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. The 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 the live streaming screen. The slides have been uploaded to the IR Presentation Material page of the 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 Oncology Late 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, 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. Let me just first tell all of you that this slide is all the presentations that we made at this current ESMO meeting. It's an enormous number of data presentations, including at least three or four registration trials, pivotal trials that can be submitted to various regulatory agencies. The three phase III studies, DESTINY-Breast05 , DESTINY-Breast11, TROPION-Breast02 , and the REJOICE-Ovarian01 . These are incredibly important to all of us, to patients, the company, and of course to the investors. 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.
Thank you very much to all the people here at Daiichi Sankyo and the patients who participated in our trials, as well as our partners, AstraZeneca and Merck. 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. I think many of you are familiar with this disease map. This one is for breast cancer, and it divides the breast cancer field into multiple lines of therapy, from neoadjuvant all the way to second line and later. Of course, also by subtypes of breast cancer, HER2+, 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 the U.S. and other major countries.
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 DESTINY-Breast11, these are the new data that was presented at ESMO. 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 the 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 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, 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. Hopefully this purple box will also soon turn into a dark purple box at some point in the future. Next slide. 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. 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 six different topics related to the DS assets from the 2025 ESMO conference. Four 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. 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 a neoadjuvant setting in high risk HER2+ early breast cancer. This was presented by Dr. Harbeck at the Presidential Symposium One. Next slide.
DESTINY-Breast11 is a global multicenter open label phase III randomized high risk patients, HER2+ early breast cancers defined as having large tumors or lymph node positive or inflammatory breast cancer. The trial randomized more than 900 patients in three arms: T-DXd followed by THP versus dose dense AC followed by THP and T-DXd monotherapy. The T-DXd monotherapy was closed following the MCA recommendation for various reasons, but not due to safety. The primary endpoint was pathological complete response assessed by 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 represented 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 most pre-specific subgroups. If 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 a reduced rate of severe grade, grade three, 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 three adverse event. Hematological toxicity and fatigue events less than in the control arm. Aside from nausea, GI toxicity was comparable between the two 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+ early breast cancer. Next slide. Moving now to the second study, which was also presented as the presentation session Symposium 1 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 a one-on-one 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 characteristics here, 46% + of the patients were randomized from Asia. Majority are HER2+, HER 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 two 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 0.0001, reducing the risk of relapse by more than 50% in this post-neoadjuvant high risk population. At three 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 was observed in all pre-specified 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 met-free interval was also clinically relevant here. At three years follow-up, 81 patients in T-DM1 had distant relapse versus 42 patients in T-DXd. Next slide. In this study, grade three adverse events were similar between treatment arms.
Rate of ILD was around 10%, and the majority of these cases were low grades. More deaths due to adverse events were reported in T-DM1 arm, five versus three. 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 two 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+ 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 into metastatic triple-negative breast cancer, and now we're talking about Dato-DXd. The first study here, or the third study, is TROPION-Breast02, which we showed at ESMO 2025.
It was presented by Dr. Tolaney at an oral session, and here Dato-DXd was tested against standard chemotherapy in first-line triple-negative breast cancer. Next slide. TROPiCS-02 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 timeframe from the prior adjuvant to recurrence of the disease for a patient to be eligible in this study. It's expressed here by 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 pre-selected 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 zero and six months, those patients are fast progressors. These populations 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 a 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 pre-specified 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 3x 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. Despite that, the rate of severe grade, grade three and more adverse event and serious adverse event were similar, and treatment discontinuation were lower in the Dato-DXd. I'd like to note here there were no deaths due to adverse event in either arm. Next slide. Most frequent adverse event related were mainly stomatitis and nausea and ocular toxicity. 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%.
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-DXd, and less than 1% of the patients experienced 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. I'm going to talk now about the fourth study, which is the second study in triple-negative breast cancer with Dato-DXd. 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 TOPO1 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 two of these two arms was response rate. Next slide. Here are the results for the arm 7. Arm 7 are the patients with any PD-L1 expression, but the majority of these patients were actually PD-L1 low. The study enrolled 62 patients, and the response rate was high, near 80%. The median of response in this population with this combination was 17.6 months, and PFS was 14 months.
