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

[Interpreted] Thank you for waiting everybody. We'll now start to Daiichi Sankyo's WCLC/ESMO 2024 highlights. This is Ken Asakura from Corporate Communications, and I will be the moderator today. First, about the language for this event. All presentations will be in English, and Q&A will be in both English and Japanese. Simultaneous interpretation is provided, so please click the interpretation icon at the bottom of the screen and select either English, Japanese or original audio. When original audio is selected, you will hear the original sound. English presentation slides will be shown on the Zoom screen as well as live streaming screen. The presentation slides have been uploaded to IR presentation material Page of Investors section on our corporate website. So please view or download as needed. Our presenter for today is Dr. Mark Rutstein, our Head of Global Oncology Clinical Development. We will take questions after the presentation. In addition, Dr. Ken Takeshita, our Head of Global R&D will open the meeting and will join the Q&A. Please note that this event will be recorded. With that, let's start the event. Ken-san, please.

Okay. Asakura-san, thank you very much for that very nice introduction. And today's session is an update on all the data we have presented at the World Congress on Lung Cancer and the ESMO, European Society for Medical Oncology Conference. We have a lot to cover. And so I'm not going to spend too much time on these introductory remarks, except just to say that what you'll see is a very steady progress in our DXd ADC portfolio. a lot of productive information and data coming from our industry collaborators as well as our academic collaborators. And also now finally, some emerging data on our new next-generation ADC. So we're very excited with all the progress we are making. And -- so let me just turn it over to you, Mark, and to start to go over the large amount of slides that we have.

