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

Thank you for waiting, everybody. We'll now start Daiichi Sankyo's ESMO 2025 Highlights. This is Ken Asakura from Corporate Communications, and I will be the moderator today. First, about the language for this event. Presentation 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 slides have been uploaded to IR Presentation Material page of Investors section on our corporate website, so please view or download as needed. Our presenters for today are Dr. Ken Takeshita, our Head of Global R&D; and Dr. Abder Laadem, our Head of Late-Stage Clinical Development. We'll take questions after the presentation. And please note that this event will be recorded. With that, let's start the event. Ken, please.

Okay. Ken Asakura-san, thank you very much for that introduction. And it's a distinct pleasure for me to give you the ESMO highlights Investor Relations meeting presentations. Next slide, please. So let me just first tell all of you that this slide is the -- all the presentations that we made at this current ESMO meeting. It's an enormous number of data presentations and including at least 3 or 4 registration trials, pivotal trials that can be submitted to various regulatory agencies. The 3 Phase III studies, DESTINY-Breast05, 11, TROPION-Breast02 and REJOICE-01. So these are incredibly important to all of us, to patients, the company and of course, to the investors. And so -- we're very excited. And I got to say that for me, this is probably our best list of presentations at a major cancer conference for Daiichi Sankyo. So thank you very much to all the people here at the Daiichi Sankyo and patients who participated in our trials, as well as our partners, AstraZeneca and Merck. So -- and we're going to go through all the details of the data, but let's just go on to the next slide, just to give you some big picture of where we stand. So I think many of you are familiar with this disease map. This one is for breast cancer. It divides the breast cancer field into multiple lines of therapy from neoadjuvant all the way to second line and later. And of course, also by subtypes of breast cancer, HER2-positive, triple-negative breast cancer, et cetera, on the left. The colors indicate the assets that we have in clinical trials and the boxes that are filled in represent approvals that we have already obtained specifically in U.S. and other major countries. So for today, I'll tell you that DESTINY-Breast09, that is a submission that is in progress at the moment at the FDA and other regulatory agencies, DESTINY-Breast05 and 011. These are the new data that was presented at ESMO. So I hope you understand that these orange color boxes that are in lighter orange will soon become dark orange boxes. In addition, on the triple-negative breast cancer, TROPION-Breast02. This is a data that we're going to be presenting later today in this session. And hopefully, this will also turn into a dark blue box in the near future. Next slide. I do want to some -- want to mention that we have additional clinical trials going on in lung cancer. We did not report any positive Phase III data in these diseases. But of course, we are certainly very much interested in doing these lung cancer trials. Next slide. Okay. In the field of GYN cancers, so REJOICE-Ovarian01. This is the data that we will also be discussing later at this session, some preliminary data on R-DXd in ovarian cancer. And hopefully, this purple box will also turn -- soon turned into a dark purple box at some point in the future. Next slide. Okay. So with this, I'm going to ask Dr. Abder Laadem to give us some details of the clinical data that was shown at this ESMO meeting.