In arm 8, 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 signal. Next slide. Across both arms, most adverse events were GI in nature, like nausea and stomatitis, and the rate of ILD was low with no severe grades. Next slide. In conclusion, the combination of Dato-DXd and durvalumab demonstrated robust anti-tumor 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 Dato-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, Dato-DXd is a Cadherin 6 directed antibody-drug conjugate with similar payload and linker like 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 patients. 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 three dose levels of Dato-DXd. Patients were randomized to receive from low dose 4.8 mg/kg, then 5.6 mg/kg, and the highest dose 6.4 mg/kg. This is like a randomization happening concomitantly. The primary endpoint of this dose optimization was ORR by an independent BICR. Next slide.
Across the three dose level arms, 107 patients were enrolled, mainly in Asia and Europe, and the median age was 60 years old, as shown here. These patients are heavily pretreated, and more than 50% of the patients received three prior lines of systemic therapy. Rapid progressors post platinum, patients who progress within three months from last platinum, represent 44% in this population. 94% of these patients have some CDH6 positivity. For the results, Dato-DXd as monotherapy demonstrated promising anti-tumor activity at all dose levels. Response rate for the three dose levels of 4.8 mg, 5.6 mg, and 6.4 mg per kilo were 44%, 50%, and 57% respectively. The disease control rate was above 75% across all dose levels. The median time when this patient obtained this response was about seven weeks. Next slide. As shown here in the waterfalls, dramatic responses observed.
The majority of patients, 50% of them responded per BICR, but many other patients have significant tumor shrinkage, which accounts for the stable disease. Next slide. As you see here in this spider plot, the treatment with Dato-DXd was associated with rapid response at all dose levels. The follow-up for this study was short, less than six months. At the time of cut-off date, more than 50% are still receiving treatment. Next slide. The safety profile of 4.8 and 5.6 mg dose levels was relatively similar, and the treatment-related adverse event occurred more frequently with a higher dose of 6.4 mg per kilo. The ILD rate was very low with Dato-DXd, less than 3% in doses 4.8 and 5.6, and no grade five reported here. Dato-DXd with 5.4 mg provided the optimal benefit risk. In fact, we're selecting this dose level to continue the study, the phase III part.
Next slide. Okay. In terms of safety, nausea, anemia, asthenia, and neutropenia were the most common adverse events. Overall, the treatment was the safety profile was acceptable. In conclusion, next slide. Dato-DXd demonstrated clinically meaningful responses across a range of CDH6 expression and dose levels. Phase III part of REJOICE-Ovarian01 will evaluate Dato-DXd 5.6 mg versus physician source in the PROC population in the phase III part. Okay, here, last but not least, a presentation to highlight the DS-3939. 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 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. Non-clinical work, non-clinical data shows has exhibited significant anti-tumor effect in multiple TA-MUC-1 preclinical models. Next slide. Next slide.
The design of the first in human is a classical dose escalation part one, followed by multiple expansion part two, targeting various tumor types. The primary endpoint of part one is mainly safety, looking at DLTs and recommended dose, and for part two is overall response rate. We're showing here results from the dose escalation part one of the study. Next slide. A total of 64 patients enrolled and treated by DS-3939. The treatment was given IV every three weeks, and we started with very low dose, 1 mg per kilo, up to 8 mg 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 this trial. Next slide. The dose level of 8 mg 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. Those levels of 6 mg were considered potentially a recommended dose. That's why we carried this dose to test this dose in various different cohorts in part two. 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 three or higher. Grade three 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. The post-cut of this data, we were informed about two deaths due to ILD were adjudicated. Both patients who died due to ILD were from a higher dose, 8 mg per kilo.
