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

[Interpreted] Thank you very much for waiting. Now we'd like to start Daiichi Sankyo's ASCO highlights. I'm Astakura from Corporate Communications Department, and I will serve as MC today. First, let me explain the language for this meeting. We are going to use Japanese and English in this web conference. Simultaneous interpretation is available. Please click interpretation icon at the bottom of the Zoom screen and select the language from Japanese, English or off. If you select off, you will hear the original sound. English presentation materials will be displayed on the Zoom screen. Presentation materials in Japanese and English are posted on our corporate website under the IR Materials section in the IR library. You can download the file for your reference, if you want. Today, 3 members are participating as shown on Page 3. President and CEO, Sunao Manabe; Head of Global R&D, Ken Takeshita; and Head of Global Oncology Clinical Development, Gilles Gallant. You can find the agenda for today on Page 4. First, Ken Takeshita will make an introduction, and then Gilles will explain the content of the presentations at ASCO, and last month's ESMO breast cancer. At the end, we will take your questions. Please note that we are recording this meeting. Thank you for your understanding. Now we'd like to begin. Ken-san, please?

Yes. Thank you very much, Astakura-san. I'm going to start on the next slide with our 5-year business plan. Our goal here in the 5-year plan is to become a global pharma innovator with competitive advantage in oncology. And we are very well on our way to achieving this goal. And by 2030, you'll see that our goal is to strive to be a global top 10 in terms of oncology revenue, have additional pillars of sources of growth, new products being source of profit in each business unit, and contributing to sustainable development of society through our business. So this is really our long-term plan. And in the next few slides, we intend to give you an update on where we stand. Next slide. Among the 5-year business plan, we have 4 pillars, and we're going to go into some detail on 2 of them. First, on the left is the pillar to maximize the 3 ADCs. The 3 ADCs are the HER2 and Dato-DXd, which are in alliance with AstraZeneca. And also, we have HER3-DXd as part of this pillar, which is being maximized from an opportunity perspective without a partner. Next slide. In terms of the 3 ADC program, these are some of the details for the 5-year plan and beyond. You'll see that we have made a major progress in DB03, DB04 and DL01 as major progress in fiscal year 2021. We are expecting also to see our data in 2022 for the TROPION-Lung01, and in 2023 for DESTINY-Breast06 and HERTHENA-Lung01. So we are really off to a great start in terms of the 2025 goal and plan. You'll see that we are also further starting as new clinical trials, like DB11, DL03, TROPION-Lung08, TROPION-Breast01, Breast02 and also HERTHENA-Lung02, and these will all contribute towards growth of our company towards the fiscal year 2026 and beyond. Next slide. The next pillar that I'd like to discuss with you is the third one here, in red, identify and build pillars for new growth. And this comes in 2 different types of strategies. First is to identify new growth drivers beyond the 3 ADCs. And second is to select an advance promising post-DXd-ADC modalities. And let me just go over with you in a little bit more detail on these 2 points. Next slide. In terms of new candidates beyond the 3 ADCs, we have already identified DS-7300 and DS-6000 as rising stars, based on the clinical data that we have so far. We can see that with DS-7300, we have a clinical signal in small cell lung cancer, and we are now preparing to start a focused-SCLC program in fiscal year 2022. For DS-6000, which is the ADC directed against deruxtecan-6, we are starting the Phase I program. And based on some early data, we have seen some very promising clinical trial data in ovarian cancer. So these are -- really have the potential to be new growth drivers beyond the 3 ADCs, and we are very hopeful that we will see good trial data from these programs. In terms of modalities, that is described on the next slide. As you are aware, our DXd-ADC technology is the one that's driving all the ADCs that are in clinical trial development right now. But beyond the DXd-ADC technology, we have a number of additional technologies in research stage, not just the naked antibodies or small molecules, but also ADC -- second and third and fourth generation ADCs with different linkers, different payloads, different binders that we wish to bring into clinical trial stage in the near future. And also, you'll see that beyond those, we have a number of innovative technologies under research biospecific antibodies, cell therapies, RNA technology and gene therapy. Next slide. And of course, beyond this, we have what we consider to be the alpha program. These are the next pillars of our drug development. And beyond the 3 ADCs, as you probably know, we have a couple of clinical trial stage programs that are yielding very interesting data. One, of course, is the quizartinib program. The data from that will be highlighted next week at the European Hematology Association Meeting. And also, we have some early data from our 3201 dual EZH program. So these are very promising, very important parts of our entire program. Next slide. Okay. So with that very brief introduction, I'm going to turn it over to my colleague, Gilles, who will go over with you in detail where we stand in our clinical development program.