Thank you, Ken, and excited to be here. Hello, everybody. My name is Abder Laadem, I'm the Head of Oncology Late Development at Daiichi Sankyo. Today, I would like to highlight 6 different topics related to the DS assets from the 2025 ESMO conference, 4 in breast cancer, covering ENHERTU in early breast cancer and Dato-DXd in triple-negative breast cancer. Another presentation, the fifth one is related to R-DXd in ovarian cancer. And the last not least, the first clinical data from our first in-human about DS-3939. Next slide. The first presentation is about DESTINY-Breast11 of ENHERTU in the neoadjuvant setting in high-risk HER2-positive early breast cancer. This was presented by Dr. Harbeck at the Presidential Symposium I. Next slide. DESTINY-Breast11 is a global, multicenter, open-label Phase III, randomized high-risk patients, HER2-positive early breast cancers, defined as having large tumors or lymph node positive or inflammatory breast cancer. The trial randomized more than 900 patients in 3 arms, T-DXd followed by THP versus dose-dense AC followed by THP and T-DXd monotherapy. The T-DXd monotherapy was closed following DMC recommendation for various reasons, but not due to safety. The primary endpoint was pathological complete response assessed by a blinded central review. Next slide. Here are the demographics. They were overall well balanced, and most patients were randomized from Asia. Tumor stage, large tumor represented near half of the population and nodal status, or lymph node positive represent near 90% of the patients. Next slide. The trial reached its primary endpoint with statistically significant and clinically meaningful improvement of pathological complete response in ENHERTU followed by THP regimen, over dose-dense AC followed by THP with an absolute rate of pCR of 67.3% and an absolute delta of 11.2% with a p-value 0.003. The improvement was also observed in both hormone receptor negative and hormone receptor positive. Next slide. The improvement in pathological complete response for T-DXd followed by THP versus control was observed across both pre-specific subgroups. We go to the next slide. An early positive trend in EFS was observed also favoring T-DXd followed by THP arm with a hazard ratio of 0.56, but the EFS maturity is too early. Next slide. The overall safety profile of T-DXd followed by THP arm was favorable versus control arm with reduced rate of severe Grade 3 and serious adverse event or treatment continuation or left ventricular dysfunction as shown here in the table over the control arm. Next slide. T-DXd followed by THP had fewer any grade and Grade 3 adverse event. Hematological toxicity and fatigue events less than in the control arm. Aside from nausea, GI toxicity was comparable between the 2 arms. Next slide. In conclusion, DESTINY-Breast11 results support T-DXd followed by THP as a more effective and less toxic neoadjuvant treatment compared with dose-dense AC followed by THP. And may become the preferred regimen for patients with high-risk HER2-positive early breast cancer. Next slide. Moving now to the second study, which was also presented as Presidential Session Symposium I by Dr. Geyer. Here, T-DXd was compared as a single agent to T-DM1, another HER2-directed ADC in the post neoadjuvant setting in high-risk HER2 early breast cancer patients. Next slide. DESTINY-Breast05 is also a global multicenter open-label Phase III, randomized high-risk patients with residual disease in the breast after a neoadjuvant chemotherapy. The trial randomized 1,600 patients on 1:1 to receive 14 cycles of either T-DXd or T-DM1. The primary endpoint of the study is invasive disease-free interval, or IDFS. Next slide. Patients and disease characteristic here 46-plus percent of the patients were randomized from Asia, majority are HER2 3+ and hormone receptor positive. The nodal pathological status was positive in 80% of the patients. Prior neoadjuvant treatment included mainly taxane, and anti-HER2 treatment almost in all patients. And anthracycline or platinum was received 50% and 50% among these 2 drugs. Next slide. DESTINY-Breast05 met its primary endpoint of IDFS, which was statistically significant and clinically meaningful with a hazard ratio of 0.47 and p-value of 0.001, reducing the risk of relapse by more than 50% in this post-neoadjuvant high-risk population. At 3 years, 92.4% of the patients are alive with no sign of disease. Next slide. Improvement of IDFS for T-DXd arm versus T-DM1 what -- was observed in all prespecified subgroups. Next slide. DFS was a secondary endpoint. It was also statistically significant and clinically meaningful with a hazard ratio of 0.47 and p-value 0.001, reducing the risk of relapse by more than 53%. Next slide. Distant disease recurrence-free interval and brain mets free interval was also clinically relevant here. A 3 year follow-up, 81 patients in T-DM1 had distant relapse versus 42 patients in T-DXd. Next slide. In this study, Grade 3 adverse events were similar between treatment arms. Rate of ILD was around 10%, and majority of these cases were low grades. More deaths due to adverse events were reported in T-DM1 arm 5 versus 3. Next slide. T-DXd was well tolerated and managed with no new safety findings. Next slide. ILD occurred with expected rate, and the majority were low grade, and 2 patients died due to ILD in the T-DXd arm. Next slide. In conclusion, post neoadjuvant T-DXd demonstrated superior clinical benefit over T-DM1 in patients with HER2-positive early breast cancer with residual disease after neoadjuvant treatment. These results present a potential new standard of care in this population post neoadjuvant setting. Next slide. Let's go to the third landmark study now. We're moving from early breast cancer in metastatic triple-negative breast cancer. And now we're talking about Dato-DXd. And the first study here or third study is TROPION-Breast02, what -- which we showed at ESMO '25. It was presented by Dr. Dent at an oral session and here, Dato was tested against standard chemotherapy in the first-line triple-negative breast cancer. Next slide. TROPION-Breast02 is a global multicenter open-label Phase III, randomized first-line metastatic triple-negative breast cancer with no prior chemotherapy for locally recurrent or metastatic disease for whom immunotherapy is not an option. Here, it's important to note. The trial did not set any minimum time frame from the prior adjuvant to recurrence of the disease for patients to be eligible in this study. It's expressed here by in the last key eligibility criteria on the table here by DFI, disease-free interval. The trial randomized 644 patients to receive either Dato-DXd or chemotherapy. The primary endpoint was a dual endpoint of overall survival and progression-free survival. Next slide. Regarding demographics in TB02 and patient characteristics, overall well balanced and consistent with first-line triple-negative population. PD-L1 status was low, which -- in the majority of the patients. And the preselected chemotherapy for the control arm was mainly taxanes. It's important to note as well here, as I mentioned in the prior slide, that the prior disease-free interval between 0 and 6 months, those patients are fast progressors. This population represent in TROPION-Breast02, 15% in this study. Next slide. The trial met its primary endpoint of PFS. Dato-DXd demonstrated statistically significant and clinically meaningful improvement of PFS compared to control chemotherapy. With a hazard ratio of 0.57 and p-value less than 0.001 with the reduction of risk of progression or death by 43%. Next slide. The improvement in progression-free survival for Dato-DXd versus control was observed across all prespecified subgroups. Next slide. The trial met also its dual OS primary endpoint. And Dato-DXd demonstrated a statistically significant and clinically meaningful improvement of overall survival compared to chemotherapy, reducing the risk of death by 21%. Next slide. The improvement in overall survival for Dato-DXd versus control was observed overall across all subgroups. Next slide. Other efficacy secondary endpoints are presented here as well, showing that Dato-DXd doubled the response rate as shown from 29.3% in the chemotherapy to 62.5% in the Dato-DXd arm. Important to note here that the rate of complete response with Dato-DXd is more than three times compared to chemotherapy -- compared to the complete response number in chemotherapy in favor of the Dato-DXd. Next slide. In addition to the doubling of this response rate, these responses were longer in the Dato-DXd arm over a year. Next slide. Regarding safety, duration of treatment was longer in the Dato-DXd more than double compared to the duration of treatment in control arm. And despite that, the rate of severe grade, Grade 3 and more adverse event and serious adverse events were similar, and treatment discontinuation was lower in the Dato-DXd. I'd like to note here there were no death due to adverse event in either arm. Next slide. Most frequent adverse event related were mainly stomatitis