No grade indian 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 one. Next slide. Those are early signs of efficacy. Despite a phase I population, encouraging anti-tumor activity, either responses per RECIST or tumor reductions were observed across multiple tumor types here, as shown in this graph. Next slide. Duration of these responses is yet too 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 anti-tumor activity across those levels and tumor types. Dose 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 will now take questions. You could ask your questions in English or in Japanese. If you have multiple questions, please ask one at a time for optimal translation and limit the number of your questions to two at most. Please raise your hand if you have questions. The first question is from Yamaguchi-san from Citi. Please go ahead.
Hi, can you hear me?
Yes.
Thank you. Good evening from Tokyo. Thank you very much for your presentations. The first question is regarding all the data you have presented. There are so many data that have been presented, and especially that the late stage of phase III data is practically changing. In order for investors to digest what's going on, it's a little bit difficult to swallow because there are so many things to happen at the same time. If it's okay, Ken, can you give me, out of those, especially three, four pivotal data, which one do you think is really so-called practice changing compared to the current therapy? Can you pick up one or two out of all those things? It's just your personal impression. Thanks. That's the first question.
Thank you for the question. You are right. It's a lot here to digest. What is considered practice changing probably are those three landmark studies, mainly the first two, the first two studies of ENHERTU in early breast cancer. What we're seeing here, ENHERTU, after extending the life of patients in late line of breast cancer HER2+, increasing their survival, increasing the PFS in first line, we're talking now about increasing the potential of cure of these patients. In early breast cancer, the treatment, today's treatment is good. It's very hard to do better, but ENHERTU pushed the boundaries and increased again this potential rate of cure by a delta of 11%, which is considered clinically meaningful and statistically significant.
Okay, thank you. The second question is regarding DS-3939, which you gave us some preliminary data. Clearly, just looking at the data, it looks like ovarian cancer and then lung cancer seem to have a more sort of response so far. Can you give me some idea where you're going to go from here as far as the cancer selection is concerned? My understanding is 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. Can you give me an idea where you're going to go for the pickup, the selection of a cancer for which you're going to go? Thank you.
Yes. Yes, I think you're referring to the fact that we have so many DXd ADCs that there's a potential for overlapping indications in patient populations. I think in ovarian cancer, as you know, we already have a very active program with the Dato-DXd program. In lung cancer, we have a very active program with ENHERTU and the Dato-DXd program. 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 DS-3939 drug versus these other competing DXd ADCs that we have in our own pipeline. That's really our number one goal here. We can do this now with the advent of various molecular and biomarker technologies that we have in-house.
I do want to mention that especially in lung cancer, based on what we know about ENHERTU and also the Dato-DXd program, which are really the more 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.
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 tackle with.
That is correct. That is our thinking.
Okay.
R-DXd in ovarian cancer, you know, you look at our data so far and in all comers patient population, the response rate is quite high. I think you're correct that lung cancer might be the greater opportunity for DS-3939.
Thank you very much.
The next question is from [Mamegano]-san from B Of A. Please go ahead.
[Foreign language] すみません、ありがとうございます。聞こえますでしょうか?
[Foreign language] はい、聞こえております。
Can you hear me? Yes, I can hear you.
[Foreign language] 素晴らしいデータ。
Thank you very much for your presentation with great data. Congratulations. These are data revolutionizing the existing standard of care. My question is about DESTINY-Breast11 neoadjuvant test. The data is great. Survival, overall survival data is the data I personally would like to see more. Clinical doctors will be more interested in the survival data, and some physicians find it difficult to utilize it for the neoadjuvant therapy in practice. Are there any possibilities that you conduct the neoadjuvant-related test, or is the neoadjuvant follow-up data 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. 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. An 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.
[Foreign language] すみません、ちょっと私の質問が悪かったかもしれないんですけども。
Sorry, maybe I should change my question in a different perspective. According to the FASIT trial, there is a neoadjuvant-based study. There was, and afterward, there was affinity test to evaluate the survival rate with adjuvant. Afterward, in practice, the medication was utilized in more than in HER2. There was great data in neoadjuvant, and I understood that. However, after that, OSS should be more and more solidly evaluated. What would you think about this evaluation of OSS?