Thank you, Ken, and we'll go to the next slide. So it's really an honor for me to come today and present the data and the work of many in the R&D organization. We have actually presented and published 28 abstract in the most -- the 2 most recent programs at ASCO breast cancer last month, and just completed ASCO 2022 with 1 plenary session on DESTINY-Breast04, an important study, a study that is looking at patients that are HER2-low. And this particular study, and this group of patients received our fifth breakthrough therapy by FDA for ENHERTU. And actually, we also published our fifth New England Journal of Medicine on DESTINY-Breast04 at the same time as a presentation at ASCO at the plenary on Sunday. Next slide. So as you can understand, I won't be able to present everything on the 28 abstracts. So we've selected very important data to present to you. I have limited time. So -- the slides are available. There will be more information on the slides, of course, that I'll be able to talk to. So let's start with the HER2-low breast cancer data we just presented at ASCO. Next slide, please. So this is really opening a new treatment paradigm for patients with HER2 breast cancer. Next slide. This presentation on Sunday afternoon was done by Dr. Modi from Memorial Sloan Kettering, one of many investigators around the world that have completed enrollment in this study. Next slide, please. The study -- I think what is important here is the status of breast cancer before Sunday, which is on the left here. You see that HER2-positive breast cancer represents 15% to 20% of all patients with breast cancer. And then the rest of the breast cancer population was really defined in the HR-positive, HER2-negative population, around 65%. And HR-negative, HER2-negative, also called triple-negative breast cancer population, which is 15%. The study is really performed in HER2-low. That's patients that have IHC 1+ or IHC 2+ with ISH-. And after Sunday's presentation, I think we redefined the metastatic breast cancer area into 3 buckets, one, of course, still remaining HER2-positive. Then the HER2-low population, we just mentioned, which represents approximately 50% of metastatic breast cancer. And finally, a smaller proportion of patients with HER2-negative breast cancer. And this study really is the first HER2-targeted therapy to demonstrate improve efficacy in HER2-low metastatic breast cancer. It establishes T-DXd or in HER2 as the standard of care for HER2-low metastatic breast cancer, and could help up to 50% of all metastatic breast cancer patients. Next slide, please. So this study was a randomized study between T-DXd and treatment of physician preference, which included 5 different drugs that are used as single agent. Patients with HER2-low as they find previously that had received prior chemotherapy were randomized 2:1. And a total of 557 patients were randomized in this study. The primary endpoint was progression-free survival determined by independent investigator in the HR hormone receptor-positive population. If that was to be positive, then secondary endpoint would be looked at, DFS by -- also the outside investigator on all patients. And then finally, OS in the hormone receptor positive and in all patients. The majority of the patients in this study were indeed hormone receptor positive. We were to enroll around 480 patients. And there was about 60 patients to be enrolled with HR-negative disease. Next slide. The population was typical. Here, I'll note that about 60% of the patients in this study had a HER2 1+ and about 40% had 2+. The patients were -- had very extensive disease with a lot -- in fact, of around 70% of them having liver metastatic disease and about 30% to 35% had long metastatic disease at baseline. Next slide. We had received a lot of different therapies in the HR-positive group. Of course, they had received hormonal treatment. But again, had received metastatic -- in the metastatic stage chemotherapy, and 1 or 2 previous lines of therapy. At the bottom there, you see that about 70% of all patients in this study had received CDK4/6 inhibitor, standard of care that is now more and more used in patients with HR-positive around the world. Next slide. This is the primary endpoint of the study, the progression-free survival, on the left, in the hormone receptor-positive population. A hazard ratio of 0.51 with a p-value of less than 0.0001, a difference in median between the standard of care and T-DXd of 4.7 months. On the right, you have all patients, including HR-positive and HR-negative. And you find a similar data here with the difference between the 2 arms at the median of 4.8 months. This is significant in terms of statistics, but also extremely important for patients. This is clinically significant as well. Next slide. In terms of overall survival, which is ultimately the most important endpoint in this patient population having metastatic disease. You can see on the left, in the HR receptor -- the HR-positive patients, a difference of months in median survival going from 17.5 to 23.9, and similar results when you include all patients. And the difference there is 6.6 months at the median between the 2 arm, something extremely clinically relevant for patients in advanced disease. Next slide, please. Of interest, of course, there was a small group, as I mentioned, of hormone receptor negative in this study, and we are displaying here the TFS and OS in this particular population. Even though these are small group of patients, you can see, again, repeating a significant difference in PFS of 5.6 months, and something that physicians were extremely happy to see at ASCO, a difference of 9.9 months in the median survival of those patients going from 8.3 months to 18.2 months. This is something that has been rarely seen in this patient population. Next slide. If you look at all the different subgroups, you can see in the forest plot that almost every subgroup benefited from this drug, including having the patients that have received CDK4/6 or not. There were no difference also between IHC 1+ or 2+, all those patients had a significant advantage here versus the standard of care. And even those with visceral disease at the bottom there, had a very significant advantage when they receive T-DXd. Next slide, please. Overall response rate is important also in those stations. The control of the disease is important. And as you can see here on the left, the HR-positive population, a tripling of the response rate in those patients and similar results also in the hormone receptor negative. The clinical benefit rate also very positive for T-DXd, and the duration of response as well at the bottom there at the table, significant difference in favor of T-DXd. Next slide. This is the waterfall plot. I think visually, you can imagine that it is quite favorable for T-DXd on the left. Next slide. And in terms of safety, there was no new signal of safety in this particular study. Nausea and vomiting are 2 of the most important effects here. We have been working with investigator to premedicate those patients specifically, and will continue to recommend nausea and vomiting and antiemetics. Neutropenia, of course, was much more frequent in the chemotherapy arm, as you can see here, and you have all the other adverse events. Next slide. When you compare adverse events, of course, you have to take consideration about the treatment duration. And those patients on T-DXd had a significant longer duration of treatment, 8.2 months versus the chemotherapy, 3.5 months. And so the exposure is significantly higher in the T-DXd arm versus the chemotherapy arm. So when you collect the safety information, of course, because you have a much longer exposure