and nausea and ocular toxicities. Fewer severe grades for Dato-DXd observed in these categories. Hematological toxicities were more frequent in the chemotherapy arm, including severe grade of neutropenia. Regarding the adverse event of interest, higher rate of mucositis and ocular toxicity occurred in the Dato-DXd. Severe grade were less than 10%. And it's important to note that none of the mucositis events led to treatment discontinuation. And ocular toxicity led to treatment discontinuation in less than 1% of the patients. Low rate of ILD observed overall in Dato-DXd here, less than 1% of the patients -- low rate of ILD observed overall in Dato and less than 1% of the patients experienced a severe grade and no grade 5 were reported here. Next slide. In conclusion, TROPION-Breast02 results with a positive overall survival and progression-free survival with a manageable safety profile support Dato-DXd as the new first-line standard of care for first-line metastatic triple negative breast cancer for whom immunotherapy is not an option. We're going to talk now about the fourth study which is the second study in triple-negative breast cancer with Dato-DXd. And this time, Dato-DXd is combined with immunotherapy, durvalumab in the first-line treatment for triple-negative breast cancer. Next slide. The study called BEGONIA is a Phase I/II multicenter and multi-arm, showing here Arm 7 and Arm 8 parts. A combination of Dato-DXd and durvalumab in the first-line triple-negative patient for whom, no IO or Topo-I was received. Arm 8 enrolled patients with PD-L1 high. However, Arm 7 enrolled patients with any expression of PD-L1. The primary endpoint of Part 2 of these 2 arms was response rate. Next slide. Here are the results for the Arm 7. Arm 7 are the patients with ED -- PD-L1 expression. But the majority of these patients were actually PD-1 low. The study enrolled 62 patients, and the response rate was high, near 80%, and the median of response in this population with this combination was 17.6 months and PFS was 14 months. In Arm 8, where the patients have high PD-L1 expression, we enrolled 33 patients, and the response rate was also high, 81.8% and the median duration of response and PFS were immature at this stage. Overall -- next slide, overall, the safety profile of this combination was manageable with no new safety seen here. Next slide. Across both arms, most adverse events were GI in nature, like nausea and stomatitis, and rate of ILD was low with no severe grades. Next slide, in conclusion, the combination of Dato-DXd and durvalumab demonstrated robust antitumor activity in the first-line triple-negative breast cancer in both PD-L1 high and with any PD-L1 expression. Next slide. Let's move now to R-DXd in ovarian cancer. In previous highlights, we shared encouraging data results from our Phase I/II in ovarian cancer with this drug. Just to remind, R-DXd is a cadherin 6 directed ADC with similar payload and linker like an ENHERTU, belonging to the same DXd platform and technology. This time, we'll highlight results from the Phase II part of the Phase II/III registration study called REJOICE-01, done in platinum-resistant ovarian cancer patients. This Phase II is a dose optimization in platinum resistant ovarian cancer patient. Next slide. We'll focus here on the middle box basically on the Phase II part for the dose optimization, where patients were randomized, patients who are platinum-resistant ovarian cancer to receive 3 dose level of R-DXd. So patients were randomized to receive from low dose, 4.8-milligram kilo than 5.6 milligram kilo and the highest dose 6.4-milligram kilo. This is like a randomization happening concomitantly. The primary endpoint of this dose optimization was ORR by an independent by BICR. Next slide. Across the 3 dose level arms, 107 patients were enrolled, mainly in Asia and Europe, and the median age was 6 years old. As shown here, these patients are heavily pretreated. And more than 50% of the patients received 3 prior lines of systemic therapy. Rapid progressors post platinum, patients who progress within 3 months from last platinum, represent 44% in this population. And 94% of these patients have some CDH6 positivity. For the results, R-DXd as monotherapy demonstrated promising antitumor activity at all those levels. Response rate for the 3 dose levels of 4.8, 5.6 and 6.4 milligram per kilo were 44%, 50% and 57%, respectively. The disease control rate was above 75% across all those levels. And the median time when this patient obtained this response was about 7 weeks. Next slide. As shown here in the waterfalls, dramatic responses observed. Majority of patients, 50% of them responded per BICR, but many other patients have significant tumor shrinkage, which account for the stable disease. Next slide. As you see here in the spider plots, the treatment with I-DXd was associated with rapid response at all those levels. So the follow-up for the study was short, less than 6 months at the time of cutoff date, more than 50% are still receiving treatment. Next slide. The safety profile of 4.8 and 5.6 milligram dose levels were relatively similar. And the treatment-related adverse events occurred more frequently with a higher dose of 6.4 milligram per kilo. The ILD rate was very low with R-DXd less than 3% in doses 4.8 and 5.6 and no Grade 5 reported here. R-DXd with 5.4 milligram provided the optimal benefit risk. In fact, we are selecting this dose level to continue the study, the Phase III part. Next slide. Okay. In terms of safety, nausea, anemia and asthenia and neutropenia were the most common adverse event. Overall, the treatment was -- the safety profile was acceptable. In conclusion, next slide. R-DXd demonstrated clinically meaningful responses across a range of CDH6 expression and dose levels. Phase III part of REJOICE-Ovarian01 will evaluate R-DXd 5.6 milligram versus physician's choice in the PROC population in the Phase III part. Okay. Here, last not least, presentation to highlight the DS-3939 asset. This is the first time Daiichi-Sankyo is sharing clinical data from the ongoing first-in-human study. DS-3939 shares also the same payload and linker of the DXd platform like ENHERTU. It's a DAR 8, the target is tumor-associated MUC1, which is this target is expressed broadly in various tumor types. Nonclinical work, nonclinical data shows -- has exhibited significant antitumor effect in multiple TA-MUC1 preclinical models. Next slide. The design of the first-in-human is a classical dose escalation Part 1, followed by multiple expansion Part 2 targeting various tumor types. The primary endpoint of Part 1 is mainly safety, looking at DLTs and recommended dose and for Part 2 is overall response rate. We're showing here results from the dose escalation Part 1 of the study. Next slide. A total of 64 patients enrolled and treated by DS-3939, the treatment was given IV every 3 weeks. And we started with very low dose 1-milligram per kilo up to 8-milligram per kilo. Various solid tumors included, as you know, as often in first-in-human, those patients are Phase I patients heavily pretreated, as expected in these trials. Next slide. The dose level of 8 milligrams was associated with high toxicity, and this dose level was dropped. The dose-limiting toxicities were mainly anemia and thrombocytopenia or platelet decrease and abdominal pain. And dose level of 6-milligram was considered potentially a recommended dose. That's why we carry this dose to test this dose in various different cohorts in Part 2. And the treatment discontinuation was primarily due to ILD and pneumonitis. Next slide. Regarding safety profile, GI or gastrointestinal toxicity, hematological toxicity and fatigue were the most common Grade 3 or higher. Grade 3 or higher AE were hematological toxicities and pneumonitis or ILD. Next slide, ILD rate occurred around 10.9%. And the median time for ILD occurrence was around 68 days. And the -- at the post cutoff of this data, we were informed about 2 deaths due to ILD were adjudicated. Both patients who died due to ILD were from a higher dose, 8-milligram per kilo. No Grade 3 of immune-related reaction observed while we observed some IRR due mainly to the absence of premedication because of the rules of Phase I trial, no premedication at Cycle 1. Next slide. Those are early signs of efficacy. Despite a Phase I population, encouraging antitumor activity, either responses were RECIST, or tumor reductions were observed across multiple tumor types here as shown in this graph. And next slide, and duration of this response is yet to mature, but preliminary observation of some durable response is noted here as shown. In conclusion, preliminary data from the novel TA-MUC1 DS-3939 DXd first-in-human show manageable safety profile in previously treated advanced metastatic solid tumor. DS-3939 demonstrated promising preliminary antitumor activity across dose levels and tumor types. Those expansion and optimization are ongoing with various tumor types. With this, I will end my presentation here, and we invite the Q&A session. Thank you.

