Small cell lung cancer versus non-small cell lung cancer. The five-year survival is very short compared to the non-small cell lung cancer, which we already know is a very bad disease. You can see that the unmet medical need is very high in small cell lung cancer. Next slide, please. Now, today we're going to be talking about ES-SCLC. This stands for Extensive- Stage Small Cell Lung Cancer. In small cell lung cancer, there are only really two stages: limited and extensive. Extensive stage means that the tumor has spread throughout the lungs or on both sides of the lungs or has spread to areas outside of the lungs, for example, the bone marrow. Extensive stage small cell lung cancer represents about 70% of all small cell lung cancer patients. Next slide. Brain metastases are a fairly common feature of extensive stage small cell lung cancer. Patients with brain metastases have even worse survival. This is going to be important later on when we talk about the most recent data that we have reported. Next slide. The small cell lung cancer field has had some recent drugs approved. You'll see that for the most part, the older drugs and chemotherapy have been used since the 1980s and 1990s. Immunotherapy with PD-1 and PD-L1 came on about five, six years ago, as well as a couple of new agents. One is lurbinectedin approved in 2020 as an accelerated approval. Also, more recently, tarlatamab, which is a bispecific T-cell engager, yet another form of immunotherapy approved as an accelerated approval in 2024. Next slide. Now, I'm going to introduce you to Dr. Abder Laadem, who's going to go over with you our I-DXd program. Abder? Thank you, Ken. Hello, everyone. I'm Abder Laadem, Head of Oncology Late- Stage Development. We are excited to share with you data in the DESTINY-Lung05 from last week. Focus this presentation mainly I-DXd program and small cell lung cancer. While other updates are shown here in the agenda. Next slide. B7H3 is an interesting antigen to exert tumor effect on multiple mechanisms. This target is expressed in many cancers, but absent in normal cells, as shown here in this graph. Its broad expression pattern creates an opportunity for us to develop this drug broadly. This antigen is often normal in absent in normal cells. Next slide. I-DXd is a B7H3 directed ADC with a drug antibody ratio. This ADC has the same linker system and payload as Enhertu. Next, we'll go over the phase I data. Next slide. This is the phase I data we showed several times before. This is the completed phase I trial. Study of tumor and selected B7H3. In dose escalation part one, I-DXd was given IV in three-week schedule, and the patient received up to 16 mg/kg. The recommended dose on the escalation we carry in the expansion was defined as 12 mg/kg. In part one, we performed three expansions in prostate cancer, squamous non-small cell lung cancer, and squamous esophageal cancer. In addition, there were a number of small cell lung cancers treated in the dose escalation, which we'll show in the data later. Next slide. The overall efficacy from this phase I in the heavily pretreated population showed very encouraging efficacy across different tumor types, including small cell lung cancer, squamous esophageal cancer, head and neck, stomach cancer, and small cell lung cancer. This study has demonstrated the broad potential of I-DXd in multiple indications. Next slide. The efficacy and safety results from the three expansions we included here were encouraging. In fact, we have started phase three already, one in prostate cancer in cetuximab naïve against cetuximab, which is the first thing, and the other one in the squamous esophageal cancer, second line. Next slide. This is the data of the escalation phase I. The results showed robust activity, tumor efficacy, high response rate of 52%, and the duration of response was 5.9 months and PFS 6.9 months and PFS exceeding a year. This was a strong signal which triggered a pivotal trial in this disease. Next slide. Now the data shown at length. Next slide. This is a phase two study in extensive-stage small cell lung cancer in a relapsing setting. The primary analysis was presented last week as an oral session. Next slide. As a reminder, this study I-DXd. This study is a phase rising of optimization with an extension part. The dose optimization was presented last year, and 12 mg/kg was defined as the dose to carry the rest of the development. The focus of this primary analysis is on the second line small cell lung cancer for patients treated with 12 mg from part one and part two. For the rest of the presentation for this primary analysis, we focus on this 137 patients, the 42 and the 95 received I-DXd at 12 mg/kg. These are the key characteristics of this population. It's a very typical population: advanced small cell lung cancer, high unmet indicator. Patients were all male, majority are men, as expected, and 28% of the patients had brain metastases. 