with T-DXd, chances are that you're going to see -- you have more chance, if you will, to have an adverse event in the T-DXd arm. Next slide. However, I think what was reassuring in the study, the adverse events of special interest in terms of ILD. We had a rate of ILD that has been consistent with other studies that have had very advanced patients having received prior chemotherapies, and the left ventricular ejection fraction also was very similar rates as our previous studies. Next slide, please. So really here, this study really established T-DXd as a new standard of care. This is practice-changing, and was so well received at the plenary. After the completion of Dr. Modi's presentation, there was a standing ovation for this particular study, something that we see rarely at the ASCO meeting. Next slide, please. So at the same thing, there was an important study that was performed by a group of pathologists led by Dr. Viale from the Milan -- based in Milan. Next slide, please. It actually -- it's a study of 384 patients coming from a little bit everywhere around the world. That look at those 384 patients that were declared as HER2-negative. And they looked at if they had HER2 1+ or 2+ to see if they were concordant with previously evaluated pathologic scores. And in fact, what we've seen is there was somewhat of a concordance, about 80% concordance. And what they also see is that in the 384 patients that were called HER2-negative, about 66% or -- in the HR-positive were actually now defined as HER2-low. And in the HR-negative, about 46% of that population was considered to be in the HER2-low patient population. So overall, about 60% of patients previously called HER2-negative are now called HER2-low, and could be eligible for treatment with T-DXd. Next slide. You see here the conclusion that they actually also tested different methods for IHC, including Ventana 4B5, which is the actual test that was used in DB04. And the concordance was similar between the different test used for this study. Next slide. So as you can see here in this over -- clinical development plan for T-DXd in breast cancer, at the top there, you have all the clinical trials that have been either completed or ongoing for HER2-positive patients. And now at the bottom, in orange, the studies that are either planned or ongoing in the HER2-low patient population. Importantly, DESTINY-Breast06 is a study that is very important that is in chemotherapy-naive patients, and as a follow-up to DESTINY-Breast04, and is currently enrolling patients. Next slide, please. And so I think the key takeaway is that we have a study here in DB04 demonstrating statistically significant and clinically meaningful improvement in both PFS and OS of T-DXd versus the chemotherapy that is usually used in the HER2-low metastatic breast cancer population, and it is consistent across several different groups, including HR status and IHC scores. This particular study is the basis for breakthrough therapy that the FDA recently granted us for this patient population. About 50% of all breast cancer patients are now reclassified as HER2-low, a new targetable patient segment. And really, T-DXd is the first targeted treatment for these patients. And finally, as I mentioned, DESTINY-Breast06 is continuing to explore the activity of T-DXd in an earlier HER2-low breast cancer population. So and HER2 pioneers, the first targeted therapy for HER2-low breast cancer. And DB04 regulatory submission are currently planned in fiscal year 2022, the first part, and I want to reiterate that our fiscal year starts in March. Next year -- next slide, please. So let's talk a little bit about HER2-positive breast cancer. Next slide. In this patient population, we were very happy to receive, on May 5, the approval in the U.S. of the metastatic breast cancer, second-line HER2-positive breast cancer patient population. This was granted by the FDA under the real-time oncology review. We worked very hand-in-hand with the FDA for this particular indication. And really, it broadens the indication, which was in later-line breast cancer to an earlier line in patients with metastatic breast cancer. This is based, of course, on the groundbreaking DESTINY-Breast03 study that showed that HER2 the reduced the risk of disease progression or death by 72% versus another ADC trastuzumab emtansine. Next slide, please. And this is the primary endpoint, on the left, of PFS by external review, a very significant difference. As you can see, with a median for T-DXd that is not reached. And on the right, same a secondary endpoint, which is progression-free survival by investigator assessment. So really, this is unparalleled. The improvement is extremely statistically significant, and very importantly -- a very important difference for patients. Next slide. So at ASCO, Dr. Hamilton from the Sarah Cannon Research Institute presented an update on the safety profile of the T-DXd and T-DM1 in this study. Next slide. It's an important review because a number of patients in this study are still being treated with T-DXd. And so the new update -- the database was closed in September of 2021, and we -- there's, again, a significant number as you'll see in a moment. Next slide, please. So at this point, 55% of the patient in T-DXd have discontinued treatment in this study versus 85% of T-DM1. Next slide. So the treatment duration, of course, is very different between the 2 arms in the T-DXd arm, patients have been on study for a median of 16.1 month. And for T-DM1, 6.9 months. And so 45% of the patient remains on treatment with T-DXd versus 15% on T-DM1. So the exposure, again, is quite significant and much longer in the T-DXd versus T-DM1. Next slide. There were no surprise, everything was consistent with the previous analysis of the safety in the database with nausea, fatigue and vomiting being the most important side effects that we see with T-DXd. And on the next slide, you will see the -- importantly, the median time to events in days. So in each arm, the median time associated with treatment discontinuation was 224 days for T-DXd versus 147 days for T-DM1. Again, a difference that is clinically very meaningful. Next slide. ILD has been noted as again in this study. However, very importantly, no grade 4 and no grade 5 have been seen in the previous analysis. And again, here in this analysis, no grade 4 and no grade 5 has been seen with T-DXd. Next slide. So conclusion, the safety signals are the same, and patients are continuing on treatment with T-DXd, and are really -- this analysis, reinforce the favorable benefit risk profile of T-DXd over T-DM1 in this patient population. Next slide. I just put here 2 slides on the management of ILD. This is an important aspect of the work we do. This is coming from a publication of a group of investigators led by Dr. Swain from Georgetown. You have the reference at the bottom. They actually talk -- it's a very good publication talking about how to identify ILD pneumonitis, how to work with other specialties to make sure that they identify. And if the event is confirmed -- you go to the next slide, please. And if it's grade 1 ILD pneumonitis, you interrupt T-DXd, and you treat fairly aggressively. If you have grade 2, 3 or 4, you have to permanently discontinue T-DXd and treat very aggressively. And with this -- these guidelines and recommendations that each and every investigators in our program are following. We have been able to really improve ILD pneumonitis in our studies. Next slide, please. As part of DB03, there were an important presentation at ESMO breast regarding the quality of life of our patients. This was presented by Dr. Curigliano, who used to be ESMO President. He's based out