opportunity as we read out these trials in the 2025 timeframe to determine that ENHERTU can potentially bring benefit to patients in earlier lines of therapy. So this is in the neoadjuvant setting ENHERTU monotherapy or ENHERTU followed by standard THP, that's paclitaxel, trastuzumab, and pertuzumab versus dose-dense AC followed by THP in high-risk neoadjuvant HER2-positive early breast cancer. And you can see these patients are receiving ENHERTU and Arm A, Arm B with the sequence of ENHERTU four cycles followed by four of THP, and then the control group.
And we anticipate readout in the first half of 2025. Next slide, please. So this is DESTINY-Breast05. And so this is the high-risk adjuvant setting. So this is ENHERTU versus T-DM1 in HER2-positive patients who have residual invasive breast cancer following neoadjuvant therapy. These patients have undergone what is believed to be adequate surgical excision with removal of clinically evident disease in the breast and lymph nodes, but they do have evidence of residual invasive carcinoma despite the surgery and despite the neoadjuvant treatment.
And so the primary endpoint for this randomized study with two arms, a big study, 1,600 patients, is invasive disease-free survival. And there are secondary endpoints including overall survival also anticipated in 2025. Next slide, please. So the last study I will profile the schema for is DESTINY-Breast09. So this is our frontline study in HER2-positive metastatic breast cancer. These patients have no prior chemotherapy or HER2-targeted therapy for advanced or metastatic disease, except that they may have received one previous line of endocrine therapy.
They are randomized to ENHERTU versus ENHERTU plus pertuzumab versus the THP standard regimen in the frontline setting, which is again paclitaxel, trastuzumab, and pertuzumab. Primary endpoint PFS by BICR, overall survival is the secondary endpoint. Data also anticipated in 2025. Next slide, please. Now we're going to look at an analysis of drug-related ILD for our TROP2 ADC Dato-DXd. Next slide, please. This is a pooled analysis of ILD from ASCO 2024. In some of our previous discussions, we have verbally mentioned this analysis but have not showed it as we do today.
ILD is an important adverse event of interest for DXd ADCs, including Dato-DXd. This is a pooled analysis across all tumor types. What we can see is that the overall incidence of adjudicated, this is adjudicated by a third-party expert committee. The overall rate of adjudicated drug-related ILD cases seen with Dato-DXd was fairly low. You can see the black highlighted numbers in the table to the left. You can see the majority of cases were low grade, grade 1 or 2. There were cases that were grade 3 and higher. Indeed, there were fatal cases. You can see the rates that are there, grade 5.
We do take this very seriously as an adverse event of interest and indeed have adopted careful monitoring and management into our clinical programs. Dato-DXd-related ILD was more commonly observed in patients with lung cancer. You can see that in the table, 6.8% rate versus breast cancer, let's say, with 2.9% rate versus all other tumors at 3.3% rate. Additional risk factors aside from underlying disease are under investigation.
So overall, considering the rate and that the majority of cases were grade one or two, and considering the efficacy that we've seen with Dato-DXd in disease states, including, as we've shown today, and highlighted EGFR mutation positive non-small cell lung cancer, this pooled analysis supports a favorable benefit-risk profile for Dato-DXd in solid tumors. Next slide, please. So we have two more slides. And what I'd like to do is close out with looking at the early clinical stage development portfolio. Next slide. So the first is to talk about DS-3939.
So this is the sixth DXd ADC directed into TA or tumor-associated MUC1. MUC1 is the target for this DXd ADC. So you can see on the top left that this DXd ADC has the DXd. And that includes the linker payload system that is shared by all the other DXd ADCs. Except here, we have a MUC1 antibody. So MUC1 is a transmembrane glycoprotein that is highly glycosylated in normal tissues. And it is present on the apical membrane of epithelial cells. Importantly, MUC1 in cancer loses polarity. And so TA-MUC1 is very distinct from normal cell-associated MUC1. And indeed, this DXd ADC has specificity for the TA-MUC1.
So TA-MUC1 is expressed in a broad range of tumors. And you can see them there, including lung cancer, breast cancer, ovarian cancer, biliary tract, pancreatic cancer, and other tumors. So we think this drug has a lot of potential. In preclinical models, it exhibited tumor regression in a number of disease states, including tumor regression after the treatment of other approved ADCs. So more to come on this asset as we're already accumulating data. And we'll be able to show that in the future. Next slide, please.
The next is DS-2243. I want to say we spend a lot of time talking about DXd ADCs, but I think when we talk about the diversity of the portfolio brought forth by our research organization, this is a good example. Here we have a first-in-class T-cell engager. This targets T cells, but also targets HLA-A*02 and NY-ESO-1 expressing tumors. If you look on the left, you can see the mechanism of action for this T-cell engager. It will bind to antigen on T cells. It will also bind to HLA-A*02 NY-ESO-1 present on tumor cells. It will direct the immune response to destroy the tumor cells.
This is a precisely targeting agent. NY-ESO-1 is only expressed in the testis in normal tissue, but it does not have HLA-A molecule. So we think there's the potential for a favorable benefit risk profile here based on the expression target profile. And then in terms of applicability to disease, NY-ESO expression is observed in sarcoma, liposarcoma, lung cancer, urothelial cancer, and other tumors. And preclinically, we saw a nice signal. If we go to the next slide, and I'd like to end my talk, I hope what I've given you is a nice update on the progress, our clinical progress.
And I hope I've made you realize that we continue in our quest to address unmet medical needs for patients wherever they may be with a diverse pipeline and a growing pipeline. Thank you. And I'd like now to turn it to Dale Schuster, my colleague who leads the Precision Medicine Organization.
Thank you, Dr. Rutstein. Could you please continue to the next slide? I'd like to start with a self-introduction of myself as head of global precision medicine. I've been with Daiichi Sankyo for 14 years. I've had a variety of roles, including global project teams working with cross-functionally, including discovery research, preclinical research, and assay development, clinical development to deliver new drugs for patients in need. In the last two years, I've been head of global precision medicine.
I worked in the pharmaceutical industry for over 32 years in a variety of roles, including drug discovery and drug development. And I note that I have worked with Agatsuma-san and Abe-san since the time that HER2 was in the preclinical stages. I am passionate for precision medicine to deliver the molecular science of our drugs in patients and their disease to enable their efficient development, smart decision-making for the project, as well as the portfolio. Next slide, please.