Yes, Ken, thanks so much. And it's my great pleasure to be here today. I'm excited to be here. My name is Mark Rutstein. I lead oncology clinical development at Daiichi Sankyo. And following on Ken's comments, I mean, the key themes we have across world lung cancer and ESMO include really making progress toward creating new potential standards of care not only in lung cancer, which was the highlight of World Lung Cancer Congress, but also in additional tumors, as we saw at ESMO, ovarian cancer, endometrial cancer, breast cancer, et cetera. So this is an exciting time for us for sure. And indeed, we also look to create new innovation for patients, including the introduction of our second ADC platform which we presented at the ESMO meeting, and we'll touch on that today. Okay. So with that, we'll get right in. So the first topic is the overall survival analysis -- final overall survival analysis from TROPION-Lung01. Next, please. So people may recall, this was a positive Phase III trial in second-line non-small cell lung cancer with Dato-DXd monotherapy statistically significant progression-free survival. But then, of course, we saw the benefit was really driven by the non-squamous histology, where we saw a clinically meaningful benefit in that subpopulation. The PFS is there on the middle of the slide, 0.63 hazard ratio and then more than doubling of the overall response rate. Next. Yes. I think this is just the schema and simply that this is a second-line plus population in non-small cell lung cancer and the design was, of course, Dato-DXd monotherapy versus docetaxel for this Phase III trial called TROPION-Lung01. And maybe just a quick reminder that we had dual primary endpoints, progression-free survival by BICR and overall survival. Next. Yes. So baseline characteristics and -- because we've shown this before, I'll be quite brief. And so you can see prior lines of therapy, the majority of patients have had -- well, second or third line, but even greater lines of therapy. So definitely high unmet need pretreated population. And the AGA population represented about a minority of patients at 17%. And then not a surprise that in terms of prior systemic therapies, patients would have been pretreated mostly with platinum and anti-PD-L1 or targeted therapy if AGA and 3/4 of the patients approximately were non-squamous. Next, please. Okay. So here's the intent-to-treat overall survival analysis. Remembering this is the dual primary end point. And you can see there's a numerical improvement with Dato-DXd, with docetaxel. However, this primary end point did not meet statistical significance. You can see p-value 0.530, and hazard ratio of 0.94. Next. Looking into the subgroup analyses, that tells the tail of this pivotal trial data set. Down bottom of the slide in this forest plot, you can see that by histology, we saw the difference overall survival by histology. Hazard ratio of 0.84 for non-squamous patients, 1.32 for squamous patients. Also difference in AGA as well with AGA present having hazard ratio of 0.66. Next, please. So here the Kaplan-Meier is kind of looking more closely at efficacy by histology. And as I noted, non-squamous population, 0.84 hazard ratio. The medians are worth pointing out, median survival, 14.6% versus 2.3%. So actually a 2.3% median improvement in overall survival, which we've indicated is clinically meaningful in this population. And then in the squamous patients in the right, you can see there is no evidence of benefit there. And then down the bottom of the slide very briefly, we looked at subgroups of subgroups, so including whether or not in the non-squamous subgroup, aged patients benefited regardless of AGA status. And indeed, there is evidence that they did. Next slide, please. Okay, for safety. So not much new here. This is 11 months additional follow-up and the safety profile was consistent with the previous analysis. No new like late onset toxicities. It remains to be the case that there were fewer grade 3 and higher treatment-related adverse events or discontinuations or dose reductions in the data arm compared to the docetaxel arm. And of course, there was a difference in median treatment duration favoring Dato-DXd. Next. This is just more closely at the adverse event profile and stomatitis events were common, but primarily grade 1 and grade 2 hematologic events, as we showed previously, were much more common with docetaxel. Now importantly, with this 11 months additional follow-up, there were no new adjudicated drug-related ILD events or deaths since the previous analysis for PFS endpoint. And overall, a really consistent profile with what we know. Next. And so conclusions here is that TROPION-Lung01 did meet its primary endpoint of PFS, statistically significant improvement, dual primary end point of overall survival did not meet statistical significance, showed a numerical improvement, but consistent benefits was seen in that non-squamous subgroup across the endpoint structure and now with the overall survival that was shown no new safety signals. So we will talk -- this last bullet really talks about that TROP2 normalized membrane ratio that QCS assay. And so, we'll move right on into the next presentation, which will follow up on this. Next, please. Okay. So at World Lung cancer, there was not only the presentation of the final overall survival analysis for TROPION-Lung01 but also this biomarker presentation that was actually at the presidential session. This was normalized membrane ratio of TROP2 by quantitative continuous scoring and showing that it could be potentially predictive of outcomes in that same study that we just presented the overall survival update TROPION-Lung01. Next. So as a background, Dato-DXd is an ADC that has a plasma stable linker. Because of that, Dato-DXd is believed to rely heavily on internalization then to release its cytotoxic payload. And we had looked at conventional IHC scoring and it was not predictive of response to Dato-DXd in non-small cell lung cancer. But seeing that conventional IHC was not going to be predictive. There were additional biomarker discovery efforts starting with TROPION-PanTumor01, the Phase I study where Dato-DXd monotherapy was given to patients with non-small cell lung cancer. And it was hypothesized that a more precise and quantitative assessment of TROP2 expression on both cell membrane and cytoplasm. Cell membrane and cytoplasm may predict efficacy of Dato-DXd and the thinking behind the cytoplasmic expression is that this could be representative -- a surrogate for internalization where when you have an ADC with a plasma stable linker, the cytoplasmic expression, therefore, may be important and beyond just the cell membrane expression or the conventional IFC. Next. So this is the methodology, and this is an assay technology that's been developed by AstraZeneca, our partner. And so it starts with conventional immunohistochemistry. You deploy a TROP-2 assay using conventional immunohistochemistry. And then there's a whole slide imaging. And the slides undergo automated image analysis, QCS or quantitative continuous scoring. What is QCS? So QCS is an artificial intelligence informed computational pathology approach. It is capable, and I'm on the bottom of the slide now of differentiating tumor from non-tumor. And then very importantly, it would look within a tissue slide at all the tumor cells within that slide and be able to quantitate the analytes, including not only membranous TROP-2 expression, with subcellular or cytoplasmic expression. So the assay algorithm that was developed on the far right is to calculate this normalized membrane ratio, looking at the ratio of membrane expression over total expression, where total expression includes membrane expression and cytoplasmic expression. And you'll remember on the previous slide, I mentioned why cytoplasmic expression may be relevant to an ADC that has a plasma stable linker. On the upper right, patient biomarker status using this algorithm was determined as follows: greater than equal to 75% of tumor cells with TROP2 NMR or normalized membrane ratio less than 0.56 is positive, less than 75% of tumor cells with that NMR 0.56 was negative. And so what's important here is that as the cytoplasmic expression goes up, the ratio goes down. And so we're really considering the cytoplasmic expression in this NMR ratio. Next, Okay. Well, these are the TROPION-Lung01 progression-free survival results in the original intent-to-treat analysis. And as we mentioned a few slides ago, PFS hazard ratio in the ITT population was 0.75, statistically significant. If we move to the next slide. So the biomarker evaluable population was a subset of the total ITT TROPION-Lung01 population, and these are patients with available tissue samples for QCS determination. And the biomarker cut points were optimized in this case, for PFS in the non-squamous non-AGA patients from TROPION-Lung01. And then biomarker cut points were rigorously evaluated using robust statistical analysis. So on the bottom left is we're going to show 2 PFS analysis, progression-free survival using these TROP2 assay QCS. The first is the total biomarker evaluable population, and that includes non-squamous non-AGA, non-squamous AGA and squamous patients. And then we're going to show the PFS for that subgroup of patients, non-squamous, non-AGA for which the assay is being optimized. On the right, you can see the prevalence of NMR positivity or biomarker positivity, 66% for non-squamous. And then within that, 63% for non-squamous non-AGA, 76% for non-squamous AGA, and then squamous at 44%. It's notable to us that the biomarker positive prevalence is higher in non-squamous and squamous patients. And perhaps, this is one contribution to the observed differential efficacy by histology with Dato-DXd in non-small cell lung cancer. Next slide. It's very important when you are looking to validate a biomarker that the biomarker evaluable population and the baseline characteristics are similar to the ITT or overall population. And that is the case. We won't go any -- over any individual numbers here, but just to show you that the baseline characteristics are very similar between the populations for which we're now going to show the biomarker evaluated efficacy analysis and the total population. Next, please. So here is that first analysis that overall biomarker evaluable population, and you can see that when you compare efficacy by NMR positive patients and NMR negative patients, so biomarker positive by TROP2 QCS versus negative TROP2 QCS. You can see that Dato-DXd versus docetaxel has an improved PFS hazard ratio. And you can see at 0.57, median PFS 6.9 versus 4.1 and overall response rate was significantly higher with Dato-DXd versus docetaxel. On the other hand, in the biomarker-negative cohort on the right, you can see the PFS hazard ratio is 1.16. And so this is evidence in this exploratory analysis. This is a retrospective exploratory analysis that the TROP-2 QCS assay may provide potential to predict efficacy to Dato-DXd in this setting. Next. Now this is the second analysis where there was optimization of the assay in the population of interest, which is non-squamous non-AGA. And so this is the progression-free survival with overall response rate. And here again, you can see improvement in PFS and higher response rate in patients that are TROP2-QCS/NMR positive PFS hazard ratio now down to 0.52, median PFS 7.2 versus 4.1 and also an improvement in response rate. So again, evidence this time in the biomarker optimized population that this assay has the potential to predict efficacy for Dato-DXd. Next. So here is the safety data, and so what you can see in the biomarker-positive population versus the negative population, overall similar safety, grade 3 and higher treatment-related adverse events rates were similar. There were some adverse events of interest where there was a modestly higher rates in the NMR-positive -- biomarker-positive population compared to the negative population. Not sure why this would be or if it's maybe related to the sub -- smaller subgroups. But overall, fairly consistent safety. Next, please. So in summary, this TROP2 normalized membrane ratio as measured by QCS demonstrated several key outcomes and the potential ability to predict outcomes in this exploratory TROP2 -- TROPION-Lung01 analysis. So biomarker positivity was more prevalent in squamous -- in non-squamous and squamous patients, and we saw that together. And patients receiving Dato-DXd who are biomarker positive had a higher response rate and longer PFS compared to those who were negative. And the overall grade 3 treatment-related adverse event rates were similar. And so -- and importantly, further investigation of this promising biomarker and assay is ongoing in 2 pivotal trials with Dato-DXd, AVANZAR in frontline non-small cell lung cancer, with the Dato-DXd durvalumab and platinum and then TROPION-Lung10, which is the Phase III frontline trial, PD-L1 50% and higher with Dato-DXd plus the immunotherapy IO bispecific agent, TIGIT PD-1 inhibitor rilvegostomig. So QCS NMR has the potential to be the first TROP2 biomarker and the first computational pathology biomarker to predict outcome for clinical response to Dato-DXd in non-small cell lung cancer. Next, please. Okay. We're going to stay with Dato-DXd here, but now I'm going to show data in an earlier line of therapy. It's important that when we study our DXd ADCs, we consider not only the advanced and metastatic setting, but also even potentially the resectable setting. So NeoCOAST-2 is a study of the efficacy and safety of neoadjuvant durvalumab plus novel anticancer agents, including Dato-DXd plus chemotherapy and then continued with adjuvant durvalumab and, in some cases, novel agent in resectable non-small cell lung cancer. Next slide. So here, we're going to focus on what's in red okay? Because there are multiple combinations tested here, including with some of AstraZeneca's agents within its pipeline like oleclumab, which is a CD73 inhibitor and monalizumab, which is an NKG2A inhibitor, we're going to focus on Dato-DXd in red. So this is resectable non-small cell lung cancer. These are EGFR ALK wild-type patients. And you can see ARM 4, they get Dato-DXd plus the PD-L1 inhibitor durvalumab plus single-agent platinum, and there are 54 patients in that cohort, then they