of Milan. And on the next slide, we use several different quality of life questionnaire in this study. And so at the top there, you see the QLQ-C30. This is a classic questionnaire. And you have there as well the other, the breast cancer 45 questionnaire by the EORTC. The EQ-5D-5L and the -- we were recording as well hospitalization. What is quite exceptional in this study is that 90 -- more than 95% of patients at baseline completed all those questionnaires, and that more than 82% of completed the questionnaire between cycle 3 and 27 in both arms. Next slide. And what did this quality of life questionnaire showed is that really, when you look at this particular forest plot, everything that is on the left favors T-DXd. Everything on the right favors T-DM1. And overall, the health status, again, favoring T-DXd. But there was a significant improvement in pain symptoms and emotional functioning on those patients that were receiving T-DXd, and that reached statistical significance. As well the visual analogue scale of EQ-5D-5L showed an improvement also of quality of life, generally favoring T-DXd. Next slide, please. Importantly, when collecting all hospitalization during this study, we were able to demonstrate a median range of time to first hospitalization of 60 days, only 2 months for T-DM1, and comparing to 220 days for T-DXd. So those patients in T-DM1 tended to be hospitalized, much quicker than those on T-DXd. Next slide, please. So I'll let you read the conclusion on your own time. We'll go on the next slide, please. And so one of the big questions we've been asked several times now in the past few years is, is ENHERTU effective in brain metastasis? Next slide. And so we did an unplanned analysis with patients in the DB03 to look at those patients that were enrolled with stable brain mets. And as you can see on the left there, the progression-free survival was quite favorable for those patients having brain mets in the T-DXd versus T-DM1. So a median of 15 months versus a median of 3 months for T-DM1, compared on the right to those patients that did not have brain metastases. And if you look at the hazard ratio on both population, it is fairly similar. This data was presented at San Antonio, by the way. Next slide. And you saw also at the same presentation that the drug really had also intracranial responses according to the RECIST criteria. Next slide. A presentation at ESMO breast cancer was made by Dr. Bartsch of Vienna University. That showed something very interesting -- this trial is called TUXEDO-1. This is an investigator-initiated study, a small study but very interesting. Next slide, please. I know you're not going to be able to read this, but what's important here is that the patients that were selected for this study had been diagnosed with brain metastatic disease, and it was active and untreated. And so those patients received trastuzumab deruxtecan or T-DXd at 5.4 mgs per kg, and they were evaluated. Next slide. And what you see here, and again, these are active brain metastatic disease, the patients did really respond very well to the treatment. Again, limited population. It's 15 patients. This was really a small study. But indicating that the drug clearly has activity, and the company is planning more studies on this. Next slide, please. That's the conclusion. The response rate they've seen in that study was very impressive with 73.3% of response. Next slide. And so in the HER2-positive breast cancer, DESTINY-Breast03, really the follow-up of safety and the quality of life data, supports and HER2 in addition to, of course, the efficacy we've seen and presented last year at ESMO 2021. We now have demonstrated preliminary efficacy in patients with active brain mets, and ongoing studies will hopefully get us further evidence. And ILD management education, as I mentioned before, are continuously important for safe view. So -- and HER2 continues to build trust in HER2-positive breast cancer therapy. Next slide. And so -- next slide. So a number of other studies have been presented in the past 2 meetings. There's more breast cancer in ASCO. We've selected a few. You have some of the other meetings that we're not going to talk about. I refer you to those if you're interested in getting more data. Next slide. So I'd like to talk a little bit about Dato-DXd and the BEGONIA study. Next slide. So this study was presented here at the -- not here. I'm sorry, at ESMO breast cancer by Dr. Schmidt from London. And it involves the combination of Dato-DXd or datopotamab deruxtecan plus durvalumab, an IO immuno-oncology drug. Next slide. This study is a study with a lot of different arms, combining durvalumab with different agents that could have activity in patients with triple-negative breast cancer. So patients in this study have not received previous therapy for Stage IV triple-negative breast cancer, and they're enrolled in one of the different arms that are available in this study. And so today, I'm talking only about the arm with Dato-DXd and durvalumab. Next slide, please. And as you can see, I guess, we shouldn't be surprised, but the waterfall plot is very similar to several we've seen with T-DXd. In this case, the combination of Dato-DXd and durvalumab in BEGONIA in 27 patients confirm responses rate of 74% in patients with triple-negative breast cancer. Quite impressive. And of course, this is something of interest to both the alliance partner, AstraZeneca and Daiichi Sankyo. Next slide, please. You see here also the -- this is an early analysis. Of course, patients are ongoing. But a signal that there are possibly long-term duration of response in this particular study as well. We are continuing to follow those patients, of course. Next slide. The adverse event has been similar to what we've seen before. Next slide, which is important for Dato-DXd. There's 1 toxicity that is very different from other of our agents from the DXd series, stomatitis has been seen with mostly grade 1 and grade 2, but can reach grade 3 in certain patients. And you see also nausea, fatigue, rash and vomiting in this particular combination trial. Next slide, please. And so the results are quite promising for this combination of durvalumab and Dato-DXd with a confirmed response rate of 74%. The responses interestingly were observed regardless of the level of PD-L1 expression. So that might be a very interesting combination to bring earlier in the disease in triple-negative breast cancer. Next slide, please. And so here are the studies that are ongoing with Dato-DXd, currently. I just discussed a little bit of BEGONIA, the bottom there. And as you can see, our program is expanding in the HR-positive disease as well as in the triple-negative breast cancer disease. Next slide. And if you overlay the DESTINY program, so the T-DXd program and the Dato-DXd program, you can see now the possible synergy, if you will, in this. The gray arrows represents right now an area of the clinical development plan that we're working on. Of course, with DESTINY-Breast04 that I mentioned. That opens up early breast cancer in the HER2-low population, and as well, the triple-negative breast cancer population could be also addressed by Dato-DXd. So we're working on expanding the study programs in those particular patient population. Next slide, please. Very interesting agent, patritumab deruxtecan that targets HER3-DXd. Next slide. There was an important oral presentation by Dr. Krop from the -- interestingly, I don't think he's from Yale. He's from Dana Farber. I just saw the error there on the slide. Next slide, please. This was a study that was dose escalation, and was presented before. And today, what they're reporting at this particular meeting is the