I'd like to start with a review of the TROPION-Lung01 study. This study met its primary endpoint, however, was not reviewed favorably with the FDA. This is a project in need of a predictive biomarker to segregate the subpopulation for those that benefit the most from Dato-DXd. Next slide. The Dato-DXd program included analysis of the target TROP2 expression by conventional immunohistochemistry using manual pathologist scoring. However, that failed to segregate the population with high efficacy, as you can see here with non-small cell lung cancer results from phase I.
Similar results were seen when conventional IHC of TROP2 was applied to the TROPION-Lung01 phase III study in the non-squamous cohort. Next slide, please. In collaboration with AstraZeneca, we have applied digital and computational pathology using the quantitative continuous scoring to improve predictive biomarkers for TROP2 and Dato-DXd. This technology relies on a conventional IHC assay, as you can see in the upper left. The whole slide images are then scanned. And then computational pathology is applied, as you can see here. This technology does two important things.
It precisely quantifies the total TROP2 expression. And it further locates, identifies the location and subcellular locations of TROP2 expression, as you can see here, looking at membrane and cytoplasm. The algorithm looked at the total amount of membrane expression over the amount of membrane and cytoplasm expression to generate a normalized membrane ratio. In this ratio, lower NMR is associated with higher cytoplasm expression. Next slide.
When this TROP2 QCS-NMR was applied to the TROPION-Lung01 study, looking at the non-squamous, non-AGA biomarker evaluation of evaluable population, you can see that it nicely segregated the efficacy of Dato-DXd into those shown with QCS-NMR positive, whereas in the docetaxel arm, there was no differentiation, and the QCS negative Dato-DXd cohort performed similarly to docetaxel. When you look at the efficacy results, the median PFS, the overall response rate, and the PFS/hazard ratio, you can see that the results are nicely enriched for efficacy in the Dato-DXd.
This is an exploratory finding from the TROPION-Lung01 study. However, AVANZAR study and TROPION-Lung10, as we reviewed earlier, will serve as potential to clinically validate this TROP2 QCS biomarker for Dato-DXd. As you also saw earlier, there's an additional trial planned in patients with biomarker-positive tumors in the second-line non-squamous, non-small cell lung cancer setting, where this selection biomarker can be used prospectively. Next slide. The hypothesis that underlies these results is a success case of hypothesis-driven predictive biomarker discovery.
Two hypotheses were important in driving the analyses that you just saw. One is that precise quantitative measurement of TROP2 in the membrane and cytoplasm and their relationship to each other would predict the efficacy of Dato-DXd in non-small cell lung cancer. The other was that increased cytoplasmic expression of TROP2 would identify a pool of TROP2 that is capable of internalizing the Dato-DXd bound to TROP2, and that would predict efficacy of Dato-DXd. So I want to emphasize these exploratory findings are based on a biological rationale related to the MOA of Dato-DXd. Next slide.
This fits into a strategy that we are applying across our DXd ADCs and other drugs, where our predictive biomarker strategies will focus on the mechanism of action, in this case here, antibody-drug conjugate mechanism of action. For conventional targeted therapies, a predictive biomarker often derives from target expression. However, conventional targeted therapies directly inhibit the target, and its expression would then be more likely to predict efficacy. With ADCs, there's multiple steps involved, as you can see here. The ADC must bind to the target.
The target must then be internalized and the payload released, and the tumor cell must then be susceptible to the payload. We have developed technologies in which we can look at each step of this mechanism of action. In the case of the first two, as you saw, digital pathology, computational pathology, help us to understand and quantitate target expression, both on the surface and in the cytoplasm, which reflects internalization. A key benefit of applying this technology will be access to large data sets with clinical results so that we can learn across different studies to better understand each of these steps.
Next slide. So I'd like to take a moment to explain how we approach precision medicine at Daiichi Sankyo. We think of precision medicine as the bridge of molecular science from preclinical to clinic and back again. So we work now from early stages in the research stage of assets, looking at how do the preclinical models inform and what are the gaps relative to the disease pathophysiology in patients, and also looking at target biology and drug MOA in the disease.
We continue to progress this type of research with focused biomarker assays into early development. And then in late development, we have learnings from the many results that we now have to help guide new agents through clinical development. In the end, we see this molecular science as delivering precise early development, but it also enables and learns from late development for new drug technologies. Next slide.
So if we look at what is unique by Daiichi Sankyo, we have deep experience, large data sets, and much potential to learn from this. If we look just at registrational studies across five DXd ADCs, this is in a number of different tumor types with a number of different targets. We have 18 registrational studies that have read out. We have 21 other registrational studies ongoing. And we have eight new studies in startup.
This will allow considerable learning with the technologies we are applying to guide the early asset programs. Next slide. Now, as we've seen with Dato-DXd, a key capability that we need is digital pathology and computational pathology. I'm pleased to say that we've already made a lot of progress on this area. We've established a strong clinical translational pathology expertise that's closely interfaced with our companion diagnostics group. We've built the global infrastructure to enable digital pathology.
And we've also established a productive collaboration with AstraZeneca to foster computational pathology on T-DXd, and as you saw here for Dato-DXd. We are now collaborating closely with Merck on digital pathology for the next three ADCs. We are enhancing our capability to bring forward this technology for the exciting new asset that Dr. Rutstein reviewed, DS-3939, as well as other early-stage projects.
We are assessing also digital and computational pathology for immuno-oncology and other complex biologies. Our future, if supported by the results and our progress, is to deploy this technology on future ADCs with this what we think will be a more successful biomarker approach. And we aim to establish seamless integration of digital pathology from preclinical all the way through approval and commercialization. Next slide. If we look at what does this take, we would start with the pathology. We need the pathology expertise and capabilities that is already achieved. \
The digital pathology part involves working with many established vendors with a lot of capabilities in this area. And we've already established those collaborations with more coming. The last part is the computational pathology, where we are already leveraging expertise of alliance partners as well as established experts in this field as we build our internal capabilities. Next slide, please. So if we continue on from digital and computational pathology, I also want to highlight just a few of the many other capabilities that we have built within precision medicine.