50% of the patients received the drug as a line therapy, and 52 patients received I-DXd as a second line therapy. Next slide. As you see here, a robust RR, 38%, like in the subpopulation of second line, the response rate was higher, 56%. Next slide. In this graph, you see that the responses obtained quickly within the first six weeks, and the duration of response was five and three months. When you look at the second line patient, the 32 patients, the duration of response was higher. It was seven months. When it comes to PFS and OS, the PFS was 4.9 months and OS 10.3 months. Among patients who received second line therapy, PFS was 5.6 and OS was 12 months. Next slide. When we analyzed the subquestion, meaningful clinical benefit was demonstrated across the subquestion here. I-DXd was active regardless of the platinum resistance as defined by chemotherapy-free interval. It's also important to highlight the activity of the drug in the brain metastases, and the response rate in the brain was 46%. Next slide. In terms of safety, the extent of median duration of treatment was eight, and patients received a median of seven cycles. Less than 10% of the patients received treatment adversely. Next slide. Safety profile is overall consistent for I-DXd overall. The ILD rate in this population was 12.7%. Majority were low grade, and two patients died due to ILD as per adjudication. The table here on the right summarizes the ILD rate according to the adjudication. In conclusion, I-DXd showed a remarkable activity in small cell lung cancer in a relapsed setting. The confirmed response rate of 48.2% and median duration of response of 5.3 months. Clinically, meaningful activity was observed regardless of platinum resistance, and it's important to note the activity of this drug in the brain. A full analysis about the brain response will be presented as the upcoming assessment. Safety was manageable and consistent with what was reported before. The phase III I-DXd in second line is ongoing. In the next slide, I'm showing the design. The next slide. I'm showing here the phase III design, testing I-DXd versus topotecan or amrubicin or lurbinectedin. Studies are found to show an OS benefit, and the study probably will complete sometime next year. Here, I would like to say that I-DXd for this indication of small cell lung cancer received a breakthrough a few weeks ago. We just this week, early this week, developed another breakthrough for another DXd, RDXd, developed for ovarian cancer. Now, the five ADC in late development received the breakthrough. A total of 15 breakthroughs have come out. I'm going to walk you now the CDP. Next slide. The vision of I-DXd is to define the treatment paradigm for a broad range of patients with solid tumors through the innovative B7H3 directed ADC. Given the broad expression of this antigen and early signal in small cell lung cancer, prostate cancer, and vaginal cancer, we started rapidly the pivotal studies in small cell lung cancer as an anchor. We are expanding the development in prostate cancer and also vaginal cancer, phase III ongoing. We are extending many other tumors, seeking efficacy signal and to enable additional pivotal trials. For small cell lung cancer, today, as I shared, we discussed second line pivotal program and another study, which is ongoing. Importantly, studying multiple combinations of I-DXd, IO therapy, and bispecific DLL3 catamic. The intent is possible combination into three lines. Regarding cell lung cancer, multiple combinations and in the possible additional trial in the future. For CRPC, phase III is ongoing, and multiple combinations also in phase 1 with different agents to potentially enable additional studies. For vaginal cancer, phase III is ongoing in the second line, and check inhibitor plus or minus chemotherapy are on to generate signal in this combination in the early line. For other tumor types, we are testing I-DXd in a bunch of studies for signal seeking and to enable additional pivotal studies. The tarlatamab is also tested in different tumor types expressing DLL3 as a single agent and I-DXd. Next, I will speak about the program we showed at this WCLC conference. Mainly, I will cover three topics: a trial in progress and a completed trial in China in second line HER2. The first trial in progress is Enhertu in combination with pembrolizumab in the first line small cell lung cancer population expressing PD-L1 less than 50%. Next slide. As you know, Enhertu is an approved drug in late line HER2 overexpressed and mutated population. This study, DESTINY-Lung06, represents a great opportunity to take Enhertu into the larger population of first line. Nearly 700 patients will be randomized in a global ACSI study with primary endpoint PFS by BICR, and the study is in the substaging. The second study, we are interested also in assessing HER3 in combo with IO in front line. This gives us multiple opportunities to position the DXd drug in front line lung. This is the design of the study. Next. This trial is another trial in progress, tarlatamab with DLL3 bispecific in combination with I-DXd in relapsed refractory small cell lung cancer. Next slide. It is important to highlight that both tarlatamab and I-DXd are co-developed together between Daiichi Sankyo and Merck. DLL3 and B7H3 are two different proteins highly expressed on the surface of small cell lung cancer. Because of their distinct mechanism of action and minimally overlapping toxicity, this combination is very interesting. The aim of this combination between I-DXd, tarlatamab, and IO is to make this combination into early line of small cell lung cancer. In terms of design, we have different parts in this study. In part one, we're addressing the combo tolerability, safety, and schedule. Part one, we're studying mainly therapy to the monitoring from 48 up to one day. The last part is a combination of tarlatamab plus IO. It's another combination we're interested in. Next slide. What about DESTINY-Lung05? The sponsor was showing final results. This study led to the approved Enhertu in China in lung cancer second line HER2. Next slide. This is the population, basically a second line and HER2 population treated with the recommended dose. The primary endpoint was RR. In the next slide, you see here a very high RR, 56%. The duration of responses was close to one year. The next slide. As shown in this, wonderful dramatic responses were obtained in this population. If you go to the next slide, a very good PFS of 9 months and OS of 21 months in the second population, high medical need. Safety. The next slide. Safety