efficacy in the different breast cancer subtypes. So the HR-positive, HER2-negative with 113 patients, the triple-negative breast cancer population with 53 patients. And very interestingly, the HER2-positive patient population with 14 patients. Next slide, please. And so you have here the confirmed response rate in the 3 different subtypes at the top there. And this is by again ?external review. The confirmed overall response rate in the HR-positive, HER2-negative is 30%. In the triple-negative breast cancer, it's 22.6%. And 43% in the HER2-positive patient population. And as you can see, lower the duration of response, it's fairly favorable. Also, the progression-free survival is very interesting in a very advanced patient population. So clearly, HER3-DXd has activity in breast cancer, and it has demonstrated in this study, even with a very advanced patient population, durable antitumor activity across different breast cancer subtypes. Next slide. And you can see here, again, the waterfall plot, many patients benefiting for this particular treatment in the 3 different subtypes analyzed in this study. And so this is very remarkable of the DXd technology that Daiichi Sankyo. As you can see from T-DXd to Dato-DXd, and now HER3-DXd having efficacy in many patients with breast cancer. Next slide, please. And so there was, of course, safety was reviewed in this particular study. ILD was present in about 6.6% of the patients, as you can see with, unfortunately, 1 grade 5 at 6.4 mg per kg. The dose we're going to pursue in future studies is actually 5.6 mgs per kg based on this dose escalation trial that I just presented. Next slide, please. And so the adverse event for this particular HER3-DXd, nausea as with other DXd programs. But what is interesting is maybe a little bit more specific for HER3-DXd, some thrombocytopenia seen, platelet count decrease and some ANC or neutrophil count decrease seen in those patients. So this is something that we have seen less in the T-DXd program in Dato-DXd program. Next slide, please. And so clearly demonstrated that HER3-DXd as possibly a role in the treatment of breast cancer, clinically meaningful durable antitumor activity in very heavily pretreated patients. Next slide, please. And so we are deepening our understanding of the DXd-ADC science. We're looking, of course, of mode of action and mode of resistance with our colleagues from translational science. We're seeking also opportunities to combine the DXd-ADC with other agents active in those diseases, and we aim to overcome the disease with multiple treatment options. So we continue to address remaining unmet needs in breast cancer. Next slide, please. Rising star. Next slide. As Ken mentioned at the beginning here, we have identified 2 particular drugs in our portfolio, DS-7300 and DS-6000 as being rising stars in our particular development programs. And at ASCO, in fact, a little bit earlier today, the first Phase I dose escalation of DS-6000 was presented. They have the potential, these 2 drugs, to become our new growth driver. Next slide, please. And so this study was presented by Dr. Hamilton from the Sarah Cannon Institute in Nashville with the co-authors here from the U.S. and in Japan. Next slide. So cadherin 6 is a member of the cadherin family. It is involved in the cell-cell adhesion, in organ development and epithelial mesenchymal transition. On the right there, you can see that it is over-expressed in various cancer, but especially in ovarian cancer and in renal cell cancer. At the bottom right, you can also see that this drug preclinically in models has been quite effective in inhibiting tumor growth, and really produce tumor regression in different models. Next slide, please. And so DS-6000 is, again, a DXd-ADC. I won't go over the different attributes, which are similar to the series. However, just to mention that this particular ADC has a drug-to-antibody ratio of 8 approximately. Next slide. And so this was a typical Phase I escalation. We started at 1.6 mg per kg and plan to go all the way to 9.6 mg per kg. And when the dose was to be established, then expand in the cohort B1 and B2 in renal cell cancer and in ovarian breast -- and ovarian cancers. And so what we're presenting today is actually the dose escalation on the left, the dose expansion has been initiated. Next slide. And so 30 patients in total were enrolled in the dose escalation, 20 ovarian cancer -- 21 actually. We have data here on 20. In renal cell, 9. As you can see at the bottom, the number of previous regimen was fairly high in the station population, a median of 4 for ovarian cancer with a range of 1 to 12. And 2 for renal cell cancer, a range from 1 to 6. Next slide. And so the data cutoff, as I mentioned, 21 ovarian and 9 renal. At the time of this data lock, we have 57% of patients still receiving treatment. So it's a very early look at the activity of DS-6000, and the median treatment duration was fairly short at that point. Next slide. But of course, the most important part of the Phase I is to evaluate safety. And as you can see here with the different dose, toxicity was seen increasing with the dose. No surprise. And the major toxicities that we're seeing were nausea, fatigue and vomiting. And on the next slide, you will see that at the dose of 9.6 milligram per kilogram, a number of patients actually add toxicity that were considered as dose-limiting. So 9.6 mg per kg was determined as the highest doses, and we will recommend doses of 6.4 and 8 mg per kg for the future studies. Next slide, please. And so immediately, as you can see on the left, we started seeing responses, both in ovarian cancer and in renal cell cancer in this patient population. And on the right, you can already see the potential for this drug, also, to have long duration of response in these patients. So the point of this presentation, 4 PRs have been confirmed in the ovarian cancer population, in particular in the platinum-resistant ovarian cancer, 3 patients. And 1 patient in renal cell had also a confirmed response. Two patients are unconfirmed PRs at this point. This study is ongoing. And 12 patients already had stable disease. Next slide, please. And so in ovarian cancer, we look specifically for markers, CA-125. And as you can see, a vast number of patients also had CA-125 responses. And the gynecologic oncologic community is quite excited by DS-6000. And of course, we will expand our knowledge with more patients in this study. Next slide. So DS-6000 was generally well tolerated. The recommended dose is 8 mgs per kg, and we'll continue the expansion cohort and enrolling more patients with ovarian and renal cell. Next slide, please. And so our DXd-ADC has currently 5 drugs in the clinic from ENHERTU, Dato-DXd, HER3-DXd, DS-7300, DS-6000. But as you can see at #6 and 7, we have more coming in the clinic DS-3939 and an undisclosed DXd-ADC. Next slide. Next slide. Importantly, and we -- it's important to mention that next week, the European Hematology Association Congress is being held. And quizartinib, the results of the QuANTUM-First study. This is the study of quizartinib in previously untreated-AML patients will be presented at the Presidential Symposium at the meeting. So I encourage all of you to follow this. This is a study that we've already announced that is positive for overall survival in favor of the quizartinib combination. Next slide. And I think that's my final slide. These are the future news flow. And I understand that this particular news flow is similar to a slide that was presented before in April, so no changes at this point. And next slide. That's it, we're done. So I know I went pretty fast again, but I think we're happy to answer questions.