Here is an example of using high-quality AI model for multiplex IHC when we look at more complex modalities and try to understand the expression of our multiple different targets in the same tumor specimen. This type of technology will help us out. We've enabled this technology, and we're going to make increasing use of it to learn the complex biology that we need to have to be more successful with predictive biomarkers. Next slide, please.
When we think of precision medicine and look particularly at our translational science, we're looking for that this translational science role is to establish efficient clinical trials, leads decision-making based on molecular scientific data, and provides an engine that continuously generates innovation from the large data sets that we establish in our late clinical development, as well as external databases. And those will guide earlier assets and allow us to better position our broad portfolio of compounds. Next slide, please. I just wanted to show one more example.
This is another example of deep focus on a mechanism of action, looking at our valemetostat, which you heard about earlier today. valemetostat is a potent selective dual inhibitor of EZH1 and EZH2, preventing trimethylation of histones. We've learned and examined how this drug works in the hematology space. But we are going beyond that to learn more than that specific disease. Next slide, please. So here is some very nice mechanistic discovery work looking in detail with single-cell analyses of epigenetics, again, in refractory hematology.
I want to highlight that this is work that's been published with our collaborators in the very prestigious journal Nature, and this shows the capabilities that we have, but important is to note that this integration of multi-omics analyses and the clinical resources are revealing epigenetics, but going beyond hematology, for instance, we've learned about upregulation of immuno-oncology targets as well as ADC targets.
These deep insights are already translating to rationalizing various combinations, including with immune checkpoint inhibitors and DXd ADCs, as you've heard about earlier in the presentation today. That completes the overview of precision medicine. I'm very pleased to continue to the next slide and introduce Hiroto Kashiwase, who will give an update on ADC manufacturing.
Thank you, Dale. I'm Hiroto Kashiwase, Head of Global Technology. I will use Japanese from now on. Please use simultaneous translation if you need. So from here onward, I'd like to explain about the manufacturing and supply of ADC. First of all, let me introduce myself. My name is Hiroto Kashiwase. I joined Bioscience Research Laboratories, the former Sankyo Company Limited, and since then, I have been working in the R&D in Shinagawa for 12 years. And in 2001, I moved to the Headquarters Planning Department, and then after that, there was an integration of Daiichi and Sankyo.
And after the completion of the integration, I moved to the CMC Planning Department in 2008, and I also worked at R&D and DSI. And then I became the Pharmaceutical Technology Unit. In 2019, I became the executive officer of the head of Supply Chain Unit in 2022. Last year, I became the executive officer and head of global technology. In 2017, before the launch of ENHERTU, and since those days, I've been involved in leading the manufacturing and also the capacity expansion of the ADC. This is what we will discuss today. First, I will briefly introduce our Technology Unit.
Then I will discuss our ADC manufacturing process and our strategy for supplying five DXd ADCs. First, let us introduce the Technology Unit. This is our global management structure as of April 2024. There are three management units: business unit, functional unit, and global corporate functions. The Technology Unit is positioned as one of the functional units. Next slide, please. This slide summarizes the role of the Technology Unit.
The Technology Unit was formed in 2023 through the merger of three units: the Biologics Unit, the Pharmaceutical Technology Unit, and the Supply Chain Unit. The main roles are to develop the candidate compounds handed over by the R&D Unit into drugs that are both efficacious and safe, and to stably manufacture the developed drugs and deliver them safely, securely, and affordably to patients around the world. We are in charge of a wide range of areas from early development through commercial production and play a part in Daiichi Sankyo's science and technology. Next slide, please.
The Technology Unit has six functions: strategy, planning, general affairs, and L&D, CMC management, CMC research and technology development, supply chain management, CMC regulatory affairs, and plant management. The company is active in five regions: Japan, the United States, Germany, China, and Brazil.
Including the plants, more than 4,000 people belong to this unit, which is equivalent to about one-fifth of the entire Daiichi Sankyo workforce, making it the largest unit within Daiichi Sankyo. Next slide, please. Next, I'm going to introduce the manufacturing process of ADC. Next slide, please. This slide summarizes the features of DXd ADC technology. As many of you may already know, since we have talked about this at R&D presentations in the past, DXd ADC consists of three components, namely antibody, linker, and payload. The antibody selectively binds to antigens specific to cancer cells.
The linker bonds covalently the antibody, and payload is responsible to be acting on the cancer cells. The linker and drug portions together are also referred to as drug linker. Next slide, please. Here is a summary of five DXd ADCs that are currently expected to have high product value. All products utilize the DXd ADC platform technology introduced earlier. And while the payload is the same, the target antigen and the average number of drug bindings, or DAR, is different. Next slide, please. This slide shows a typical ADC manufacturing process.
As introduced earlier, an ADC consists of multiple components, and each component is manufactured and managed separately. This is the manufacturing process of ENHERTU, where separately manufactured drug linkers and antibodies are conjugated to produce the ADC drug substance. The ADC drug substance is aliquoted into vials, lyophilized to make it final formulation, and packaged and shipped as the final product. As each component must be manufactured and managed individually, the supply chain is more complex than that of a conventional small molecule drug product.
I will explain the manufacturing process for antibodies, ADC drug substance, and ADC drug product in detail in the following slides. Next slide, please. This is an antibody production process. The antibody production process consists of two major steps, namely a culture process called upstream and a purification process called downstream. In the culture process, the culture scale is expanded step by step through the process of thawing the working cell bank, expansion culture, seed culture, production culture, and harvest to grow cells to a certain density and produce antibodies.
In the purification process, impurities and viruses are efficiently removed by multiple chromatographies to isolate the target antibody at high purity. Next slide, please. Next is the manufacturing process for the ADC drug substance. ADC drug substance is synthesized by reducing the disulfide bonds of antibody and conjugating it with drug linkers. Then, impurities are removed by a variety of filtration to isolate only the target ADC drug substance with high purity.
The process may appear simple at a glance, but the manufacturing process for each step is elaborately designed and controlled, ensuring a high degree of control over the distribution of drug-to-antibody ratio. So we can produce high-quality ADC drug substance with high reproducibility. Next slide, please. Finally, there is a manufacturing process. This is the manufacturing process of the drug product. As shown here, the formulation process includes drug substance thawing, compounding, sterile filtration, filling, lyophilization, visual inspection, and packaging.