Thank you, Abder. We'll now take questions. You could your questions in English or in Japanese. [Operator Instructions] The first question is from Yamaguchi-san from Citi.

Can you hear me?

Yes.

The first question is all the data you have presented, there are so many data has been presented and especially the late-stage Phase III data are practice changing. But in order for investors to digest what's going on, it's a little bit difficult to swallow because there are so many things that happen at the same time. So if it's okay, Ken, can you give me out of those, especially 3, 4 pivotal datas, which one do you think is really so-called practice changing compared to the current therapy? Can you pick up 1 or 2, which out of those -- all those things? It's just your personal impression. That's the first question.

Yes. Thank you for the question. And you are right, it's a lot here to digest. So what is considered practice changing probably are those 3 landmark studies, mainly the first 2, the first 2 studies of ENHERTU in early breast cancer. So what we're seeing here, ENHERTU, after extending the life of patients in late line of breast cancer HER2-positive, increasing their survival, increasing the PFS in first line. We're talking now about increasing the potential of cure of these patients. So in early breast cancer, the treatment, today treatment is good. It's very hard to do better, but ENHERTU push the boundaries and increase again this potential rate of cure by a delta of 11%, which is considered clinically meaningful and statistically significant.

Okay. The second question is that regarding DS-3939, which you gave us some preliminary data. And clearly, just look at the data, it looks like ovarian cancer and lung cancer seems to be have a more sort of response so far. But can you give me some idea where you're going to go from here as far as the cancer selection is concerned? Because my understanding that this is the so-called first Daiichi Sankyo 100% owned asset in a sense that you can choose whatever you want to. But at the same time, you have to be careful about the current therapy or current alliance you have already. So can you give me the idea where you're going to go for the pickup, the selection of cancer for 2 years ago?