[Interpreted] We'll now would like to go into Q&A session. Let me explain how you can ask questions. If you want to ask questions, please click the reaction button at the bottom of the Zoom screen, and select raise-hand button. [Operator Instructions] When you're done, please click the reaction button to select the lower-hand button, and turn on mute again. Now we'd like to open the floor for questions. The first question is from Mr. Hidemaru Yamaguchi from Citigroup Securities.

[indiscernible].

So let me try to answer that question, and I will also ask Gilles to make his own comments. I think the -- it's important to note that the HR-negative patient population analysis or an exploratory analysis, but the numbers look very, very good. And why is this drug active in this patient population? Basically, these are triple-negative breast cancer patients. And traditionally, this is a type of disease that has been treated with chemotherapy, cytotoxic agents. And so perhaps that is the reason why we saw the data that we did. Even though these were highly refractory patients, so highly refractory to standard chemotherapy. It is quite conceivable that because of the nature of the disease that it was effective in these patients. It's really a speculation at this point that we guess we do need to understand how far we can go with an HER2 in this patient population. I don't know, Gilles if you any other additional speculation from you?

Not much. I think triple-negative breast cancer patient population in general is considered chemo-sensitive. But you're right, in this particular group of patients, they had received multiple therapies before. So it is remarkable that the drug was so active. And if you look at the overall population, I mean, this small group of 60 patients with HER -- HR-negative didn't really influence, if you will, the data overall. And so then the benefit seems to be the same in both HR-positive and HR-negative.

[indiscernible].

Yes. These data in HER2-low, the DESTINY-Breast04 study really opens up the question that you just mentioned. How low can we go with the HER2 expression and HER2 still be active? And so far, the data indicates that we can go quite low, at least to the HER2-low expression level, basically IHC 1+. So the lower range of expression for -- at the definition of IHC 1+ is 10%, low level expression in the tumor bed by the pathology assessment. And so we're about 9% or 8%. Or I think we're very interested in this question, and we actually have now clinical trials actively enrolling to answer this question. Gilles, do you have anything to add to this question?

The clinical trial in question is DESTINY-Breast06. It's enrolling patients again earlier in their disease, have not received chemotherapy before, but they have HER2-low with 1+ 2+, and ultra-low as well in that study. So the study compare our agent to the standard of care, the chemotherapy and is ongoing and is enrolling. So that's very interesting. We do have some data in patients with HER2-0, and that comes from a study in France, the DAISY study. And they have demonstrated and reported up to now about a 30% to 40% response rate in HER2-0, which is quite provocative. And so I think the DESTINY-Breast06 will really answer the question as to the benefit in this particular patient population.

Next, Mr. Muraoka from Morgan Stanley Securities.

[Interpreted] Yes. First, as was mentioned, DB06 study. As for the timing, according to [indiscernible], the results will be available in June next year. June next year is the correct timing, or do we have some information earlier than this? Or any possibility of a delay in the availability of the data? That's my first question.