Normally, small molecules are finally sterilized thermally, but in the case of biologics, it cannot be thermally sterilized. Therefore, sterility is assured through the sterile filtration and strict control of the manufacturing environment. In addition, lyophilization allows a long shelf life while retaining the property of the drug substance. Next slide, please. I will then discuss the supply strategy for the five DXd ADC. Next slide, please.
Currently, we have positioned five DXd ADCs as our most important products, including three ADCs, ENHERTU, Dato-DXd, and HER3-DXd, plus I-DXd and DS-6000, which are expected to be new growth drivers and are working to maximize their product value. The Technology Unit recognizes that our most important mission is to deliver those promising five DXd ADCs to patients, and we are working as one to build a stable supply system. Next slide, please. This slide summarizes the projected future demand for five DXd ADCs.
The overall demand forecast for five DXd ADCs is growing rapidly, with factors such as the strong progress of ENHERTU product sales, the emergence of new growth drivers following three ADCs, and the strategic partnering with AstraZeneca and Merck in the United States. This figure here illustrates that the peak annual demand for all five DXd ADCs is more than 50 million vials, which is approximately 1.5 times higher than the demand forecast in the fifth midterm plan. We must establish a supply system capable of meeting this peak demand. Next slide, please. This is the supply strategy for five DXd ADC.
We will balance and leverage two axes, namely capacity, with expansion of production capacity by capital investment, and with establishing and expanding a global supply system, and capability with improving productivity through technology, with developing and strengthening biotech-savvy human resources, and with enhancing the productivity through organizational transformation. So we can maximize the supply. Next slide, please. This slide summarizes the ADC-related capital investment plan in-house and CMO capacities.
Currently, we are either executing or considering capital investment in the ADCs at four locations in Japan, namely Onahama, Tatebayashi, Hiratsuka, and Odawara. Globally, three sites in New Albany, United States, Pfaffenhofen, Germany, and Shanghai, China, have made or are considering capital investments in ADCs. We will refrain from giving details on capital investment in the CMO, but we plan to make a combined capital investment of approximately JPY 600 billion in-house and the CMO capacity and capability.
Once these capital investments are completed, we expect to have enough supply capacity to meet the peak demand for the all five DXd ADCs. Next slide, please. This slide illustrates ADC manufacturing and supply routes. We have secured the supply capacity by balancing in-house and CMO capacities to cope with rapid demand increase. With multiple manufacturing and supply routes globally, product supply risk will be minimized at natural disasters or other problems.
Next slide, please. We are also actively working to improve productivity by leveraging our technology in the development and early stages of production. The process is established using relatively small facilities with low risk, and then switching to a larger facility to structure an efficient product production system. In addition, we are currently studying a more efficient antibody production process by utilizing highly productive cell lines and optimizing culture conditions.
Next slide, please. It is also important to develop and strengthen human resources with expertise in biotechnology in order to develop and supply many ADC products in a timely manner and also securely. In the Technology Unit, the areas of manufacturing process development, quality control, quality assurance, regulatory affairs, and manufacturing were identified as focus areas for strengthening.
By promoting measures such as effective utilization of internal human resources through recruitment and reskilling, we can accelerate the development and strengthening of the biotech specialists through training programs and simulate personal exchange through integration of organizations and functions. We are actively working to develop and secure the necessary biotech specialty. Thank you.
We'll now take questions. When you have questions, please click the raise hand icon at the bottom of the screen. I will call your name in order, and when your name is called, please unmute yourself and ask your question. You could ask your question in English or in Japanese. If you have multiple questions, please ask one at a time for optimal translation. When you have no further questions, please lower hand and mute yourself again. Please raise hand if you have questions. First question is from Yamaguchi-san from Citi. Please go ahead.
[Foreign language] Can you hear me okay? Thank you. Thank you very much. So this is Yamaguchi from Citi. Thank you very much for the presentation. The first question regarding Dato. First of all, even though there are the big challenging things that happen on the lung stage, but are you at the moment very confident to get the approval on the U.S. breast PDUFA date January 29? Is there any kind of interactions like lung or not? Thank you. That's the first question.
So, you know, we are very close to the PDUFA date for TB-01. You know, we don't, we're not really able to read the minds of our FDA reviewers, but I can only tell you that discussions are ongoing, and it is my understanding that from the FDA side, they will meet the PDUFA date, or perhaps even a little bit earlier than that. So that's where we stand on the TROPION- Breast01.
Okay. So, upon that, even though the big challenge had happened at TROPION-Lung01, then you can respond to five with a TROPION-Lung01 and a TROPION-Lung05 together on the EGFR mutated things at the same time. In this event, all sort of, how would you say, discussion with the FDA and you change the strategy, which was the challenging one, then you responded to raise the probability of success to get the approval because you got the BTD.
So can you give me what was the kind of sequence of events regarding this TROPION-Lung01 to go to TROPION-Lung01, TROPION-Lung05 EGFR mutated filing? Thank you.
So the TROPION-Lung05 filing is a result of various discussions we had with the FDA on TROPION-Lung01.
Right. Okay. Thank you. もう一つお願いします。 Another question is about the ADC capacity. Thank you very much for your explanation about the ADC manufacturing capacity. As of now, what is the number of vials that you are manufacturing right now? The peak time, you are expecting 50 million vials. But what is the present capacity and where the conjugation is taking place right now?
Thank you for your question. それぞれ今日。 For each plant of our own, ADC manufacturing, where is it taking place? I have made that information open, but then what mode of manufacturing is taking place in each plant? That part is something that we would like to refrain from disclosing, so please understand. And in terms of the present capacity, we are now building up the capacity right now. Therefore, on a later date, when we are ready, we will let you know.
Thank you.
Probably we won't be able to give you an answer, but CDMO commissioning, you are not able to disclose the proportion of CDMO manufacturing. Well, I can give you a general idea, but then I can't give you an actual target proportion of CDMO usage. That's not something we are disclosing.
Okay. So you are using CDMOs, right? According to your chart, that's what I read.
Yes, we are using CDMOs.