undergo surgery and they get durvalumab alone. And what we're going to focus on here are the primary endpoints -- a primary endpoint of pathologic complete response rate, that means clearance of the tumor, no residual tumor found in the surgical specimen. And then there's also a major pathologic response rate, which is less than or equal to 10% residual tumor in the surgical specimen. We're also going to look at some safety, including feasibility of surgery. Next slide, please. Okay. Again, I'm going to focus on the red. Now Dato-DXd plus durvalumab plus chemotherapy, we can see 54 patients started neoadjuvant therapy. And very importantly, there was a higher rate of patients that could go to surgery. If you give a neoadjuvant treatment before surgery, a key aspect is to understand if patients can tolerate that presurgical regimen enough to continue on to surgery. And indeed, in the Dato-DXd containing arm 4, only 2 patients did not make it there to surgery. And there was also a high rate of what we call R0 surgical resection, which is when you look at the tumor margins, and you see negative tumor at the margins. And a majority of patients were able to start the adjuvant therapy. So this is a good sign toward tolerability. Next, please. Okay. Again, focusing on the red on the right. Dato-DXd, durvalumab and chemotherapy showed a pathologic complete response rate of 34.1% and a major pathologic response rate of 65.9%. So this is a relatively modest sized Phase II data set, and it is a preliminary signal, but it is a promising preliminary signal when one considers the historical control pathologic complete response rate of chemotherapy and immunotherapy alone, which is really in the mid-20% range. Next slide, please. just quickly showing that, again, focusing on the red on the right. Among patients who had that path CR rate of 34.1% in arm 4, there were pathologic complete responses observed across PD-L1 status with a gradient though with higher pathologic complete response rate at higher PD-L1 expression levels. Next, please. So here is the safety profile and I already showed you that the majority of patients could go on to surgery after receiving the Dato-DXd containing neoadjuvant regimen. I'll focus to the left, where we see in the neoadjuvant phase where Dato-DXd is given, the grade greater than equal to 3 treatment-emergent adverse event rate was 18.5% and AEs leading to discontinuation was less than 10%. On the right side, when we look at the types of adverse events that we saw in the neoadjuvant phase, you can see that cytopenias were observed which isn't surprising with chemotherapy onboard. And otherwise, some very typical adverse events associated with what you would expect from that triplet regimen. The majority of events being grade 1 to 2. Next, please. Okay. So fundamentally, what we say here is that in this Phase II study in perioperative non-small cell lung cancer, the combination of Dato-DXd, durvalumab and chemotherapy showed a promising -- it is a Phase II data set, but nonetheless, a promising pathologic complete response rate and major pathologic response. And as I indicated, there was a manageable safety profile with the ability to continue the surgery comparable to already approved regimens. This is the first global Phase II study showing encouraging efficacy and manageable safety of an antibody drug conjugate in the neoadjuvant setting for patients with resectable non-small cell lung cancer. Next, please. Okay. We'll continue with Dato-DXd and now as we've explained when we provide our R&D strategy, we look to what we call expand, which is, we focus originally on breast cancer and lung cancer, but then look at earlier lines of therapy like we just presented with NeoCOAST-2 and also additional tumors beyond breast and lung cancer. So the pan-tumor -- TROPION-PanTumor03 study was presented, and this is monotherapy Dato-DXd in ovarian cancer and endometrial cancer. Next slide, please. Okay. So in this study, there's a cohort of 35 ovarian cancer patients. They progressed on at least one line of platinum, but no more than two lines of therapy for advanced or metastatic disease. And then there are 40 patients in the endometrial cohort. And all of these patients, by the way, are unselected for TROP2 expression. But in the endometrial cohort as well, they progressed on at least 1 prior line of platinum therapy and had no more than 2 prior lines. They get Dato-DXd monotherapy, and the primary endpoint is overall response rate and safety. Next, please. Okay. So here are the baseline characteristics for this ovarian and endometrial cohorts and we'll focus on the previous lines of therapy, third from bottom. You can see these are significantly pretreated patients in the ovarian cohort, nearly 69% of patients had received 2 or more regimens. And in the endometrial cohort, about 28% of patients had received 2 or more regimens. But these patients are all pretreated. You can see the pretreatments there, including 100% of patients receiving platinum and then a number of other standard of care regimens. On the bottom, in the ovarian cohort, you can see that the majority of the patients are platinum resistant, which represents a particularly unmet medical need. Next slide, please. So here is the efficacy in this signal fighting study for ovarian cancer. You can see the overall response rate in the total population was nearly 43%, duration response close to 6 months. And you can see in the smaller cohort with platinum-sensitive disease, nearly a 67% response rate but a small sub-cohort and then the platinum-resistant population with nearly a 35% response rate. If you look to the waterfall plot on the right, you can see what is a promising figure. And if we move to the next slide, please. Now the endometrial cancer cohort confirmed overall response rate of 27.5% and we can see, interestingly, the median duration response for those who responded was 16.4 months. The waterfall plot on the right, also favorable. So then again demonstrating the potential of Dato-DXd in additional tumors, including pretreated ovarian cancer and endometrial cancer. Next slide, please. So we look at the treatment duration, and it was 5.6 months in the ovarian cohort and 5.2 months in the endometrial cohort [indiscernible]. In fact, there were no grade 3 events in the ovarian cohort. And then you can see the most common adverse events below in the slide are typical of what we'd expect for Dato-DXd. Next slide, please. Okay. So overall, Dato-DXd monotherapy demonstrates encouraging efficacy in ovarian cancer and endometrial cancer. And we've already covered the numbers, but we would say encouraging early efficacy and the safety profile is manageable and consistent with what we already know about Dato-DXd. Next slide, please. Okay. We'll now transition to trastuzumab deruxtecan. So we know that in HER2 or T-DXd is approved in HER2 mutation positive non-small cell lung cancer. So this is a signal-finding cohort in HER2 overexpressing non-small cell lung cancer. This is DESTINY-Lung03 Part 1. Next slide, please. So here is the study design, and you can see it has multiple cohorts, but we're going to focus on Part 1, which is T-DXd monotherapy, patients getting 5.4 milligrams per kilogram every 3 weeks. The patients in this Part 1 had 1 or 2 prior lines of therapy, and those who are eligible to receive targeted therapies had to have received previous targeted therapy. Key end point included overall response rate and other efficacy parameters as well as safety. Next slide, please. Here are the baseline characteristics. I'm going to focus on the right. And you can see that about half the patients were IHC 3+ or IHC 2+ and all patients were required to be 2+ or 3+ to get into this HER2 overexpressing cohort. For PD-L1 status, the majority of patients were less than 1% or 1% to 49%. And importantly, on the bottom right, there were a significant percentage of patients who are EGFR -- who had received EGFR TKI, therefore indicating EGFR mutation positivity. Next slide, please. So here is the efficacy. So in the 36 patients enrolled in this arm 1D Part 1, T-DXd monotherapy, a confirmed response rate of 44% and you can see the median duration of response was 11.0 months. So a notable and encouraging signal of T-DXd in the HER2 overexpressing population. Next slide, please. So here we show the responses according to PD-L1 status and HER2 expression status. And you can see on this waterfall plot that there were responses across the spectrum of PD-L1 expression and across the 2 subgroups of 3+ and 2+ IHC expression. What I'm not showing but will be mentioned on the conclusion slide, is that there was a higher overall response rate in patients who were actually EGFR mutation positive. And I think we'll see that on the conclusion slide, but I wanted to verbalize that here now. We looked at multiple subgroups within this data set. Next slide, please. So for safety. So overall, we don't see anything new here related to T-DXd. On the left, drug-related AEs relating to discontinuation of less than 10%. About 20% of patients had dose reduction. Importantly, in this lung cancer population, the rate of ILD was about 5%. There were 2 events and they were both grade 2. Now there was 1 death and it was due to neutropenic colitis. On the right side, you can see the most common adverse events, which are really consistent with what we already know about T-DXd. Next slide, please. So in summary, we see an encouraging signal for T-DXd monotherapy in pretreated IHC 3+ and 2+ HER2 overexpressing metastatic non-small cell lung cancer. We see responses regardless of IHC status and PD-L1. And we also did see, and it's that the third bullet down high response rate in EGFR TKI pretreated patients than those who weren't pretreated, but I want to say that these are pretty small subgroups. And so overall, if we take the total cohort, we do see an encouraging signal. So these data are suggested that T-DXd can improve outcomes in this setting. No new safety signals identified. And this study, DESTINY- Lung03, continues with T-DXd-based regimens, including combination with immunotherapy and chemotherapy and immunotherapy. Next slide, please. Okay. So now we're going to shift to our HER3-DXd. So as Ken alluded to in his comments, we're presenting data here from collaborators. And so this is a study -- a Phase II study with HER3-DXd monotherapy in advanced hormone receptor positive HER2-negative breast cancer. It's run by a collaborating institution, Gustave Roussy in Paris. Next slide, please. So here's the study design. And so the patients are unresectable advanced hormone receptor positive HER2-negative breast cancer patients. They had to have progression on CDK4/6 and endocrine therapy, and they had to have all received prior chemotherapy. They received HER3-DXd of 5.6 milligram per kilogram every 3 weeks and also I'll mention that they did not receive prior T-DXd. The primary endpoint here is overall response rate and there was a very robust translational analysis here. I'm not going to have the time to go over all the translational data because we're covering so much today, and we could certainly follow up on that more of interest. But I will tell you, if you look at the bottom of the slide, blood and tissue is mandatory at several time points in the trial. And when in a study like this, you're able to capture blood and tissue sequentially like that pre and post treatment, you can do multiple investigations that were done by our French collaborator looking at predictors of response and predictors of resistance and these type of aspects. Next slide, please. Okay. So here are the baseline characteristics. On the bottom left, you can see that the majority of patients or the highest percentage subgroup were actually IHC 0 for HER2. There were some patients that were IHC 1+ and then a minority of patients that were 2+ or 3+. However, 30% of patients there was unknown HER2 status. In the upper right, you can see that HER3 membrane expression by conventional immunohistochemistry was also looked at to be able to correlate HER2 expression with efficacy. And you can see a range of HER2 positivity in the membrane, but the majority of patients had at least greater than or equal to 75% membrane positivity. And you can see that the median prior number of lines of therapy was 2, virtually everybody had received prior CDK4/6 inhibitor and endocrine therapy and all patients had received prior chemotherapy. So this is a heavily pretreated population. Next slide, please. So here is the key efficacy data. And what you see is a confirmed overall response rate of 53.5%. Importantly, this is not a very small Phase II data set. You have nearly 100 patients with a sample size of 99 with 2 complete responses. And overall, the clinical benefit rate was nearly 63%. The waterfall plot on the left gives you a clear impression of an efficacy signal in this population with tumor shrinkage in 90 out of 99 patients. There was no significant association between HER2 expression and efficacy. And in addition, though it's not shown in what I'm going to present, there was no clear association between HER3 expression and response rate either. Next slide, please. Here is the duration of response and progression-free survival. So the median duration of response was nearly 9 months, the median PFS was 9.4 months. So this is evidence of a very significant antitumor effect. Next slide, please. So overall safety. So the safety profile was overall manageable and consistent with what we've seen in our HER3-DXd studies, patients with treatment-related adverse events, grade 3 or higher was 50%. 