So DESTINY-Breast06 is under the leadership of our colleagues at AstraZeneca. So they've established the time line. And so we must believe what they've put together, I can assure you that the study is enrolling very well right now. But at this point, I cannot comment more on this. June 2023 is fairly soon. However, there is no possibility for earlier data only, I think if the follow-up was to be accelerated, but that's not possible. So I think we have to believe that particular date.

[Interpreted] Understood. And another question about ENHERTU. CDK4/6 comparison -- or CDK4/6 combination either of the 2, do you have any plans for that for first line or earlier stage?

Yes. These data really raised a number of very interesting possibilities for combinations, including CDK4/6 agents. So yes, we are considering them. Gilles, do you have anything to add?

That's okay.

Very good.

[Interpreted] What about the comparative studies? Are you considering [indiscernible] comparison?

Yes. Ultimately, that's what we will have to go with. And yes, those are something that we are considering now.

Next question from Mitsubishi UFJ Morgan Stanley, Mr. Kumagai. Sorry, it's Ms. Kumagai.

[indiscernible].

Right now, the -- it's too early to tell exactly what the labeling will say, but it certainly it is our hope that the label will reflect the primary and key secondary endpoints of the clinical trial, which would include, therefore, both the HER2, I mean, in hormone receptor positive and negative patient populations.

[indiscernible].

Well certainly based on the data that it would be very important to understand that this will be accepted not just by the regulatory agencies, but also by the practicing oncologists who are seeing the data. Yes.

[indiscernible].

Well, there is ongoing discussions, and we will start the study as soon as possible. This is, again, a study that is under easy leadership. And so we're working very hard with our colleagues at AstraZeneca to start the study as quickly as possible.

Next, Mr. Hashiguchi from Daiwa Securities.

[Interpreted] Hashiguchi from Daiwa Securities. My first question is about HER2-low and unheard potential in HER2-low. In 04 and 06 studies, the next development after 04 and 06, basically, the combination therapy is going to be your strategic direction. Next, regarding combination 08 study, dose modification was presented this time. Additional efficacy -- what is your sense of the add-on benefit in terms of efficacy?

I don't know. Gilles, do you want to answer that question?

Sure. So DESTINY-Breast08 is a series of combination studies with different combinations. It is, again, under AZ leadership at this point. It is looking really more for safety signal than efficacy at this point. It's a small number of patients being studied with a different combination in this trial. And this is ongoing study, so we have little results. We've seen responses. No surprise. But it is very early. And at the end of the study, the goal is really to establish if we can combine T-DXd with other agents that are used in HER2-low patient population. And then I think ultimately, other trials will be needed to really establish the efficacy of those combinations.

[Interpreted] The second question is about how HER3-DXd positioning? You have shown efficacy in many different breast cancer types as well as the lung cancer. That's been announced. But it had an Dato-DXd development, if that's successful. I think you will be seeing overlapping of the patient groups. So how would you differentiate in terms of the positioning of HER3? ENHERTU and the Dato-DXd to be followed by HER3-DXd, is that a possibility?

Yes. Certainly, that is a possibility that we are actively discussing the question of sequencing, and also how to use these multiple active agents we have in both breast cancer and lung cancer, should they be used in sequence or in combinations or some other sequence? I think these are really very important questions for us. Really, we are not yet quite at the stage where we can make data-driven decisions, but it is a very important question that you raise.

Next, Mr. Sakai from Credit Suisse Securities.

[indiscernible].

Okay. We did not quite catch that question. I understand it's an ILD question, but if you could just repeat the question again, please.

[indiscernible].

I think I understood. The question is ILD in HER2-low patient population. We have seen, as we mentioned before, ILD in this patient population. And unfortunately, 3 patients with a grade 5 ILD. This patient population is a very advanced patient population, and could be in a way compared to the DB01 study that we reported earlier. And so with heavy previous therapies, there seems to be more -- the presence of ILD. In DB03, those patients have received less previous therapies, and we saw really lower level of ILD. Now as I mentioned, what is important with this particular side effect is to really recognize the adverse event as quickly as possible, question the patients about symptoms like cough, like dyseneia, and aggressively treat those patients as quickly as possible, discontinue the treatment if patients have grade 2, 3 or 4 ILD. And that is something that we constantly enforce and talk to our investigators about.

[indiscernible].

Well, I think what we can only comment on is that is really the outstanding performance of our ADC DXd technology. We can see that it continues to outperform. I think all the other ADC technology out there, that's really our opinion. And so therefore, on that basis, we think that the active use of this technology for the Dato-DXd program is a very good one. But it's a little difficult to say how much greater confidence we have in the Dato-DXd program. I think -- because we have always been quite confident of our program, but does DB04 data add more to what we already think is a very good program? I'm not sure that it's a very big gain in additional confidence on already what is highly good ADC.

Next. Nikkei BP, Mr. Hashimoto, please.

[Interpreted] Earlier, HER2-low was presented at ASCO Plenary There was a standing ovation there. If you were in the audience, how was it? What was the excitement there, on that side?

No. Okay. Well, I think we should both answer this question.

Yes.

So I think both of us were in the room, and there's a lot of energy in the room, a lot of emotions. And you can see a lot of tears in many people in the audience, resumable many of them were patient advocacy representatives and also the presenter herself. It was a very important experience for all of us, not just to hear people at Daiichi Sankyo, bravo for the entire oncology community.

I think it was a very emotional moment for all our colleagues at Daiichi Sankyo and AstraZeneca. I think this was not expected. This is not something you regularly see at ASCO. Actually, you see this very, very rarely. And so we are a little bit taken by surprise. But to me, it represents the advancement we're making here for patients. And people recognize that this study is really practice-changing, and really going to help a tremendous number of breast cancer patients. So again, very emotional for all of us, for patients, and even for investigators that were part of this study and investigators that will be part of future studies with ENHERTU as well.