Okay, I just want to make sure we understand the question. The question refers to DS-3939. Is that correct?
[Foreign language] はい、そうです。
Yes.
Okay, you are asking about overall survival data, correct?
[Foreign language] はい。
Yes.
Okay. Just to make sure for all of us to understand, in the DB-11 trial, it's going to be a long time before we actually see definitive overall survival data at that planned maturity. In DB-11, what we can say right now is that a surrogate for overall survival are things like pathological complete response and event-free survival. Right now, we are seeing very statistically significant and clinically meaningful difference in pathological complete response. EFS is early, but we are seeing an early trend in event-free survival with a hazard ratio of 0.56. It's very immature data for, I think, at the level of about 5% information. When we look at surrogate endpoints for overall survival, all the indicators, pathological complete response and event-free survival, are both pointing in the right direction. Ultimately, we have to wait quite a while before we see some overall survival data.
[Foreign language] ありがとうございます。ということは。
Thank you very much. As an OS surrogate marker for that, the PCR has been applied. With the data from the test for the neoadjuvant, the patients, 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. Am I understanding in saying that? Am I understanding correct?
Okay. 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 DB-11. However, we do believe that this package of two trials, DB-11 and DB-05, represents both a very strong package for approval at the FDA for both DB-11 patient populations, that's the neoadjuvant patient population, and DB-05, the post-neoadjuvant patient population, both of them.
[Foreign language] 今回のデータは素晴らしいな。
This data, I also understand that the data is great. The DB-05 test, this is only for the non-PCR patients. The operable patients will be, if [ should be applied for the initially operable patients, you need to conduct a test for the mixture of the adjuvant. Do you have such a plan to conduct such a study in the future?
Let me clarify the population of DB-05. DB-05 is applied, and HER2 was given to patients who already went through neoadjuvant and surgery. However, these patients who included in DB-05 did not achieve pathological complete response. That's why they require to receive more treatment. If you take the two populations, the two studies together are basically complementary. The DB-05 has a strong and meaningful clinical endpoint, which is IDFS, and which is statistically significant and clinically relevant.
[Foreign language] はい、分かりました。はい、ありがとうございます。
I understand. Thank you.
The next question is from Hashiguchi-san from Daiwa Securities. Please go ahead.
[Foreign language] です。ありがとうございます。
Hello, this is Hachiguchi speaking. My question is about the DXd, and I'd like to understand more about the study design. Page 52 says that the phase II has 260 patient sample size. As you just introduced, those optimizing analysis, it has 108 cases. There is the difference of the 150. 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? I'd like to understand about the current stage of the enrollment. 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 a total of 260 patients, but we're presenting here a pure dose optimization from a randomized population at this cutoff. 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 mg, to enroll more patients, more than 100 patients. Yes, as you know, also, we get the Breakthrough Therapy Designation from FDA last several weeks. Discussion with the health authorities is underway. The phase III is starting very soon because now we have the recommended dose to apply this dose in the phase III part.
[Foreign language]
Phase II part have enrolled 260 patients, and 150 patients have received 5.6 mg. Is that what you mentioned?
Not yet. We're extending this arm to enroll more patients on it.
[Foreign language]
Do you have any plan or estimate when you get the data to be available for that phase II part?
Yeah, this data, we'll announce when we get this data. This will be announced at a future time.
[Foreign language] ありがとうございました。以上です。
Thank you. That is all from me. Thank you.
The next question is from Wakao-san from J Morgan. Please go ahead.
Thank you for taking my question. This is Wakao from JP Morgan. I have two questions. Firstly, about R-DXd, and maybe overlap question from Hashiguchi-san. Can I understand that you will submit for approval regarding Dato-DXd with this data? Is it correct? At ESMO, there was a comment that the PFS data from the phase II trial will be presented in the near future. When can we expect those PFS results to be released? Will the PFS data from the phase II part be subject to trigger an accelerated approval application?