Yes. So yes, I think you're referring to the fact that we have so many DXd-ADCs that there's a potential for overlap in indications in patient populations. I think in ovarian cancer, as you know, we already have a very active program with the R-DXd program. And in lung cancer, we have a very active program with ENHERTU and the Dato program. So what we are doing now here is to understand whether or not there are any potential overlaps or lack of overlap to the patient populations that are responsive to the 3939 drugs versus these other competing DXd-ADCs that we have in our own pipeline. That's really our #1 goal here. And we can do this now with the advent of various molecular and biomarker technologies that we have in-house. And I do want to mention that especially lung cancer, based on what we know about HER2 -- ENHERTU and also the data program, which are really the more the later-stage pipeline drugs approved or about to be approved in various lung cancer patient populations. We do think that there are still a lot of opportunities in lung cancer.

So you're kind of hinting so far, there might be some chance -- more chance maybe in lung cancer rather than any other areas because it's such a big area to talk with.

That is correct as that is our thinking. R-DXd in ovarian cancer, it's -- you look at our data so far and in all-comers patient population, the response rate is quite high. And so I think you're correct that lung cancer might be the greater opportunity for 3939.

The next question is from Mamegano-san from BOfA.

[Interpreted] Thank you very much for your presentation with the great data. Congratulations. So these are data revolutionizing the existing SoCs. My question is about DB11, neoadjuvant test. So data is great. So survival [ OSS ] data is the data I personally would like to see more. Clinical doctors would be more interested in survival data. And some physicians find it difficult to utilize it for the neoadjuvant therapy in practice. So are there any possibility that you conduct the neoadjuvant related test? Or is this the neoadjuvant follow-up data would be good enough?

Okay. Thank you for the question. To your question, yes, we are following this population for clinical endpoints, EFS and overall survival in the future. However, the pathological complete response is a standard endpoint in this population of neoadjuvant. It's -- let's put this pathological complete response in the context of the study and the population. We're not talking about all breast cancer here. We're talking about a proportion of breast cancer with a high risk of relapse and increasing pathological complete response in this specific context is a very good surrogate marker for the clinical outcome like EFS and survival in the future. This has been demonstrated in many meta-analyses, and we have confidence that ENHERTU with the highest rate ever observed in this population is extremely positive.

[Interpreted] Sorry, maybe I should change my question in a different perspective. According to the [indiscernible] trial, there is a neoadjuvant-based study. There was -- and afterwards, there was affinity test to evaluate the survival rate with adjuvant. And afterwards, in practice, the medication was utilized [Audio Gap]. There was a great data in neoadjuvant. And I understood that. However, after that, OSS should be more and more solidily evaluated. What would you think about this evaluation of OSS?

Okay. So I just want to make sure we understand the question. The question refers to DB11, is that correct?

[Interpreted] Yes.

And you are asking about overall survival data, correct?

[Interpreted] Yes.

Okay. So I just to make sure to -- for all of us to understand it, in a DB11 trial, it's going to be a long time before we actually see definitive overall survival data at that planned maturity. But -- so -- but in DB11, what we can say right now is that a surrogate for overall survival are things like pathological CR and event-free survival. And right now, we are seeing very statistically significant and clinically meaningful difference in pathological CR. Now -- and EFS is early, but we are seeing an early trend in EFS with a hazard ratio of 0.56. Now we -- it's a very immature data for, I think, at the level of about 5% information, but -- so when we look at surrogate endpoints for overall survival, all the indicators, pathologic CR and event-free survival are both pointing in the right direction. But ultimately, we have to wait quite a while before we see some overall survival data.

[Interpreted] Thank you very much. So OSS, surrogate marker for that, the pCR has been applied. So with the data from that test for the neoadjuvant, the patient, it's possible to win the approval not the entire adjuvant therapy, but for that particular patient group, ENHERTU will be leading the therapy option. So am I understanding saying that, my understanding correct?

Okay. So of course, we're not the FDA, and it's the FDA that makes the ultimate decision about whether or not to approve the data set based on the data set of DB11. However, we do believe that this package of 2 trials, DB11 and DB05 represents both a very strong package for approvability at the FDA for both DB11 patient populations, that's the neoadjuvant patient population and DB05, the post neoadjuvant patient population, both of them.

[Interpreted] So this data, I also understand that the data is great. The DB05 test that this is only for the non-pCR patients. So the open-label patients would be if ENHERTU should be applied for the initial open-label patients, you needed to conduct a test of the mixture of the adjuvant. Do you have such a plan to conduct such a study in future?

Let me clarify the population of DB05. DB05 is applied and ENHERTU was given to patients who already went through neoadjuvant and surgery. However, these patients who included in DB05 did not achieve pathological complete response. That's why, they're required to be -- required to receive more treatment. And if you take the 2 populations, the 2 studies together are basically complementary. The DB05 has a strong and meaningful clinical endpoint, which is IDFS, and which is statistically significant and clinically relevant.