For what process and how much CDMO usage is there?
That's not something you are not disclosing.
Yeah, that's correct. Thank you.
The next question is from Wakao-san from JP Morgan. Please go ahead. Wakao-san, maybe you're on mute. Okay. Can you hear me?
Yes. Thank you for taking my question. This is Wakao from JP Morgan. I have three questions. So first, about the potential of Dato. Regarding the following result of TROPION-Lung01 and withdrawal of the submission for approval based on TROPION-Lung01, expectations for Dato in the stock market have dropped significantly. I'd like to know how your evaluation of Dato has changed over the past year. Additionally, based on the current result for Dato, including QCS, how do you assess the possibility of success for the AVANZAR trial? This is the first question.
Despite what happened with TROPION-Lung01, I just want to make sure to send you a reminder that we remain very interested in the Dato program in non-small cell lung cancer. As you know, we have three frontline clinical trials in non-small cell lung cancer and a couple more that are coming with a unique combination through the AstraZeneca partnership. And so I think we remain very interested in Dato.
As far as AVANZAR and probability and how QCS is impacting, the QCS technology does give us possible avenues in terms of patient selection that would be very advantageous in how we show the value of Dato-DXd in the AVANZAR study, as well as I think in other frontline non-small cell lung cancer clinical trials.
Okay. One more update. Do you have plan to release any data update before next year's AVANZAR result that could increase expectation for success for AVANZAR? For example, will there be OS result based on the TL01 QCS analysis or update from TL 04? Something?
No, I don't think so.
Okay. Thank you. Regarding the second question about enhanced SC formulation, could you comment on any timeline for development when it's expected to end the clinical trial or when it's anticipated to be launched? And also, can we assume that AstraZeneca is involved in this project?
Yes. So hi, it's Mark Rutstein, and thanks for that question. Yes. So we expect to enter clinical trials with a subcutaneous ENHERTU in the coming months. Don't have an exact date to provide. And at this point, not able to share a broader clinical program in detail, so not able to talk about anticipated potential approval date. And then, yeah, when we talk about the developments of ENHERTU, strategically, these are discussed and aligned with our partner, AstraZeneca, including ENHERTU program.
Yeah. Okay. Thank you. [Foreign language] My last question is about production. On page 87, you talked about the—you have shared with us a chart of the conjugate and whatsoever.
So the place to manufacture the antibody or the place to conjugate, and each individual process, you might do that at your company on an in-house production system versus you may do that in a CDMO. So in each step, you might use your in-house capability or you might use a CMO. Is that a correct understanding? And going forward in the manufacturing stock, will you be thinking about unifying the production process? Well, it seems like you are doing this here and that there, but you may be consolidating into the in-house capability or maybe the CDMO alone. What do you think about that?
Thank you very much for your question. Currently, in each manufacturing step, we may do that in-house or at CMO. That is the current situation.
Going forward, we are now planning to have an expansion of the manufacturing plant and also the existing plant, and we are going to do more on our in-house capacity. In principle, in the same place, you make antibody and link it and then purify, and I think that is more efficient. Don't you think so? When you think about efficiency only, that might be true. However, we also have to cope with the risks. If we do everything in a single place, then this has a high risk. Therefore, that should also be considered. Thank you.
Thank you. This concludes my question.
The next question is from Matsubara-san from Nomura Securities. Please go ahead.
Can you hear me?
Yes.
Okay. Thank you for your great presentation. I'm Matsubara from Nomura.
Regarding Vanflyta, so EFS and OS were improved in FLT3-ITD negative patients, but the difference of CR rate is kind of limited. So I think it depends on the current phase III trial result, but will it be possible to treat Vanflyta to all FLT3-ITD negative patients, or do you need new biomarkers to improve efficacy?
I just want to make sure I understand the question. Your question is about whether or not we need a biomarker selection in a Vanflyta clinical trial. Is that correct?
Yeah, yeah, that's correct. So it's up to phase III trial data, but yes.
Okay. So the new clinical trial that was discussed today, the new one, not the old one that resulted in approval, but the new clinical trial excludes those patients with a FLT3-ITD mutation because we already have approval in that patient population.
It's all the other types of AML. So therefore, this clinical trial is referred to as the FLT3-ITD wild-type clinical trial sometimes.
Okay. ありがとうございます。二つ目がADC. The next question is about ADC development and improvement of COGS, as you have shown us, the scaling up, and also there are different factors at play, like medium and etc. Any other measures to improve the COGS, and when are you going to be able to achieve the further improvement of COGS?
Thank you very much for your question. In terms of COGS, it is very sensitive information. Therefore, I would rather refrain from answering your question. Having said that, in terms of the improvement of COGS, we consider that to be very important. That's our awareness. And then that is the basis of the medical access to expand indications. Therefore, we are very much focusing on that. So that's what I can clearly say.
Thank you. Understood.
The next question is from Muraoka-san from Morgan Stanley. Please go ahead.
[Foreign language] DB-09 and 05, and I'm asking for the ENHERTU commercial potential and the patient number and also expected duration of treatment and situation of the competition. So commercially speaking, which is the most important factor?
Okay. We don't have that information. We'll have to get that from our commercial colleagues, and we can get back to you on the question.
Understood. Thank you. Thank you. Second question is HER3-DXd, and it's a question about the CMC. And since Kashiwase-san is with us, so what about the HER3 CMC issue? And I think that would be completely resolvable, and so that would be resolved quite easily. Am I correct to interpret in such a way, or is there anything which still remains as a stumbling block to clear the issue?
Thank you for your question. The challenge at the CMO has been already or they're being resolved, and we are working on this. So this is no longer a major issue for us. That's my understanding.
Thank you. So you are going to resubmit pretty soon, am I correct?
[Foreign language] On behalf of CMC, we do not believe there remains any issue any longer.
Understood. Thank you. Thank you.
The next question is from Mamegano-san from BofA. Please go ahead.
[Foreign language] I am Mamegano from BofA. Thank you very much for this opportunity to ask you questions. TL05 and TL01 subgroup analysis is my question presented at ESMO. EGFR mutation, different types are there, and you have shown us the data. E xon 20, usually EGFR-targeting drug does not work for that, but then it seems your drug works on that particular mutation as well. Is my understanding correct?