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. It is your classic way to achieve accelerated approval in the U.S. and maybe certain other countries. Yes, additional data like progression-free survival or event-free survival will be part of the package. For accelerated approval purposes, response rate will be the end duration response or the important endpoints. As we explained earlier, we will be able to announce that approach at some point in the future, hopefully near future.
Okay. Thank you. You got a second question about TROPION-Breast02. Overall data was very strong. Regarding the subgroup analysis of PV-02, I'd like to understand why the hazard ratio for OS among U.S., Canada, and Europe exceeded 1.0. At the congress, it was mentioned that post-treatment may have had an impact. I'd like to know more detail on this point. Could this data negatively impact market penetration in Western markets if 02 is launched?
Okay. We're starting to talk about various subgroup analyses, and the numbers get smaller and smaller. It is 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.
Yeah. Yeah, thank you. It's a very important question. While TROPION-Breast02 did not allow crossover, we have data, but 30% of these patients in the control arm get an ADC. This ADC could be TRODELVY, could be ENHERTU, could be other things, something active in triple negative breast cancer. If we compare this rate to the TRODELVY study, in the TRODELVY study, about 50% of the control arm crossover to TRODELVY. The rate between 30% and 50% is not so far. Here we are showing a strong overall survival and PFS ever shown. We feel confident about the overall efficacy data of Dato-DXd in triple negative breast cancer from both perspectives, efficacy and also safety profile.
Okay, thank you so much.
The next question is from Muraoka-san from Morgan Stanley. Please go ahead.
[Foreign language] ありがとうございます。
Thank you for taking my question, Murakawa from Morgan Stanley. Sorry to repeat the similar questions again, but the R-DXd regulatory filing is my question. How can I put the question here? Next year, April, the first quarter before the first quarter's financial earning announcement, are we going to hear your news that you have made accelerated approval filings to be done for R-DXd, 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.
[Foreign language] 分かりました。では、次のテーマはどうでしょうか。
Understood. Looking forward to the next update, maybe the third quarter update, I believe. 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. This ESMO, the third Dato-DXd milk cow Dato-DXd, although it is a Chinese population-only study, but the EGFR-mutated T-DXd late line had made very good data. Regarding this, in a competitive landscape for Dato-DXd, how do you interpret that data?
Yes, so I think you're referring to the data from China, and it is, as you know, very good data in Chinese patient populations. How does that translate into broader applicability to non-Chinese patients? It's a little unclear. As you know, we do have our own clinical trial in that same patient population as a randomized study. At some point, though, we hope to be able to look at our study data and compare it to how it compares to these other drugs to targeting drugs.
[Foreign language] 分かりました。ありがとうございます。
Understood. Thank you. That is all from me.
The next question is from Matsubara-san from Nomura Securities. Please go ahead.
[Foreign language] ノムラ証券の松原です。聞こえますでしょうか。
This is Matsubara speaking from Nomura Securities. Can you hear me? Thank you very much, and congratulations for your great data. First question is the DXd, and for the TP-02 test, DP-L1, there was an effect from the combination with the inhibitor. Of course, the cancer type is different, but for the Avanza trial, do you have more confidence now with this situation on the AVANzAR test or trial?
Okay, I just want to make sure I understand the question. Are you asking about our AVANTAR trial thinking or something related to TB-02?
Avanza [Foreign language] に関して知りたいという形です。つまり...
I'd like to know more about Avanza first line, and there will be their combined use with their IM1. Bless the two, the better data was out. Do you have more confidence now in the outlook for AVANZAR test?
Okay, I understand the question to be that based on TB02 data, do we have more confidence in the AVANZAR trial. Is that correct?
[Foreign language] はい。
Yes.