11% of patients had discontinuation due to toxicity, and they were 20% of patients with a dose reduction. There was one adverse event leading to death, but this was not related to HER3-DXd. This was with a pleural effusion. And interestingly, in this population, there were 7 ILD events -- 7.1%, but they were all grade 1. They were all grade 1. So overall manageable safety profile. When we look on the right, we can see what we -- the type 2 events we know for this HER3-DXd ADC with fatigue and nausea being most common and also some cytopenia, including decreased neutrophil count as well. Next slide, please. So just a brief overview of the types of biomarker analyses that were done, but we're not going to have time to show the results of all of them, though there will be a few summary statements on the conclusion slide. So our colleagues at Gustave Roussy looking at sequential blood samples and tumor biopsies look to see whether or not HER3 expression could predict response to HER3-DXd, look to see whether or not they were genomic alterations or mutations that could predict response and looked at the characterization of the tumor microenvironment, including the immune aspects of the tumor microenvironment to try to determine any characteristics that may help predict the response to HER3-DXd. And so if we move to the next slide, please. So this is our conclusion. So HER3-DXd showed a clearly clinically meaningful activity in a manageable safety profile in this population of heavily pretreated hormone receptor positive HER2-negative metastatic breast cancer patients. We reviewed the efficacy results together already. I won't repeat them. The activity was observed across HER3 and HER2 membrane expression levels, so those analytes did not predict response to HER3-DXd. And with the limitations of small sample size, and I'll just summarize here because even though I didn't get into all the details of the biomarker data, the distribution of HER3-DXd in the tumor was seen to potentially play a role in determining better treatment response in addition to up-regulation of genes involved in immune response, such as interferon alpha and gamma. So overall, and importantly, the efficacy and safety profile of HER3-DXd monotherapy in this setting make it an optimal candidate to now study this drug in further larger trials. Next slide, please. Okay. I think we're getting almost toward the end of my presentation, and I appreciate all your attention. So a couple more topics. We're going to talk about I-DXd, our B7-H3 DXd-ADC in extensive stage small cell lung cancer, the interim analysis from Phase II study IDeate-Lung01. Next slide, please. So Phase II study IDeate-Lung01, this update was presented at World Lung. This is small cell lung cancer. So these are patients with extensive stage small cell lung cancer. They've received at least 1 line of prior platinum and less than or equal to 3 prior lines of systemic therapy. So overall, this is a second line plus advanced small cell lung cancer population. And patients with brain mets were permitted. And of course, brain mets are -- have a high prevalence in this particular disease state. Patients who were randomized to 2 doses of I-DXd are B7-H3 DXd-ADC 8 milligrams per kilogram and 12 milligrams per kilogram. This is a very important study for our small cell lung cancer program because we were allowed -- we're able to use this data to select a dose for our ongoing Phase III study that we just started which is IDeate-Lung02, which is a pivotal global trial of I-DXd monotherapy versus standard of care in second line small cell lung cancer. And you'll see the data that I show you explains why we chose 12 milligrams per kilogram for that pivotal trial. Importantly, after this randomized dosing component, we extend enrollment at that chosen dose of 12 milligrams per kilogram Q3 weeks, adding another 70 patients in a third line plus population. So we're going to gather additional data in a very advanced population primary endpoint response rate, and of course, safety is included in addition to these efficacy endpoints. Next slide, please. Okay. So on the left, I'll point out that the discontinuation rate due to AE was on the relatively low side median treatment duration in that lower dose cohort 8 milligrams per kilogram was 3.5 months. It was 4.7 months at the higher 12-milligram per kilogram cohort. Now if we look on the right side, we see the baseline characteristics. 40% of patients had brain mets at baseline. And you can see again, as stated, this is really a second line plus population. So these are very advanced patients with a high unmet medical need. They've received a number of prior treatments, including 3/4 of them receiving immunotherapy, which is often given in the frontline setting in this disease state. Next slide, please. So here is the efficacy data. You can see on the left, the 8-milligram per kilogram cohort with a 26.1% response rate on the right, you can see the 12-milligram per kilogram cohort with nearly a 55% response rate. And you can see a very favorable waterfall plot. In addition to that, the disease control rate represented in the table below shows you that at 12 milligrams per kilogram, the disease control rate was exceeded 90%. So it was on this basis with a significantly higher, although these were not statistically compared these cohorts, but just empirically, what we can see is that we can see much higher rates of response at 12 milligrams per kilogram, and this promoted us to choose that dose for pivotal trials and for expansion in this Phase II study. Next slide, please. So here are what we call spider plots. And what they show you is that you get rapid response and you get durability of response as well. Duration of response, you can see down below 7.9 for the 8-milligram per kilogram cohort, 12-milligram per kilogram cohort at 4.2. And some might say, now, why is that? You have a lesser DOR and the higher dose. And this is likely explained by the limited number of responders at the 8-milligram per cohort, the smaller subset of responders in addition to the fact that there were some differences in baseline characteristics between the 8-milligram per kilogram and the 12-milligram per kilogram cohort with a higher percentage of second-line patients in that lower dose cohort. Next slide, please. So here's the PFS and OS, remembering that this is a Phase II study, and so these time-to-event endpoints have limitations in their interpretation. But what I would point out to you is that the 12-milligram per kilogram cohort for both PFS and OS were numerically higher for PFS and OS in the lower dose. And in addition to that, at 12 milligrams per kilogram, the median survival was nearly a year, and that is notable in this very high unmet need advanced small cell lung cancer population. Next slide, please. Okay, the safety summary. So you can see median treatment duration was longer at 12 milligrams per kilogram. Adverse events leading to discontinuation was also higher at 12 milligrams per kilogram including dose delay and reduction. But overall, we believe there's a manageable safety profile at both doses. If you look below, there was 1 case -- 1 related death, which was a pneumocystis pneumonia that was deemed related to study treatment in the 12-milligram per kilogram arm. Otherwise, the rest of the deaths were not treatment-related. If we move to the next slide, please. And so here are the most common adverse events at both doses and what you'll notice is that there are some higher rates of adverse events, both GI and hematologic at the 12-milligram per kilogram cohort, Relative to what we already know about I-DXd, we have no new safety findings. But overall, we believe the profile is manageable at both doses, including the chosen dose of 12 mg per kg. In terms of ILD in the lower part of the slide, there were 4 cases of ILD at 8 milligrams per kilogram. There were 5 or nearly 12% at the 12-milligram per kilogram cohort. And in that 12-milligram per kilogram cohort, one was grade 1, three were grade 2 and one grade 3. There was one death due to ILD in the 8-milligram per kilogram cohort. Next slide, please. So in summary, I-DXd continues beyond what we saw in the Phase I trial to demonstrate promising efficacy in advanced small cell lung cancer. There was an improved efficacy or higher efficacy rates at the 12 per kilogram dose relative to 8. Overall, there were some higher adverse event rates observed at the chosen dose of 12 but manageable for both doses. And -- though I didn't show it here for the sake of time, I-DXd did show prominent intracranial activity with intracranial overall response rates of 50% to 60% across both dose cohorts and 12 milligrams per kilogram, as I mentioned, has been selected for the ongoing Phase III study in second-line small cell lung cancer IDeate-Lung02. Next slide, please. So this is our last topic. And as we mentioned, our goal is not just to progress in bringing new standards of care to patients with high unmet medical needs across tumor types, but also to continue to bring new innovation. The DXd platform has been remarkable so far in bringing in HER2 and approved drug, but also some promising efficacy signals with some of our other DXd ADCs, which -- the majority of which have now advanced into late-stage trials. But this is evidence that this presentation that we're bringing new innovation, new platform, another ADC platform, this is DS-9606, which is a Claudin 6 directed antibody drug conjugate in patients known to express Claudin 6, and this is a first-in-human study. Next slide, please. So as background, DS-9606 is an ADC composed of a humanized anti-CLDN6 monoclonal antibody, has a cleavable linker and a modified PBD payload that is pyrrolobenzodiazepine, PBD payload. So this is different than the Topoisomerase I payload that is DXd in our ADC technology that we've presented to date. So about CLDN6. It is a component of tight junctions between cells and it is nearly absent in adult normal tissue, but expressed in several tumor types, and we can see them to the right. This includes ovarian cancer, endometrial cancer, gastric, germ cell tumor, including testicular cancer, which we'll talk about in few slides and non-small cell lung cancer. And the expression of CLDN6 can be associated with poor prognosis and this is the first report from our ongoing Phase I trial of DS-9606 in patients with advanced solid tumors. Next slide, please. So here is the study design is a classic dose cohort escalation Phase I trial and are actually still in the dose-finding phase. So we're showing you preliminary data and this data will continue to evolve. And key eligibility of patients that were known to have tumors, tumors known to express Claudin 6 and they had to had progression of disease on prior standard of care. So this is a typical Phase I population with high unmet medical need. If we move to the next slide, please. Okay. So we have multiple doses every 3 weeks here and 1 milligram per kilogram basis of DS-9606. And what I'll point to you really is the bottom of the slide and probably the far right column there, when we look at the majority or the highest percentage of patients were -- had ovarian cancer, second highest germ cell tumor, particularly testicular cancer, also gastric GE junction, lung cancer, some patients pancreatic, breast and endometrial. And also on the far right column, in the totals, the median number of prior therapies was 4. So this is a very heavily pretreated population. And you can see nearly 40% of the patients were ongoing at the time of this analysis and this is a very preliminary analysis. Next slide, please. So here is a safety overview. And importantly, there were no dose-limiting toxicities to date. And there were actually no discontinuations due to treatment-related toxicity. So overall, well tolerated so far in the dose escalation and the maximum tolerated dose or dose for randomized trials has not yet been determined. And I would show you that -- if I focus across all the doses to the far right column, you can see there were only 3 Grade 3 related adverse events, 2 related serious adverse events and only a modest number of patients or just a few patients required, that required interruption or reduction due to treatment-related adverse events and there were no deaths. Next slide, please. Okay. So here's the safety. And again, the safety was tolerable with the majority of adverse events being grade 1 to 2 and a clear minority of events in green being grade 3 or higher. There were no grade 5 events, most common events were GI in nature but also there was anemia. And there were no Grade 4 or 5 treatment-related adverse events. And I did mention on the previous slide, there were only 3 Grade 3 related adverse events and 2 of those were anemia and one was rash. So overall, this is an emerging safety profile but clearly, so far, a manageable profile. Next slide, please. Yes. And actually, just to mention actually safety that we also did see some skin talks, which was lower grade as well. But overall, very well tolerated drug to date. So here's the efficacy and preliminary efficacy demonstrates there have been 4 responses according to RECIST. You can see 2 of those are germ cell tumor and 1 of those is gastric. And one of those is non-small cell lung cancer and response rate was highest at that 0.15 milligram per kilogram dose, which is one of the higher doses tested. So if we will move to the next slide, please. I want to spend a moment here just on the germ cell tumor. So again, these are patients that are heavily pretreated and refractory and 2 out of 7 patients that were eligible for tumor assessment with germ cell tumor had a PR or RECIST, and you can see that there on the left. And then on the right side, 5 out of 7 patients who are evaluable for efficacy with germ cell tumor had a greater than equal to 90% reduction in tumor markers. So this is an early signal but it is a very notable signal for antitumor activity in a very heavily pretreated high unmet medical need setting. Next slide, please. Okay. This is my last slide. And overall, what we can see so far is the safety profile is manageable for this asset. There is some promising early antitumor effect but we're still in dose selection. So it is early and particularly in germ cell tumor, where we see that signal so far. And then, of course, we'll continue with the enrollment and dose escalation to determine the maximum tolerated dose and the dose for randomized trials. So that is my last slide. I would like to extend a sincere thank you to listening to the presentation because it was lengthy. I hope you can see the progress across our pipeline. I hope you can see the breadth and depth of our pipeline, not only in advancing our DXPs across tumor types and lines of therapy but also continuing to -- on the quest to bring new innovation by bringing this second new ADC platform, all with the goal and clear mission to basically provide new treatment options to people who are sick and either don't have options or running out of options. Thank you for your time.