Yeah, hi, it's Mark. We don't have a subgroup analysis of efficacy in these various EGFR mutation aberrations. So I'm not able to answer the question about specific efficacy in different subtypes. But we generally have seen, and some of them are actually small. But which one, again, do you have specific interest in? You mentioned. Yeah, exon 20. You mentioned one in particular.
Exon 20. Exon 20.
Oh, yeah, sorry, exon 20. Yeah. So we don't have the efficacy broken out by the different mutational profile, but we would expect efficacy in these subgroups. I mean, there are different exon 20 mutations. So we don't have today a breakdown of efficacy according to all of the different exon 20 aberrations. But we have generally seen efficacy across EGFR mutation profile. The issue is that some of the mutation representation in that subset is very small, so it's hard to draw a conclusion. But in general, we see broad efficacy in EGFR mutation-positive non-small cell lung cancer.
[Foreign language] I have another question. May I?
Yes, please.
[Foreign language] Thank you. [Foreign language] Dato-DXd biomarker trial, I have a question about that trial. Second line. And I'm looking at page 15. In second line. New study is about to start. That's my understanding from this chart. Page 15. So biomarker trial is being considered for the second line as well? This is my first question. And then AVANZAR trial, I think biomarker is being explored in AVANZAR setting. And this is a combination study, and if the results are positive, key to the combination.
I think from a clinical perspective, key to the combination is something that is desired to be explored. So key to the combination for the first line using this biomarker, is this something that you can positively consider going forward?
Yes, so to the first question, yes, we have announced that we plan to do a pivotal trial of Dato-DXd versus docetaxel in the second line plus of TROP2 QCS-NMR positive, so QCS positive population. And this is in the non-squamous non-AGA subgroup. So that trial is what's. It's the one that's referenced there on slide 15. We'll provide more information as soon as we can. Yes, but this trial is planned, and we should expect this to start pretty soon. And you had a question about combination with Dato-DXd and immunotherapy, pembrolizumab.
So indeed, I mean, we are interested in that combination with Dato-DXd in general. We've seen efficacy in triple-negative breast cancer with the combination of immunotherapy and Dato-DXd. And of course, we're studying Dato-DXd with immunotherapy in a number of studies. You referenced one of those, which is the AVANZAR study. And in that study, yes, there is a pre-planned analysis, a TROP2 QCS analysis of efficacy endpoints in AVANZAR. And we'll have that data, and we've announced in the second half of 2025. We also plan QCS analysis in the TROPION-Lung10 study as well.
So you asked about combination with immunotherapy, and that is where we're using Dato-DXd in the frontline setting, PD-L1 high population with rilvegostomig, which is the TIGIT PD-1 bispecific for AstraZeneca. So with those two ongoing pivotal trials, we will look at QCS, TROP2 assay with Dato-DXd in combination with immunotherapy and different immunotherapy agents in non-small cell lung cancer. And then in terms of being forward-looking, yes, we're generally interested in combinations with our DXd ADCs, including with immunotherapy. I hope that answers your question.
[Foreign language] Thank you very much. Thank you.
T he next question is from Sakai-san from UBS. Please go ahead.
[Foreign language] This is Sakai of UBS. I have two questions. The first one, I'm sorry, this is a backward-looking question, but what has gone wrong with FDA communication when you withdraw the application of TROPION-Lung01? Now, Dr. Mark Rutstein, you have been very confident about your communication with FDA. And without OS data, the probability of approval was, I was thinking about more than 50%. Was that something that you tipped? This is my personal take, by the way. Then, looking at the history, you switched the application or indication to non-squamous.
Then, now looking at this EGFR mutation data, this is a very decent, very reliable data. So why didn't you choose first-line EGFR mutation submission first? Is that some sort of timing mistake? I'm sorry, yeah, this is a very backward-looking question. But unless you clearly explain this process, we're not going to be sure how future submission of all these mutations, not mutations, sorry, indications, ADC indications coming. And that's my first question.
Yes, so I think we learned from doing the TROPION-Lung01 study. And indeed, when we had multiple discussions with FDA, I don't think any time we gave a probability of success of that particular filing of the TL01 study in non-squamous non-small cell lung cancer. But we did indeed present that we saw evidence of efficacy in the non-squamous population.
Certainly, it wasn't until we ran the study that we learned that, first of all, patients with squamous histology didn't benefit and that patients with non-squamous histology benefited. And we had been in discussions with FDA for some time. And overall, we saw what we thought was a positive benefit risk profile in the broader non-squamous population. However, it was discussed over time with the FDA, and it was determined that the most benefit was observed in the EGFR mutation-positive subgroup.
And that's what led to the change in the filing strategy and the withdrawal of the broader non-squamous filing and then the pivot to the EGFR mutation-positive filing. And sometimes during the conduct of the studies, we learn, and we can't always predict ahead of time where the most benefit may be evident.
I think the research process and the clinical trial process is, in general, one of learning. But I hope that describes to you how the data was discussed and then what led to the change in submission strategy was recognition that if you look within the data and the data sets evolving, and if you look within the data as we acquire more data over time and follow-up, the regulatory agency and Daiichi Sankyo could see that the observation that the best benefit risk profile was in that subgroup of patients for which we've now submitted accelerated approval filing.
Okay. So the process was a planning process, and the communication with FDA was pretty much straightforward. That's the way we should understand.
Yeah, that's right. We learned during the conduct of the trial. And then whenever we file the data, we have discussions with the regulatory agency, and sometimes those discussions take time
. Yeah. Okay. Thank you. Second question for Dr. Schuster. Thank you very much for a very interesting presentation and pretty much interesting translational research. First, on page 62, the collaboration with AstraZeneca was mentioned. Now, what's the future plan with AstraZeneca? Now, translational research at Daiichi Sankyo, that remains to be investigating the biomarkers or just going to more clinical, not clinical, real clinical setting side.
That means the one thing that I'm interested in right now is the, for example, HER2-low, HER2-positive, HER2-ultra-low research, how it works, how ENHERTU is going to work on this type of biomarkers or HER2 biomarkers. My question is probably a bit vague, but if you could lead me to the kind of right direction at future Daiichi Sankyo translational direction, I would pretty much appreciate it.