Okay. I think, of course, in general, we are very happy to see our data program succeed in breast cancer. That's very important. How does that translate into applicability to a completely different cancer, lung cancer? You know, I think from a, of course, it does help somewhat to show that there is a lot of activity of the data program, the data drug in breast cancer, but we can look at also the toxicity profile and see that it's a manageable profile. Does it improve our chances of Avanza being positive? I would say probably yes, to some extent, but a lot of the information that we have gleaned from data in TB-02, I think that most of us, all of us, at least from Daiichi Sankyo, were aware.
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 a greater confidence for Avanza.
[Foreign language] ありがとうございます。で、次が...
Thank you. Next is DS-3939. Yamaguchi-san, the question, you will be focusing on the NSCLC, but the conclusion, it was stated that the various cancer types will be evaluated, so which is correct? Right now, you focus on the various types of the cancer type, but for the time being, you are focusing on NSCLC. Am I understanding right?
No, lung cancer is just one of the many different possible future development paths for DS-3939. The TA-MUC1 antigen is expressed in many different types of cancers besides lung cancer. 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 it's hard to ignore lung cancer data because that was actually presented at the conference here at ESMO.
[Foreign language] 分かりました。ありがとうございます。
I understood. Thank you.
The next question is from Tony Rens from Macquarie. Please go ahead.
Hi, thank you for the opportunity. Can you guys hear me?
Yes.
Okay, perfect. Yeah, 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, you know, on a subgroup analysis, if you go to slide number 15, right, when you look at the PCR rates, it appears to me that the PCR rates in the rest of the world appear to favor dose-dense AC followed by THP. The footnote says that these countries are Brazil, Bulgaria, Peru, Poland, Russia, and Saudi Arabia. Just wanted to understand why, you know, why the control arm appears to do so much better in these countries compared to the rest. Thank you.
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. It's a little premature to say that the 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. Yeah, the number is quite small. My second question is also on DB-11. It's about the eligible patient population. In Berlin, I spoke to a number of KOLs as well, including the discussants and presenters. Some of them said that very few patients they see actually fit the DB1-5 enrollment criteria, right? In the West, there's very extensive screening of breast cancer. 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 high risk. Obviously, I'm having difficulty reconciling these two statements. Anything that you can help me understand this situation better?
I think that we are more in line with the AstraZeneca analysis. That will be our thinking about this eligibility criteria and how it relates to the clinical practice setting.
Okay, understood. Yeah, thank you.
The next question is from Michael. [crosstalk]
[Foreign language] マイケル・ネダルコヴィッチさん、TD講演の方です。どうぞ。
Thanks for the question. I have two. My first is on the topic of Tropion Breast O2. It's actually a follow-up from one of your first questions, and it's not a very fair one. When you were asked what the most impactful trials were that were presented at ESMO, you omitted TROPION-Breast02 I'm just curious if you do not view that trial as practice-changing. If not, why would that really not be incorporated into the frontline standard of care based on TROPION-Breast02 ?
The TROPION-Breast02 , I think we did include that as a practice-changing. I felt that that wasn't properly conveyed. Let me just be very clear and say to you that TB-02 data, frontline setting in metastatic triple-negative breast cancer, is a very bad disease. It's very important to note that we are showing overall survival benefit in TB-02. The very first time, I believe, that that's been shown. Yes, very important and practice-changing for sure.
Thanks for clarifying. 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? Crossover to an ADC.
The crossover, we would like to focus really on how many patients crossed over from the control 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 two studies. This number is 30% in our study in TB-02 versus 50% in the Trodelvy study.
Right. That 30% is trial-wide in all geographies?
Trial-wide, yeah. We're focusing on the control arm, yeah.
Yeah, got it. Very helpful. Thank you. One more question on DESTINY-Breast11 . I have to confess, I'm still a bit confused as to why eight cycles of ENHERTU would underperform ENHERTU plus THP unless it showed a higher discontinuation rate, which did not seem to be the case. What's the prevailing hypothesis for the monotherapy arm underperforming?
Yeah, we are still figuring out this. The one thing is for sure, it was not due to a safety issue, okay? The pathological complete response is probably a little bit lower than the control. When we compare the trend of EFS, so far, there's no big difference overall, quite equal. A lot of patients in the single agent eight cycle were offered by, according to the DMC, to receive standard of care or stay actually under T-DXd single agent.