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

[Interpreted] This is Hashiguchi speaking. My question is about the R-DXd, and I'd like to understand more about the study design. Page 52 says that the Phase II have a 260-patient sample size. And as you just introduced those optimizing analysis, it has 108 cases. So there is the difference of the 150. So is this because of the dose expansion part involved, if it is the case? Phase II part data should be the basis for the applications of the accelerated approval, is there any possibility for the applications of accelerated approval? And also, I'd like to understand about the current stage of the enrollment, so is it at the Phase II part expansion part? Or are you already entering into the Phase III part?

Yes. Thank you for the question. Yes, in fact, the Phase II enrolled the total of 260 patients, but we're presenting here a pure dose optimization from a randomized population at this cutoff. And the -- as you see here, the size of this Phase II, now we are defining the dose. We're extending one of the arms, the 5.6 milligram to enroll more patients, more than 100 patients. And yes, as you know, also we get the breakthrough therapy from FDA last several weeks. And discussion with health authorities is underway. And the Phase III is starting very soon because now we have the recommended dose to apply -- to apply this dose in the Phase III part.

[Interpreted] So Phase II part have enrolled 260 patients, and 150 patients have received 5.6 milligrams. Is that what you mentioned?

Not yet. We're extending this arm to enroll more patients on it.

[Interpreted] So Phase II part, so do you have any plan or estimate when you get that data to be available for that Phase II part?

Yes, this data that -- we'll announce. When we get this data, this will be announced in a future time.

The next question is from Wakao-san from JPMorgan.

This is Wakao, from JPMorgan. I have 2 questions. Firstly, about R-DXd and maybe overlap question from [ Hashiguchi-san ]. So can I understand that you will submit for approval with -- regarding R-DXd with this Phase II data? Is it correct? And so at ESMO, there was a comment that the PFS data from Phase II trial will be presented in the near future, when we can expect those PFS results to be released? And will the PFS data from the Phase II part be -- Phase II part be sufficient to trigger and accelerate approval of application?

So the -- I hope you can understand that the way the study is designed, it is designed to have a primary endpoint of response rate as the efficacy endpoint. And so this is your classic way to achieve accelerated approval in the U.S. and maybe certain other countries. So yes, additional data like progression-free survival or event-free survival will be part of the package. But for accelerated approval purposes, response rate will be the -- and duration response are the important endpoints. And as we explained earlier, we will be able to announce that approach at some point in the future, hopefully near future.

So you got a second question about TROPION-Breast02. So overall data was very strong. Regarding the subgroup analysis, so TB02, I'd like to understand why the hazard ratio for OS among U.S., Canada, Europe exceeded [indiscernible]. It was mentioned that post treatment may have had an impact. I'd like to know more detail for this one. Could this data negatively impact market penetration in Western market [indiscernible] launched?

Okay. Well, so we're starting to talk about various subgroup analyses and the numbers get smaller and smaller. So it's very important to note that we're no longer talking about very statistically meaningful differences, but we do have some information for you, especially in light of -- I think you're concerned about the crossovers and who got what at the time of crossover.

Yes. Thank you. Very important question. While TROPION-Breast02 did not allow crossover, we have data, but 30% of this patient in the control arm, get an ADC. This ADC could be TRODELVY, it could be ENHERTU, it could be other thing, something active in triple-negative breast cancer. And if we compare this rate to TRODELVY study, in the TRODELVY study about 50% of the control arm crossover to TRODELVY. So the rate between 30 and 50 is not so far. But here, we're showing a strong overall survival and PFS ever shown. And we feel confident about the overall efficacy data of DATROWAY in triple-negative breast cancer from both perspective, efficacy and also safety profile.

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

[Interpreted] Muraoka, from Morgan Stanley. Sorry to repeat the similar questions again, but R-DXd regulatory filing is my question. So how can I put the question here? Well, next year, April, fourth quarter -- before the fourth quarter's financial earning announcement. Are we going to hear your news that you have made accelerated approval filings to be done for R-Xd? Or is it too early to say that?

Okay. I think that we have not made any announcements so far. So please hold off until our next update to all of you about when to expect such a submission to the FDA. I'm sorry about this, but that's about as much as we can say for today.

[Interpreted] Understood. Looking forward to the next update, maybe third quarter update, I believe. And the second question from me. It's not directly related to today's presentation, but I have received a question from the non-Japanese analysts or investors. At this ESMO, the third TROP-02 [indiscernible], although it is Chinese population only study, but the EGFR-mutated [indiscernible] late line had made very good data. And regarding this, competitive landscape for Dato, how do you interpret that data?

Yes. So I think you're referring to the data from China, and it is, as you know, a very good data in Chinese patient populations. How does that translate into a broader applicability to non-Chinese patients. It is a little unclear. As you know, we do have our own clinical trial in that same patient population as a randomized study. And so at some point, we hope to be able to look at our study data and compared to how it compares to these other TROP-02 targeting drugs.

The next question is from Matsubara-san from Nomura Securities.

[Interpreted] This is Matsubara speaking, from Norman Securities. Can you hear me? Congratulations for your great data. First question is Dato-DXd and for the TP02 test -- TB02 -- [indiscernible], there was an effect that from the combination with the inhibitor. Of course, the cancer type is different. But for AVANZAR trial, do you have more confidence now with the situation on -- in the AVANZAR test or trial?

Okay. So I just want to make sure I understand the question. Are you asking about our AVANZAR trial thinking or something related to TB02?