Yes, we are very interested in learning how our ADCs work, particularly in HER2, where we have most of the data. Dr. Rutstein presented a subgroup analysis, including the HER2- ultra-low, where we still also see efficacy. We think this may be related to the potency of our DXd ADCs, in this case, T-DXd, and perhaps sufficient HER2 expression, even at low levels when we have such potent ADC.
With AstraZeneca, what are you aiming at?
I'm sorry, I do not understand the question from AstraZeneca.
Yeah. I mean, on the page, slide 62, collaboration with AstraZeneca to foster blah, blah, blah.
Okay. Sorry, I see now. So we have done some work with AstraZeneca and computational pathology for T-DXd, of course. And it has changed our plans for biomarkers for T-DXd. T-DXd.
Any details can you talk about?
No, I have no details at this point.
Okay. Thank you.
The next question is from Wada-san from SMBC Nikko. Please go ahead.
[Foreign language] I'm Wada from SMBC Nikko. Can you hear me okay? Yes. QCS? QCS is my question. [Foreign language] Specific method of QCS. QCS-NMR positive or negative. What is the cutoff or threshold for positive and negative? And depending on cancer type or squamous and non-squamous, do you apply different threshold or cutoff for QCS-NMR positive or negative?
So I would like to explain that the QCS-NMR that we have applied was optimized in the non-squamous, non-AGA population.
[Foreign language] What about other cancer types? And what about the squamous? You need to set the cutoff or threshold newly or differently?
So we have looked at squamous non-small cell lung cancer, and we also are looking at other tumor types. We have no data that we are able to share at this time.
Thank you. [Foreign language] It is. AstraZeneca is a patented technology. That's my understanding. So HER3, that's a Merck collaboration. So you can't really use this technology for a Merck collaboration. You have three ADCs, HER3 and B7-H3 and Cadherin, these three targets with Merck. In terms of immunohistochemistry, can you target these targets with immunohistochemistry, or do you need to have QCS-like biomarkers? And if you need to have QCS biomarkers for these three targets with Merck, what kind of QCS biomarkers are you going to use to stratify patients?
Yes, allow me to explain. The QCS that was applied in the Dato-DXd program is specifically developed for TROP2 expression based on clinical data from the Dato-DXd program. QCS is based on a digital pathology and computational pathology. There are many different companies that provide those technologies, and we can work with Merck, as shown in a presentation, applying digital pathology and computational pathology for the targets that we have in the Merck Alliance ADCs, so we expect to be able to learn insight on the biology, including internalization, working with other companies.
It does not require that we have QCS as developed by AstraZeneca to proceed with similar technologies to understand the target expression quantitatively, as well as its distribution within cells for the Merck Alliance assets, three ADCs.
[Foreign language] Thank you.
The next question is from Sogi-san from Bernstein. One question at a time, please. Please go ahead.
Thank you very much. I have a question regarding QCS or biomarker as well as T-cell engager. The first question is for Dale. This is related to what Wada-san has just asked, but how early on within your experience of data, how early on now you can start understanding whether the cancer type or the target or ADC require a certain type of biomarker? And also, this is probably the question that Wada-san asked, but you didn't answer, but do we already know what type of biomarkers are potentially required for the five ADCs of the earlier in development?
Okay. I think your question is with regard to biomarkers across the five ADCs and maybe especially those newer assets. I would say that we are investigating for all of the ADCs, the conventional IHC. Conventional IHC has worked very well in the T-DXd program.
It was not sufficient, as we've seen in the Dato-DXd program. We are still learning about conventional IHC in the other assets. However, because we know about the complex mechanisms of action, we also want to apply the digital pathology for better quantitation, as well as computational pathology to understand distribution within a tumor cell. We think that will allow us to be more effective. We also are in preclinical stages and preclinical research, investigating more about target biology, including newer assets to supplement the research that we will have in the clinical setting.
I see. So does that mean that for Dato-DXd, we felt that the confirmation or the understanding of QCS came a little bit late at the end of the actual first phase III? So should we expect that the QCS type, the biomarker, or the potential other biomarkers for the earlier ADC programs can be applied earlier in the development stage?
Yes, we can apply this technology in earlier stages. We should understand that understanding their value will require potentially larger studies.
I see. And other than the conventional IHC and the QCS type in digital, the computational pathology, are they the main biomarkers, or are other potential biomarkers that can be quite critical for new ADC development?
So for our DXd ADCs, we are applying them especially on target biomarkers. We also are interested to see if they may have value with other parameters. That research is early yet, and we have nothing to disclose.
Okay. Thank you very much. [Foreign language] So the next question is about T-cell engager. This question goes to Abe-san. You are differentiating yourself with ADC modality. And about T-cell engager and the modality-wise, is it different from existing ones? Are there any special characteristics with that?
Thank you for your question. And together with the ADC, I'm also working with the bispecific antibody, and the target is something we are expecting. And I will not go into any technical detail, but this is differentiated and also very efficacious to patients. That's what we are now proposing.
Thank you. So about T-cell engager, the cancer cell, the target that has been disclosed, but on T cell target hasn't been disclosed. Is there any background of that?
Yes. That is also the technical detail, and that will be explained more going forward in the future.
Yes, I'm looking forward to it. Thank you very much.
The next question is from Michael Nedelcovych-san from TD Cowen. Please go ahead.
Hi. Thank you so much for the questions. I have two. My first relates to patritumab deruxtecan and Dato-DXd. So it seems very likely that in the next 12 months, both of these agents could be approved in late-line EGFR mutant non-small cell lung cancer. How do you envision them being positioned relative to each other? For example, do you imagine that physicians will sequence them? And then my second question is related to your PBD-based ADCs.
Could you just educate us a little bit on the relative benefits of a PBD payload relative to DXd? And why did you choose CLDN6 as the first target for that program? Thank you.
Yes. So to the first question, this is Mark. To the first question, indeed, Dato-DXd and HER3-DXd both have demonstrated efficacy in the EGFR mutation-positive non-small cell lung cancer space. I think that what we see is the potential for optionality for prescribers should these drugs be approved, which we think is beneficial to patients. The drugs, of course, are not the same. They do have some differences in, for instance, the safety profile. So I think the optionality and the benefit-risk profiles get weighed against one another for considerations.