Got it.
We're going to do more analysis and more follow-up on this patient, and more to come in the future, I guess.
I look forward to it. Thank you so much.
The next question is from Barker from Jefferies. Please go ahead.
Yes, hi, Steve Barker from Jefferies. My question is about the DB-11 and regarding slide 14 specifically. You can see that there was a big difference in efficacy between HR + and HR -. Three-part question. Firstly, were you surprised by the pronounced difference between these subgroups? Secondly, what do you think explains the difference? Thirdly, what are the implications for how doctors are likely to deploy ENHERTU in the neoadjuvant setting?
Go ahead.
It's been long known that the biology of HR positive breast cancer and HR negative breast cancer is very different. There is a tendency actually for HR negative breast cancer to be a bit more responsive to cytotoxic drugs and chemotherapy than HR + breast cancer. The fact that we are seeing higher pathological complete response rates in HR - breast cancer compared to HR positive breast cancer is not a surprise. We can see that phenomenon for both the experimental arm and the control arm. What is therefore important to note is that even in what I would call the HR+ 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 pathological complete response positive achievement in the experimental arm with the T-DXd.
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. 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.
Understood. Thank you.
The next question is from Wada-san from SMBC Nikko. Please go ahead.
SMBC [Foreign language] 日光証券、ワダです。ありがとうございます。
SMBC Nikko, Securities Wada speaking. Thank you very much. Thank you very much for sharing the very good data. TB-02 is the test I have. Question. TRODELVY ASCENT-03 data is now available. If you compare versus that, TBS, OS, ORR, and grade 3 and higher adverse event for all of those items, that seems to be superior. What is the factor leading to these differences between the two medications? I'd like to know the positioning of how you will decide 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, has 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 events very well managed, and we don't have toxic death in our trial. I'm happy to elaborate more, but we believe that the Dato-DXd is a better drug for this population.
If I could just comment on one aspect of these cross-trial comparisons, which is always very difficult, 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 were in the control arm of that study. Many people have speculated that maybe the reason why the ASCENT-03 study did not achieve a meaningful difference in overall survival, whereas TB02 achieved a meaningful difference in overall survival, maybe that difference in OS has to do just with the availability of a crossover in a TRODELVY study versus no crossover in the TB02 study. I'm going to go to some speculations now. What we know is that in a TRODELVY study, about 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 antibody-drug conjugate of some sort at the time of progression. When I say antibody-drug conjugate of some sort, it would be the antibody-drug conjugates that were already approved at the time the clinical trial was ongoing. They would be things like ENHERTU, TRODELVY, and perhaps a T-DM1. Based on our data, we can see that about 30% of the patients in the TB-02 control arm received such an antibody-drug conjugate. I am not sure that the OS benefit that we saw in TB-02, 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.
[Foreign language] 分かりました。ありがとうございます。
Okay.
Thank you. One more question, if I may. The immunohistochemistry, is it working as a biomarker? I'd like to give you two simple questions. The first question is the RESOURCE- Ovarian 01 test. On this test, the stratification factors include CDH6 immunohistochemistry, which was mentioned. In the subgroup analysis, I see stratification factor. Is it, are there any data that is it working? Also, DS-3939, the TA-MUC1 expression, related expression, was studied further as a subgroup analysis? Those are two questions.
Okay, 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. As a general law, you can assume that we're going to have a biomarker strategy in all of our ADC programs. Now, with respect to the Dato-DXd program and the DS-3939 program, we haven't yet presented any data on the subgroup analysis based on IHC expression patterns. Please wait for that. That should be forthcoming sometime in the next few months.
[Foreign language] ありがとうございます。
Thank you.
[Foreign language] はい、以上です。
Okay, we are reaching the scheduled time, and we will now conclude Daiichi Sankyo's ESMO 2025 highlights. Thank you very much for joining today.