Thank you, Mark. Now let's go to Q&A. But before we go to Q&A, there were some issues with simultaneous interpretation audio. And we will upload a recorded version of this event on our corporate website soon, so please visit our website then. We apologize for the inconvenience. Now let's go to Q&A. 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. And 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. The first question is from Yamaguchi-san from Citigroup.

Hello. Can you hear me okay?

Yes.

So I have three questions. I'll try to be very brief. Thank you for the explanation. It was very helpful. The first question is that after this TL01 OS data, the financial markets seem to be a bit worried about the probability of success or approval of probability at the PDUFA date in December. And direct I'd like to make a basic question once again but is it a dual endpoint data and the PFS is already status significant, OS was a bit weakish, but it's still trending -- the number is trending. So with these conditions after this OS data updated, is it fair to say that the probability of -- the probability is go down or not really. My understanding is that PFS is good enough to get approval. But is there something new things happening to make you guys less confident about our probability of the data? That's the first question.

Thank you very much for that question. And currently, we are still in discussion with the FDA on our submission and we will be able to update you once we have some definitive decisions coming from that submission. But it's still an ongoing open submission right now.

Mark-san, do you have any comments?

Yes. So no additional comment except that to confirm what you stated, which is PFS statistically significant, overall survival dual primary end point, not significant. What we saw in that subgroup of non-squamous non-small cell lung cancer patients, this is where we saw the benefit. And we're still ongoing discussions with regulatory agencies. So no update to provide yet but they have been provided these results and we will issue an update as soon as we can.

Right. So still that during the point, meaning one of which is not significant, meaning the trial itself is a success, right?

Right. So the PFS primary endpoint was statistically significant. So that means that there's a positive trial, correct.

Okay. And second quick question is that this non-squamous things, including QCS. It looks like you have some idea of why there's a difference between non-squamous and squamous, especially the top 2 membrane or penetration into the cells. Do you have any idea why there is a sort of difference between the non-squamous and squamous, and also how FDA is viewed this sort of difference? And is there any scientific evidence to see the difference of non-squamous and squamous at this point?