And that is assuming, of course, that both drugs actually do get approved. Then you asked about sequencing. I think that's something that we're trying to understand now. We have data sets in flight to try to understand DXd resistance in general. So if it's target-mediated, if it's payload-mediated, I'm not able to share sort of data from those ongoing data sets now.
But certainly, what it means is that we are very focused on understanding how, for instance, if sequencing would be feasible, and then how we might go about that. And so have ongoing clinical analyses and also translational analytics in that regard. And then you asked. I'm sorry. You asked about the pyrrolobenzodiazepine, the PBD-based ADC. Can you repeat your question again and how that was? I maybe need you to repeat that question.
Sure. Basic question. What are the relative benefits of PBD as a payload compared to DXd? And why did you choose CLDN6 as your first target for the PBD-based ADC program?
Yeah. So I think we have six DXd ADCs now in the clinic. And what we certainly want to do is build a diverse pipeline and continue to innovate. And so the PBD-based platform was a second platform that we brought forward.
I think one of the benefits to bringing a platform forward with a different payload, right, is, and we kind of discussed that a bit a moment ago, as you start to think about how you might overcome resistance or how you might sequence use of one agent relative to a DXd, it's really about the diversity of the pipeline, opportunities to offer benefit beyond DXd ADC as much as we feel very strongly and continue, of course, with these six assets, including within HER2 that's approved. We look for diversification of pipeline and ADC technology, and that includes the payload.
Then CLDN6, yeah, so CLDN6 is a known tumor antigen, and that is relevant in different solid tumor disease states with high unmet need. So in thinking about our portfolio, just continuing to seek to address unmet needs. The spectrum of disease there includes gastric cancer, ovarian cancer, lung cancer, germ cell tumors. So really a tumor antigen that's relevant to address unmet medical need.
Thank you so much.
The last question is from Tony Ren from Macquarie. Please go ahead.
Yeah. Thank you for taking my question. Just a clarification on slide 28. I see from the table and the graph, my area of interest is on stomatitis. So you can see that from the table, there are roughly 69% stomatitis, right? And if you look at the graph there, that appears to be 59%. So there is a little bit of a discrepancy there. Just want to clarify. That's why probably it's due to the sample sizes being different. Also, on discontinuation from stomatitis, you guys stated the second bullet point that there is no discontinuation due to stomatitis.
Just want to see what's the, it's a little bit surprising given my interaction with the KOLs and including people who participated in the trials. I just want to see how you attributed this discontinuation due to stomatitis. It feels a bit difficult to comprehend given the feedback that I've heard. Obviously, you guys had the positive news from the Japanese expert panel, PMDA, under the Ministry of Health, Labour and Welfare, recommending the TB-01 approval in Japan. How do you think that will affect the decision in front of the FDA and other regulators? Eventually, EMA, I would imagine.
So that's a couple of questions on Dato. And also, can I just confirm that I heard you guys saying that the HER3-DXd manufacturing CMC issue has been resolved and that you guys are proceeding with application with the FDA? So yeah, so these will be my two questions. Yeah. Thank you.
Yeah. So a few questions there. So right, in terms of the data, I mean, I can only rely on what's there in the graph. In terms of incidence rate, it breaks down grade one, two, or grade greater than or equal to three. So that's 59%. Then it is right that there were no treatment discontinuations due to stomatitis. I know you had questioned that. There were dose modifications. And of course, I mean, we continue to collect a safety database and to learn about the management of stomatitis and to optimize and risk mitigate.
But in this particular study, fortunately, dose modification in the form of reduction and delay prevented the treatment discontinuation. So it is accurate as presented. And then you asked about the influence of the Japan recommendation for approval of Dato-DXd based on TB-01. Yeah, hard to speculate how that would influence other regulatory agencies.
I mean, we did discuss that really nothing that we can disclose in terms of ongoing discussions with FDA on TB-01, but PDUFA is kind of around the corner. But I think it would really be pure speculation if I would say that the Japan recommendation would influence the other agencies. And then you asked a third question. Sorry.
Yeah. It's about the HER3-DXd manufacturing CMC issue had that been completely resolved?
Yeah. So Kashiwase-san mentioned that the CMC issues had been addressed. Yeah. So this is an ongoing proceeding with the regulatory agency now around the closure of the CRL and the submission process. But we really don't have any specifics to update here today. We'll do it as soon as we can. But certainly, there's been progress on the CMC side, as you've heard from our colleague.
Yeah. Thank you, Mark. So just a quick follow-up on slide 28, right? So you can see from the graph, indeed, we have 59% stomatitis under the table, right, in the brackets under AEs of special interest. The percentage is 69%, right? So I just want to see what's causing this discrepancy here. Is it just because you used the different numbers of patients?
Oh, I see. I got it. Yeah. I think right. So now I understand. Yeah. Thank you for pointing that out again, right? So in the bottom right table, yeah, we categorize adverse events of special interest. And so the adverse events of special interest bring in additional preferred terms or adverse event terms. You can see that the events may have expanded beyond the term stomatitis and may include other events that when we're calculating adverse events of special interest, we're pooling adverse event terms.
And therefore, you get a higher number of patients and a broader incidence rate when you talk about the combination of stomatitis and oral mucositis as events. So I don't have the detail of all the adverse event term structure for calculating the adverse event of special interest rate, but it does have to do with pooling of events for the adverse events of special interest when we analyze them versus the adverse event graph on the upper right, which is individual terms. Does that make sense?
Yeah. Absolutely. And thank you very much. How do you guys start dealing with stomatitis aside from chewing on ice cubes and prophylactic mouthwash and any other major strategies?
Yeah. So we do have. You've mentioned a couple of key strategies. I mean, in our protocols, there are management algorithms which absolutely do invoke mouthwashes, do invoke ice chips. But there are additional considerations around oral and dental health. And so we do look at it holistically. But you've mentioned a couple of key interventions right there. And we're continuing to study further how we can further optimize and risk mitigate. Yeah.
Okay. Great. Yeah. Thank you very much.
We have now run over the scheduled time, and we will now conclude Daiichi Sankyo's Science and Technology Day 2024. Thank you very much for joining today.