[Interpreted] So CEO, Sunao Manabe you are -- yes. So could you also mention what's your impression through the ASCO presentation?

[Interpreted] Yes. This is Manabe speaking. About the standing ovation. When I heard about that, and it's very rare, so as Daiichi Sankyo is actually the first experience. And AstraZeneca, CEO, Pascal, send me an e-mail saying that this is the third time for him from his history or experience. And of course, he has more experience in the area of oncology. But still, including us, and through his own history, and also through my own experiences, it's a great thing. And that the T-DXd researchers as well as developers, all of these people, I put so much trust in all of these people, and I really appreciate their efforts.

[Interpreted] One more question. HER2-low definition was explained for the study, I was able to have a good understanding. For the future, this definition is going to be taken for granted, like a common place or if a competitor brings a different concept. Daiichi Sankyo's definition can be interfering? What's your view?

Currently, as of today, the definition of HER2-low is based on the clinical trial protocol that we ran, and the definitions that we used. Certainly, as the field advances, the definition of HER2-low or HER2-0 may change over time. But that -- as of today, HER2-low as we defined it in our clinical trial.

Let's take next question from JPMorgan Securities, Wakao-san.

[Interpreted] I am Wakao from JPMorgan. I have some questions. First is a simple question. DB05 results IHC 1+ and 2+, there was no difference. So what's your take on that? By standard effect, is that there? Or mechanistically, is there any more information you have?

Okay. So my answer to your question will be a speculation really about why there's no difference between 1+ and 2+. And I would really speculate that this drug is so effective that the difference in the numbers of target HER2 protein on a cell surface doesn't really matter all that much to the drug that even small numbers of HER2 protein existing on a cell surface or the tumor cells, for example, at the 1+ level. That is enough for the drug to get inside the tumor cells, release the payload and cause set of toxicity to not just that particular cell but also the nearby standard cells. So that's really our speculation, really that the drug being so highly effective that it is able to recognize tumor cells expressing low levels of HER2 protein.

[Interpreted] I understand well. Next, DESTINY-Breast06 study, DB04 results were great. So you have higher confidence by now. Under these circumstances, DB06 target is chemo-naive patient population, and chemotherapy progression-free survival. How much is it in general? According to various publications, in this patient population, PFS with chemotherapy is not so long. DB04 and ENHERTU, 10 months is PFS chemotherapy in the second line. This is higher than that. So what do you think?

We can only say that our confidence level in DB06 is quite high now. I don't know, Gilles, any comments on that?

Yes. And you're right. publications on PFS and overall survival in this patient population varies very much. And the improvement also over the years of PFS with similar regiment has been noted. Now in our study that we mentioned today, you saw the median in the second plus line, if you will, of chemotherapy. You would estimate that in first line to be a little bit higher, of course. And I think that's what I would feel that would be appropriate as a starting point if you make some calculations. And again, we are much more confident on the DB06, and we are more confident to bring this drug earlier in the disease as well.

[Interpreted] Understood. So about DB06 again, HER2 ultra-low is recruited and enrolled in this study. And in HER2 ultra-low, If you can obtain positive results. Would you like to get an indication for ultra-low be approved? And Ultra-low diagnosis in the real life clinical practice, has it been established already or can you establish in the future going forward?

I think you can understand that we're doing studies in patients with ultra-low HER2 for a reason. And we think that patients can still benefit in this patient population. Now with DB06, of course, we have to define very clearly from an IHC perspective, what is IHC 0 ultra-low. And so we are working with partners in the diagnostic world to establish better assays to really identify those patients for that particular study. The current study, DB04, use a currently available IHC-based. We work with Roche Ventana assay that's called 4B5 for that particular study. But for DB06, we will introduce a new assay to identify patients better.

Next, Citigroup Securities, Mr. Yamaguchi, please.

[Interpreted] Brief 2 questions. [indiscernible].

I don't know. Gilles, do you have an answer to this question?

So we -- in all our programs, we usually bring forward more than 1 dose. And actually, more recently, health authorities have been questioning how do we justify the dose in our programs. And so we have worked with the different health authorities to do exactly that. In the case, we're talking about DS-6000. We have now identified a dose that is too high, which is 9.6 mg per kg. And so we're going to be exploring more than 1 dose, of course, in the next studies. 8 mgs per kg is the next lower dose that we did in the Phase I, and this will be one of the dose. And then again, we'll try to justify that dose versus a lower dose, probably 6.4 mg per kg in this case. And so that's our plan to always do some kind of randomized study to establish the safety of the dose, and justify the dose for health authorities.

[Interpreted] So finally, this has nothing to do with your presentations, but I'm sure that there are a lot of questions from investors. Seagen arbitration will take place in the middle of this year. What about the time line? Any change or any change in the content? And this question goes to Manabe-san.

[Interpreted] Yes, Manabe. Would like to answer this question about arbitration. Seagen has announced the timing, and that is our expectation as well. So we are waiting for the decisions to be made by arbitrator. So we don't have any additional information. Once the results are out, we will let you know.

[Interpreted] It's now the time to close. Here, we'd like to close Daiichi Sankyo's ASCO highlights meeting. Thank you very much everyone for joining today. Thank you very much. [Portions of this transcript that are marked [Interpreted] were spoken by an interpreter present on the live call.]