Yes. So thanks for the question. So what I showed in the presentation from World Lung is that the prevalence of biomarker positivity was higher in the squamous patients -- excuse me, in the non-squamous patients compared to the squamous patients, yes. So we think this could be one contributor and potential explanation for why we see differential efficacy according to histology. Now we haven't -- we don't have a firm and clear explanation for this differential efficacy according to histology but it may not only be related to this differential -- this different biomarker prevalence, there are also characteristics of squamous versus non-squamous histology, that also at a biological level, who could potentially explain differences in efficacy to Dato-DXD. But at this point, it's still an ongoing investigation but one good clue is provided with that QCS analysis. And in terms of -- I think you commented on the regulatory. Yes, so at this point, we're not able to provide an update on what FDA thinks of the differential activity according to histology. But of course, they can see in the data that we provide that there's very clear evidence of differential activity according to histology. And we've seen that not only in TROPION-101 trial but also in external Phase II data sets. So we believe this is a significant finding.

The final question is that regarding the new generation of 9606. It is -- it looks pretty [ pre-mid ] at this point because you are still in the process of raising doses. I understand that and it looks very safe in all things. But also, there are some commentary and you pointed out as well. There's a new sort of potential side effect especially on skin tox has been emerging, so already only 1 or 2. Do you think this is going to be dose remitting factor in the future? Or it really doesn't matter? And how do you -- how long do you see the more response, especially like cancer, ovarian cancer, which should be the main target of this indication, the drug?

Yes. So in terms of the skin tox is, we're seeing some skin tox, and this has been seen with some PBD type payloads. Of course, ours is a modified payload. So it's hard to predict whether or not the skin tox will become dose limiting. So at this point, we're really still increasing those doses. Because skin tox is something that's been recognized with this type of payload. It's possible for it to be -- eventually be dose limiting. But at this point, it's hard to predict. And then yes, you commented on, I think, efficacy in other tumors like ovarian and gastric. Yes. So what we have to do here is complete the dose escalation and then choose the dose we want to take into further study. And what we will do is we will then take expansion cohorts. So we look at specific tumors of interest based on the signals that we observed in the dose escalation. And of course, as I mentioned, we have seen a response in gastric cancer as an example. And so we will be able to in that -- in those expansion cohorts look at those key tumors, including ovarian cancer, as you cited.

The next question is from Wakao-san from JPMorgan.

Seiji Wakao JPMorgan. A question about TEAEs [indiscernible]. So do you think that [indiscernible] of the 95% confidence interval for the OS hazard ratio exceeding one point could be [indiscernible]. I'd like to know your thoughts on this point.

Yes. So I think when we look at the efficacy in the subgroups, right, which were not statistically tested, right? So the descriptive analysis. We look at multiple characteristics to determine what we think is clinically relevant. So the 95% confidence interval, I think you're referring to the upper bound going to like 1.05%, I think in the OS hazard ratio. And this is only one aspect that we look at. Importantly, we look at the medians as well. We look at the hazard ratio. I think here, in the case of the medians, right, we saw a median of 14.6 months overall survival and a delta or a difference in survival, a median of 2.3 months. So it's really the totality of the data by which the subgroup efficacy results would be considered. So we don't just look at that 95% confidence interval alone but the totality.

Next is about biomarker strategy. So I understand that Daiichi Sankyo does not have biomarker on technologies like QCS and I'm concerned that lack of such technologies could pull the challenge for your ADC pipeline, particularly for those partners with AstraZeneca. Could you please clarify whether it is necessary to have in-house technology like QCS?

Maybe I'll start and then I'll hand it to Ken. Yes. So I want to say that biomarker technology is very important to us at Daiichi Sankyo. It's true that AstraZeneca developed this QCS technology but we internally at Daiichi Sankyo are working very deeply and comprehensively on biomarker programs on establishing predictive biomarkers for all of our assets. And we're deploying multiple different technologies. I don't think we have shared the details of all that we're working on but with time, we will, but I want it to be assured that we are very capable and very much underway in those efforts, including the remainder of assets beyond Dato-DXD for which the TROP-2 QCS has become prominent. Ken, would you like to add anything additional?

Yes. Thanks. So yes, I think I just want to add to Mark's comment that QCS agropathology just represents one of many different types of technologies and modalities identify predictive biomarkers. And so yes, we have a number of technologies that we're looking at to identify predictive biomarkers. And in addition, AstraZeneca has been working on the digital pathology in GCS for many years. But more recently, many other groups, academic groups as well as industry groups have developed their own methods for digital pathologies. So we can certainly tap into them to acquire necessary digital pathology expertise.

Okay. Last, we have about 9606. So could you comment whether the result of this Phase I results suggest any difference in aspects such as the linker or payload between 9606 and DXD ADC? What clinical difference are you expecting for 9606, also second generation safety or efficacy or something?

Yes. So at this point, I'm not able to comment in too much detail about what are the mechanistic or structural characteristics to this new ADC platform versus DXD. At this point, what we're able to offer is the target, which is Claudin 6. The fact that it is a PBD payload but it's modified and we're not really discussing at this point how we modified it. And also, we do say it's a cleavable linker. And so that's pretty much where we stand now in terms of what we are able to offer. We'll have more information with time but we think this ADC platform, which is a new platform could be a potential new addition to the treatment landscape.

Next question is from Hashiguchi-san from Daiwa.

[Interpreted] This is Hashiguchi from Daiwa. In NMR QCS, I have a question. I think we have been researching and starting various biomarkers and keeping this data in order for you to select the optimal patient group. How much does QCS NMR is promising to select optimal patients? And are you going to -- or have you already decided to use this biomarker for the selection of the patients or you'll be continuously exploring other biomarkers? And if you try to roll out this particular biomarker, then many of patients with NSCLC, you need to have an access to this biomarker measurement or testing then -- but it would be the hurdles if you try to do so. How do you -- would you try to overcome this difficulty? And how you'll be able to propagate this measurement testing in the field? How long will it take?

So there is a considerable amount of the work being done by our collaborator, AstraZeneca on this particular QCS assay. And they have already pointed out in their own Investor Relations conference that we have obtained additional information beyond the TL01 clinical trial in other indications. So it's quite possible that this QCS technology is applicable to other diseases besides lung cancer. But it's very exciting. And not only this, they have thought about how this might be used in the patient care setting. And they have partnered with a diagnostic company, [ Roche ], to be able to provide essential pathology services where physicians can submit pre-slides from a patient sample to get the QCS results.

[Interpreted] So now you kindly explained what AstraZeneca has been doing. And what about Daiichi Sankyo? For Dato-DXD, Daiichi Sankyo decided already to use NMR by QCS for Dato-DXD treatment? And if so, how long does it take?

And we together are very interested in the QCS facilitator program, and we are working very closely together with AstraZeneca to commercialize the assay as well as at the time of data approval. So yes, we're very interested and we have a very important collaboration on that.

Next question is from Mamegano-san from BofA. While we wait for Mamegano-san, we will -- before that, we would like to go to Muraoka-san from Morgan Stanley.

[Interpreted] Muraoka is my name from Morgan Stanley. Can you here? Well, the first question, TL-01 regarding this AGA in relation to that. With OS AGA was related, I have understood that. But in terms of PFS also AGA because of AGA, the difference in response similarly, have you been seeing that. Could you let me know about that please?

Yes. Thank you for the question. So previously, we had presented progression-free survival and we've seen this difference in AGA as well. So the differential evidence of efficacy or antitumor effect within the AGA subgroup compared to the non-AGA has been consistent across some of these endpoints yes. But I have to point out, though, that as we always do, that the AGA population in TROPION-Lung01 was actually a minority of the patients.

[Interpreted] IDXd, regarding this, a very good data, I think you have obtained. Now in the near future, with this data, are you thinking that application is possible? Or will you be waiting for another while in order for the data to be accumulated, which is the case?