[Interpreted] I'd like to know more about AVANZAR first line. And there would be the combined the use with [indiscernible]. So Breast02, the better data was out. So do you have more confidence now in the outlook for AVANZAR test?

Okay. So I understand the question to be that based on TB02 data, do we have more confidence in the AVANZAR trial? Is that correct?

[Interpreted] Yes.

Okay. Well, so I think, of course, in general, we are very happy to see our Dato program succeed in breast cancer. That's very important. How does that translate into applicability to a completely different cancer, lung cancer. I think from a -- of course, it does help somewhat to show that there is a lot of activity of the Dato program, the Dato drug in breast cancer, but -- and we can look at also the toxicity profile and see that it's a management profile. So does it improve our chances of AVANZAR being positive? I would say, probably, yes, to some extent. But a lot of the information that we have gleaned from Dato in TB02, I think that most of us, all of us, at least from Daiichi Sankyo were aware. And so that -- I don't know that it increases our thinking about AVANZAR, but possibly, from your side, I think it is reassuring that TB02 is positive with a very good safety profile and tolerability and that should translate into greater confidence for AVANZAR.

[Interpreted] Next is DS-3939. So Yamaguchi-san had a question, the -- you would be focusing on NSCLC, but the conclusion, the -- it was stated that the various cancer types would be evaluated. So which is correct? Right now, you focused on the various types of the cancer type, but for the time being, you are focusing on NSCLC. Am I understanding right?

No, it's -- lung cancer is just one of the many different possible future development paths for 3939. The TA-MUC1 antigen is expressed in many different types of cancers besides lung cancer. So yes, we're very much interested in looking at a survey of a range of potential activities of this drug in many different cancers. I think -- but it's hard to ignore lung cancer data because that was actually presented at the conference here at ESMO.

The next question is from Tony Ren-san from Macquarie.

Thank you for the opportunity. Can you guys hear me?

Yes.

Okay. Perfect. Yes. So first of all, congratulations. I mean, you guys are definitely the big winner at ESMO in Berlin this year. Two questions from me on DESTINY-Breast11 study. Again, on a subgroup analysis, if you go to Slide #15, right, when you look at the pCR rates. It appears to me that the pCR rates in the rest of the world appears to favor dose-dense AC followed by THP and the footnote says that these countries are Brazil, Bulgaria, Peru, Poland, Russia and Saudi Arabia. Just wanted to understand why the control arm appears to do so much better in these countries compared to the rest?

So it's -- I think it's a little premature to say that the control arm performed better in that rest of the world group. It's a very small number of patients. And you can see on that slide that the confidence interval is quite wide, and it goes into the DXd THP portion of that slide. And so it's a little premature to say that control arm did better. I think we just have to do more analysis to understand why we are seeing the data that we're seeing.

Understood. Yes, the number is quite small. My second question is also on DB11. It's about the eligible patient population. So in Berlin, I spoke to a number of KOLs as well, including the discussions and the presenters. Some of them said that very few patients they see actually fit the DB15 enrollment criteria, right? Because in the west, there's very extensive screening of breast cancer. So most of the patients they see in the neoadjuvant setting are not that sick. That being said, last night at the AstraZeneca event, they had a slide showing that they think 80% of the patients in the neoadjuvant setting before surgery will be higher risk. So obviously, I'm having difficulty to reconcile these 2 statements. Anything that you can help me understand this situation better?

So I think that we are more in line with the AstraZeneca analysis. So that will be our thinking about this eligibility criteria and how it relates to the clinical practice setting.

The next question is from Michael Nedelcovych from TD Cowen.

I have two. My first is on the topic of TROPION-Breast02. It's actually a follow-up from one of your first questions. and it's not a very fair one. But when you were asked what the most impactful trials were that were presented at ESMO, you omitted TROPION-Breast02. So I'm just curious if you do not view that trial as practice changing. And if not, why would that really not be incorporated into the frontline standard of care based on TROPION-Breast02?

So the TROPION-Breast02, I think we did include that as a practice changing. So we felt that wasn't properly conveyed. Let me just be very clear and say to you that TB02 data, frontline setting in triple-negative breast cancer is a very bad disease. It's very important to note that we are showing overall survival benefit in TB02, very first time, I believe that that's been shown. And so yes, very important and practice changing for sure.

One more clarification actually. You mentioned that crossover in the control arm was 30%. Was that across the entire trial? Or was that just for the Western geographies? Do we need...

So the crossover, we would like to focus really on how many patients crossed over from the control, okay, to receive like an ADC, like an active ADC, like TRODELVY or ENHERTU or other ADC. Those numbers. We're comparing the rate of crossover in the control arm between the 2 studies. And this number is 30% in our study in TB02 versus 50% in the TRODELVY study.

And that 30% is trial wide in all geographies?

Trail-wise, yes. When -- again, we're focusing on the control arm, yes.

Very helpful. One more question on DESTINY-Breast11. I have to confess, I'm still a bit confused as to why 8 cycles of ENHERTU would underperform ENHERTU plus THP, unless it showed a higher discontinuation rate, which did not seem to be the case. So what's the prevailing hypothesis for the monotherapy arm underperforming?