Yes. So thank you for that question. So we are expanding that Phase II study. We're going to add 70 patients in third-line plus small cell lung cancer. And in addition to that, we, of course, have announced the start in August of our randomized global pivotal trial in the second line of small cell lung cancer. So we're not commenting on any specific regulatory strategy yet. But what I can tell you is that both our partner, Merck and Daiichi Sankyo realize this is a very high unmet medical need, and we will, we will examine different option, and we will examine and look for options to bring this drug to patients as soon as possible who are in need and who have a high unmet medical need. As soon as we can update any particular regulatory strategy, we'll do that.

[Interpreted] Let me repeat myself. Okay. Then that means that you will accumulate a little more data and then would make the application of the plan towards the authorities? Is that the case?

Yes. So we're actually not commenting on the regulatory strategy in terms of how much data -- more data we would need to accumulate before we talk to the health authorities about like a filing pathway. My comment was just that we are accumulating more data both in Phase II and in Phase III, and we will seek a registration path that is efficient, and we'll try to get this drug to patients as soon as possible. But we're not prepared at this point to discuss how much more data from which study we will use to seek registration.

[Interpreted] My last question is second-generation ADC regarding this, very promising preliminary but promising data, I think you have. And this second-generation ADC using that newly TROP2 ADC to be redeveloped. That kind of option are you thinking about?

Yes. So we have -- we do plan to use this platform, this new ADC platform to bring additional agents. So DS-9606 will not be the only drug that uses this platform. But we're not describing at this point, what additional targets that we've chosen or will choose in the additional drugs that we'll bring forward using this platform. We'll do that as soon as we can as these assets come forward. But I can't comment on specifically whether or not TROP2 will be a chosen target for this particular platform.

Next question is from Barker-san from Jefferies.

Yes. Steve Barker from Jefferies. My first question is about the TL-01 overall survival data and I was hoping I can get your comment on why do you think the hazard ratio deteriorated from 0.77% at interim to 0.84% in the final analysis.

Yes. So I think when we have follow-up of overall survival, I mean, there are a number of factors that data can evolve. I mean the hazard ratio is similar. So I don't have anything specific to offer as to why the hazard ratio went up a bit. But as you say, numerically, it did increase. What I can say is what I had stated, which is that when we look at that median in delta of 2.3 months and the median survival of 14.6 months in the data arm, we find that very encouraging. But I have no specific comment on exactly why it goes 0.77% to 0.84% just changed with some -- with additional follow-up, which can happen over time in the conduct of a trial and when we do multiple analysis over time for a time-to-event endpoint.

Okay. So you don't -- it doesn't make the data less approvable in your view?

Yes. So it's hard -- I mean, at this point, we're not commenting on the discussions that we have ongoing with the regulatory agency. And so no update that I can provide on specifics about the data and how it impacts the ability for approval.

And then regarding the delta 2.4 months between the docetaxel arm and the treatment arm, the docetaxel arm 12.3 months, it seems high. It seems high compared to what you saw in the squamous, which is on the 9.4 months and high compared to historical controls. Do you have any comment on why that was so high?

Yes. So I mean, you get a range when you have similar control arm across pivotal trials, you do get a range of outcomes. And this can depend on the specific patient population that gets enrolled into one trial or another. Sometimes it's not readily explainable. But what we see with docetaxel in historical trials and then sometimes the older trials show different results in the newer trials. Over time, there has been, I would say, a trend toward docetaxel overall survival outcomes improving over time. But typically, we've seen 12 months or less typically. And one of the potential reasons by which overall survival outcomes for docetaxel have improved relative to historical runs is that in the post-IO setting, patients who received previous I-O and then get docetaxel. This may have had an impact. But this is a hypothesis when this topic has been discussed.

And then my last question is regarding DS-9606. Can you share with us any information about the linker and how that differs from the [indiscernible] technology?

Yes. I'd like to, but today, we can't do that just yet. All we're commenting about the linker at this point is to say it's a cleavable linker, which has implications for ADC structure but not commenting anything more specific about the linker. As we have done for the DXd technology, we have commented on more structural aspects but at this point, not quite ready to share anything more detailed than the fact that it's a cleavable linker.

Okay. And then just a follow-up question, again, regarding DS-9606. So the PBD payload, highly toxic, effectively very low concentrations. Is there something strategically? Are there certain targets that are going to be better suited to this platform as opposed to the DXP platform?

Yes. I think when we look at the spectrum of target indications for this first asset DS-9606 using this new platform, we really guided, I'd say, I mean, in part by the payload, but really mostly by the target expression of Claudin 6. I mean with ADCs in general and with our ADCs, including DXd and there's not really much of a difference here in terms of when we think about the indication spectrum, we consider multiple factors but one of the key factors is target expression. And so when we talk about DS-9606, what we're looking at, what we mentioned, germ cell tumor, lung, gastric, ovarian, and so really guided by target expression. There are some cases when we look at the payload and think about whether or not that payload has particular sensitivity in certain tumors versus others. That is a consideration we make. But at this point, with this asset at its preliminary stage, I think what we're focused on is more on the target expression when we're thinking about what might be potential tumor types.

Next question is from Haruta-san from UBS.

[Interpreted] I'm Haruta of UBS Securities. This is my first question. T-01s result, first-line impact. How should we conceive First line combination with immune checkpoint inhibitor and first line, that would be the central world. But without jeopardizing this immune checkpoint, but then the antitumor effect has to be exerted therefore, first-line clinically meaningful result. I think the hurdle is high, but then I don't think it's directly related to the trial, but the second line details are available. How should we think about the impact for the first line?

Yes. So I think in TROPION-Lung01, I mean, what we've seen, we've seen what is clinically meaningful efficacy in the non-squamous population. And so as a monotherapy, we saw Dato-DXD doubling response, increasing duration of response. So this is a drug which demonstrates clear antitumor activity in non-small cell lung cancer. Now when we think about the frontline trials, it is a different situation because we're combining with other drugs. But based on TROPION-Lung01, we think Dato-DXd has potential in non-small cell lung cancer and we're very committed to this. In fact, when you look at the program, I mean, we have now 7 pivotal trials in non-small cell lung cancer. And looking to answer multiple questions. So not only adding on different combination partners like, let's say, immunotherapy and TL08 or immunotherapy and chemotherapy in TROPION-Lung07 and the AVANZAR trial being run by AstraZeneca. But in addition to that, even looking at biomarker segment like AGA population. And we've already talked about in the AGA population, we saw a nice signal in the TROPION-Lung01. So that's the basis by which we have 2 pivotal trials in EGFR mutation-positive non-small cell lung cancer TL-14 and TL-15. So what I would say is that it is, as you note, challenging just to extrapolate from monotherapy to combination settings and different lines but I think what we learned from TROPION-Lung01 is that Dato-DXd has potential. And we think it's a very -- it could end up being a very important drug in non-small cell lung cancer, and we have a very comprehensive program across different lines of therapy, different patient segments. And we're even now seeing, as I mentioned earlier, with the NeoCOAST, we're seeing preliminary antitumor effect even in the resectable setting. So overall, we remain confident in this drug and have a very broad comprehensive non-small cell lung cancer program to provide evidence of that confidence.

[Interpreted] My second question is IDXD that area. Second line, accelerated approval. Regarding that, you said you can't say much. But let us suppose that you're going to target that the accelerated approval, this SCLC progression is fast and then limited treatment options at an early stage also from the market whether it could be effected by or like -- and SCLC compared against chemotherapy, how much benefit there is on PFS and OS? How much incremental benefit could be shown, whether that would be more important. In the case of SCLC, the treatment option is limited. But regarding that point, what is your idea?

Yes. So I mean we do have the ongoing randomized pivotal trial, and it's hard to say exactly what kind of efficacy increment will see but how much better in PFS and OS we would see compared to the investigator's choice of therapy. But I think we're encouraged, though, because we see in ID-8101, I presented nearly a 55% response rate. And this is a response rate that's holding up over time, right? We saw in Phase I, now Phase II. So when you see a response rate like this, and the preliminary, showed preliminary PFS and OS from Phase II, when you see those kind of consistency of endpoints in this type of efficacy signal, I mean that gives us confidence that when we compare in a randomized trial to the standard of care, I mean we wouldn't do the trial unless we thought we potentially could have a positive outcome. But it's hard for me to hypothesize exactly what kind of efficacy increment that we'll see at this point. What I can say is that we're very interested in taking IDXD into small cell lung cancer. And I'll add, it's not only in monotherapy when we compare to the second line standard of care -- we're also -- we've launched a Phase Ib trial to combine IDXD with chemotherapy and cytotoxic therapy, and that's in the frontline setting. So in thinking about the ability to eventually go into the frontline setting. And I'll also add that in small cell lung cancer, we recently extended our co-development and co-commercialization agreement with U.S. Merck for MK-6070, which is a trispecific T-cell engaging DLL3 agent. And we've announced that we're going to combine that with IDXD in small cell lung cancer. So we're very optimistic here. But of course, can't think of exactly what kind of outcomes we'll see, and we'll just have to let the data mature.

Next question is from Mamegano-san from BofA.

[Interpreted] I have two questions. First is regarding Dato-DXD TL-01. This time, [indiscernible] clearly showed the differentiation of the benefits in different sub-group and TROPION-Lung trial and [indiscernible] trial, I think they use the same biomarker. And concerning second line? I think is my understanding correct that you cannot use this? I think currently, you're preparing the filing but this biomarker is not available for that filing. Is that understanding correct?

Yes. So to your first comment or question, yes, it's the same assay, the TROP-2 QCS assay that has been shown in this retrospective exploratory analysis at the World Lung of TROPION-Lung01. The same assay is to be used in AVANZAR and the same assay has to be used in the additional -- the TROPION-Lung10 study that I referenced. Then you asked, could the QCS analysis we show in TROPION-Lung01 could that be used for regulatory submission for TROPION-Lung01. And so as we stated, we're not commenting on specific proceedings at this point of what discussions have been with the regulatory agency about the QCS data. The agency is aware of the QCS Data, of course, they have it. But it's important to remember that the analysis we presented at World Lung was a retrospective exploratory analysis. And as our colleagues from AstraZeneca offered earlier this week, that assay will be validated, right, in the other studies, including AVANZAR.

[Interpreted] My second question is about HER3-DXD. And press release just I think you announced showed positive trial results. And MARIPOSA-2 is going to be your competitor. And as I also shared the positive data of OS at ESMO. And also [ amivantamab ] will be also your competitor, I guess? Now I think that you have a positive data PFS, so you'll be probably going for filing. And with amivantamab, do you consider any combination with your assets? What is your strategy going forward?

Yes. So thanks. So we did have a press release today announcing top line and meeting the PFS endpoint. And we're not able to comment on the details about that data or details of our regulatory strategy, but we'll do that in the future for sure. We do recognize, as you cited, I mean, actually, it's great for patients, right? There have been positive trials reading out in EGFR mutation-positive non-small cell lung cancer recently, like MARIPOSA, [ FLORA-2 ], MARIPOSA-2. So we do recognize this is a competitive space and we'd be glad if we can add to the treatment armamentarium in this space because we think there are still unmet medical needs. In terms of whether or not we would combine HER3 DXD with amivantamab specifically, nothing to share on that. But I would say generally, though, we are looking at multiple potential combination partners for HER3 DXd and our other DXd ADCs in multiple settings, including non-small cell lung cancer. But no specific combination yet to share, including for amivantamab.

Next question is from Sogi-san from Sanford Bernstein.

Thank you very much for a very comprehensive presentation. I have a question regarding QCS. So currently, QCS really focusing on the identifying patients TROP-2 status whether it's on the surface of the cell or inside the cell. And it also appears to be is kind of a static matter, not necessarily -- it doesn't really look like the dynamic, the movement of TROP-2 between the cell surface, the inside the cell. So I think that -- please correct me if I'm wrong. But the next question is you are saying that you are exploring different approaches of the biomarkers and QCS just is one of them. But my question is, are these other -- the biomarker option that you're exploring? Are they also really focusing on the location of the dose, the target of ADC or it's also looking at something else?

Yes. So to your first question, you're right. It's -- so it's not a dynamic assessment of the expression. It's using immunohistochemistry at first and then deploying the artificial intelligence-assisted computational pathology, and it's sweeping that all the tumor cells in that tissue slide to identify the cytoplasmic expression, the membrane expression. But that's looking at that point in time. So it's not an ongoing or a dynamic assessment, so to speak. But I would point to the results, though, that -- and this is -- I mean, this -- well, first of all, the results themselves suggest nice potential, albeit an exploratory analysis for this particular assay with this methodology, to potentially predict efficacy to Dato-DXd. And I would also say that there are other assays, right? And I would say the majority of assays would use this type of, I guess, non-dynamic type of assessment. When we characterize analytes or biomarkers that can predict response to efficacy of drugs in general. And then sorry, your -- your second question, I forgot..

My second question is around the other biomarker options that you are mentioned. Is it also around just the location of the targets?

Yes. Good question. So we have a broad campaign for biomarkers. So we do -- we are interested in digital pathology, right, which allows you to look within the tissue slide at different analytes, certainly, but beyond that as well. So not just this type of methodology. I mean, digital pathology is an important biomarker campaign for sure. But we recognize that we have to look further than this. And so we look at additional technologies as well.

Could you actually give us the kind of the examples of what kind of things you are looking at?

Yes, sure. So I mean -- yes. There could be -- as an example, we can look at genomic alterations as an example, which is commonly done, right? We could also look at plasma-based biomarkers, biomarkers that circulate in the blood just as examples. But those are not uncommon. So yes, I don't have anything too much more specific to offer, but we're looking broadly at methodologies and types of biomarkers, whether it be genetic, plasma, digital-assisted different types.

I see. And the second question is around the second-generation ADC. So you mentioned that the second generation, the ADC has a linker, cleavable linker. And I understand that Daiichi Sankyo usually takes a really kind of specific approach in terms of developing a new ADC, new modality to solve some of the challenges that exist in the current modality. So I'd like to understand, you are saying that this new version is a cleavable one. What was the kind of the challenges you identified behind it to develop such a new modality?

Yes, it's a good question. And we really can't speak too much about this quite yet. Really, what we're saying is it's a new payload to modify PBD payload. And when we talk about the target Claudin, so if we talk about a cleavable linker. But we're not describing at this point how this is different than the DXC technology and what specifically was thought about that needed to be overcome. But I would say in general, I mean, we -- and this won't be the -- I mean we'll have additional new ADC platforms in the future, right? So this is the next one we're presenting the second one, but there'll be more. I think when you kind of step back and think more broadly, I mean, we look to at new targets that as an example, which would allow us to address new unmet needs in new tumors. We can look at new linker technologies, we can look at different payloads to optimize benefit/risk in multiple ways. And so we're -- we look quite broadly and when we consider next-generation ADC platforms and what they could bring in terms of advance. But in terms of this specific platform and how it compares to the DXd ADC technology, I'm not able to offer details quite yet.

The last question is from Tony Ranson, Macquarie Capital.. Looks like we lost Tony Ranson. So we will now go to closing. But before we close, again, we apologize for the issues with simultaneous interpretation audio, and we're going to upload a recorded version of this event on our corporate website very soon, so please visit our website. So now we will close and conclude Daiichi Sankyo's WCLC and ESMO 2024 highlights. Thank you so much for joining today.

Thank you. [Portions of this transcript that are marked [Interpreted] were spoken by an interpreter present on the live call.]