Yes. We are still figuring out this. The one thing is for sure, it was not due to safety issue, okay? And the pathologic complete response probably a little bit lower than the control. But when we compare the trend of EFS, so far, it's -- there's no big difference overall quite equal. But a lot of patients in the single agent 8 cycle were offered by -- according to the DMC to receive standard of care or stay actually under T-DXd-single agent. We're going to do more analysis and more follow-up on this patient and more to come in the future, I guess.

The next question is from Barker-san from Jefferies.

Steve Barker, from Jefferies. My question is about DB11 and regarding Slide 14, specifically. So you can see that there was a big difference in efficacy between HR-positive and HR-negative. So a 3-part question. Firstly, we're surprised by the pronounced difference between these subgroups. Secondly, what do you think explains the difference? And thirdly, what are the implications for how doctors are likely to deploy ENHERTU in the neoadjuvant setting?

Well, so it's been long known that the biology of HR-positive breast cancer and HR-negative breast cancer is very different. And there is a tendency actually for HR-negative breast cancer to be a bit more responsive to cytotoxic drugs and chemotherapy than HR-positive breast cancer. So the fact that we are seeing higher pCR rates in HR-negative breast cancer compared to HR-positive breast cancer is not a surprise. We can see that phenomenon for both the experimental arm in the control. What is, therefore, important to note is that even in the what I would call the HR-positive breast cancers that are less likely to be responsive to cytotoxic agents, including the payload like the DXd. We can still see improvement in the pCR positive achievement in the experimental arm with the T-DXd. So here, in both cases, both types of breast cancers with different biology underlying the cancer, the T-DXd combination is better than the control arm. So I think that's the most important point for the prescribing physicians that in both cases, the T-DXd THP is a better regimen.

Right. So you expect doctors to use it across both groups of patients equally?

Yes.

The next question is from Wada-san from SMBC Nikko.

[Interpreted] SMBC Nikko Securities, Wada speaking. Thank you very much for sharing very good data. So TB02 is the test, I have a question. TRODELVY, ASCENT-03 data is now available. So could you compare -- if you compare versus that [ TBS ], OS, ORR and Grade 3, so Grade 3 and higher adversarial event for all of those items, DATROWAY seems to be superior. So what is the factor leading to these differences between the 2 medications? I'd like to know the positioning of the -- how you will design using those medications in what circumstances?

Thank you for the question. First, we did not have a head-to-head comparison with TRODELVY. What we believe -- we believe that Dato-DXd is a better drug, have a stable linker. That's why you see a huge differential in terms of response rate, in terms of rate of complete response. As you know, PFS and OS is positive. And even from safety profile, we do have some adverse event very well managed, and we don't have toxic death in our trial. So that's happy to elaborate more, but we believe that Dato-DXd is a better drug for this population.

And if I could just comment on one aspect of these cross-trial comparisons, which is always very difficult, but we've had a chance to review the New England Journal paper on the TRODELVY data. And we can see that the study allowed for crossover in patients who are in the control arm of that study. So many people have speculated that may be the reason why the ASCENT-03 study did not achieve a meaningful difference in overall survival, whereas TB02 achieved a meaningful difference in the overall survival. Maybe that difference in OS has to do just with the availability of a crossover in the TRODELVY study versus no crossover in the TB02 study. So now I'm going to go to some speculations now. But I'm going to -- so what we know is that in the TRODELVY study, about 50% of the patients actually received -- 50% of the control arm patients actually received TRODELVY at the time of progression. In our study, TB02, crossover was not designed into the protocol. However, we do know that a substantial number of patients in the control arm received an ADC of some sort at the time of progression. So when I say ADC of some sort, they will be the ADCs that were already approved at the time the clinical trial was ongoing. So there will be things like ENHERTU, TRODELVY and perhaps, T-DM1. And we -- based on our data, we can see that about 30% of the patients in TB02 control arm received such an ADC. So I am not sure that the OS benefit that we saw in TB02, but not in ASCENT-03 can be ascribed to the lack of a protocol-defined crossover in ASCENT-03, but lack of a protocol-defined crossover in TB02.

[Interpreted] And one more question, if I may. The immunohistochemistry, is it working as a biomarker? I'd like to give you 2 simple questions. And the first question is REJOICE-Ovarian01 test. On this test, the stratification factors include CDH6 immunochemistry was mentioned. In the subgroup analysis, I see stratification factor. Is it -- are there any data that is it working? And also DS-3939, the TA-MUC1 expression, related expression was studied further as a subgroup analysis? Those are 2 questions.

Okay. So in all of our programs, we do have a biomarker strategy because after all, these are DXd-ADCs defined by the antigen that the tumor is expressing. So as a general, you can assume that we're going to have a biomarker strategy in all of our ADC programs. Now with respect to the R-DXd program and the 3939 program, we haven't yet presented any data on the subgroup analysis based on IHC expression pattern. So please wait for that. That should be forthcoming sometime in the next few months.

So we are reaching the scheduled time, and we will now conclude Daiichi Sankyo's ESMO 2025 highlights. Thank you very much for joining today. [Portions of this transcript that are marked [Interpreted] were spoken by an interpreter present on the live call.]