profile was acceptable. The safety profile is very consistent with HER2. The ILD rate here was 12%, 12.5%, and very few, less than 2%, of higher grade. Next slide. With a median follow-up time of more than 20 months, the DESTINY-Lung05 final analysis showed that Enhertu induces durable response and clinically meaningful survival benefit in patients from China with pretreated metastatic HER2 in the population. The antitumor activity was observed across HER2 mutation subgroups, and the safety profile was consistent with the normal profile of T-DXd or HER2. This will end the highlight for WCLC. Thank you for listening. We're here to the question part. Thank you, Abder. We'll 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, 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. Everyone, can you hear me? Yes. Thank you. This is Yamaguchi from Citi. I have two questions. The first question is regarding a complete response of I-DXd at the third line, which is very interesting, but we don't see anything in the second line. Also, regarding this one, is there any background on why you get the BTD for this asset? Is it related to this CR rate at the third line? Thank you. That's the first question. Okay. Let me try to answer some of the questions, and I'll ask Dr. Laadem to add any comments. I think your first point was about your observation about CRs in third line patients versus second line patients. Is that correct? Yes. You know, it's a little bit difficult to speculate why we're seeing CRs in third line versus second line. It may just be a coincidence because, as you know, we do expect a greater efficacy in the second line rather than third line. It's flipped in the study yesterday. It's a little difficult to know why that is. Now, in terms of the breakthrough therapy designation, we received a breakthrough therapy designation for I-DXd based on the data that you just saw. The breakthrough therapy designation applies to small cell lung cancer for I-DXd. There's a separate recent breakthrough therapy designation for RDXT in ovarian cancer. We're going to talk about the ovarian cancer today, but you know, we're very happy to talk about that if you're interested. Quickly on the second question, it's too early to say, but everybody's trying to compare what's on the market and what you are developing, so the competitive landscape. The inhibitor, BYTE, did show some interesting data already, and it's on the market. Just looking at PFS or RR or maybe OS, they seem to be the same range rather than different range. Can you talk about what you are trying to differentiate in the future as a plan? Thank you. Yes. Okay. So you're referring to the drug called tarlatamab, which is a T-cell engager. The mechanism of action is very different from our drug, which is DXd ADC. The target is also different between B7H3 versus DLL3. As you pointed out, the response rate is pretty much similar. The response rate being reported in the tarlatamab, I believe, is about 40%. Numerically, our response rate is close to 50%, 48%. I think we're about in the same ballpark as tarlatamab. I don't claim to be superior in terms of response rate. What is different is that the toxicity profile is quite different between these two drugs. T-cell engagers typically are associated with cytokine release. With the tarlatamab, this occurs at an incidence of about 50% of the patients, any grade of grade 1 to maybe more. In most severe cases, it requires a hospitalization and monitoring and administration of IL-6 drugs to treat cytokines. It can be a bit cumbersome to have to manage a cytokine release syndrome. Whereas in our case, the I-DXd cytokine release syndrome is not at all seen. It's a very different safety profile. I think this kind of a difference in the toxicity profile may help the prescribing physician to choose which drug is appropriate for their patient. Thank you. That's all for me. Thank you. The next question is from Wakao-san from JP Morgan. Please go ahead. Hello. This is Wakao from JP Morgan. Thank you for taking my question. First question, this question may be overlapping with Yamaguchi-san, but can I ask? It's very important. As you commented, I-DXd seems to be better than tarlatamab in terms of the side effect. From this point, can I assume that if this drug is approved in second line plus setting, I-DXd will be used before tarlatamab or chemotherapy? That's a very good question. Ultimately, it's up to the physician really to choose which one. What I did point out was that there are major differences in the toxicity profile. Of course, from our side, we do know that physicians that use I-DXd treat their small cell lung cancer patients. Ultimately, in the absence of a head-to-head comparison of the two drugs, there's no direct data guiding the physician on which one to use. It's mostly a comparison of whatever the information is up in the level. Thank you. Okay. It's a kind of question about the competitive landscape in the development among the development products. In this WCLC session, where I-DXd was presented, favorable results were also reported for other B7H3 ADCs and for ADCs with different mechanisms targeting SCLC. Could you share your view on the advantages of I-DXd over these other candidates and any strategy to maintain its competitive edge? It is clear that I-DXd currently has a lead in terms of development speed compared to these other programs. Okay. So let me just point out a couple of things that's very important for our program. One of which is that we are much ahead from a timeline perspective compared to other B7H3 programs. You can see, for example, that we have pretty much completed our first trial intended for regulatory submission. I hope that you understand that that plus the fact that the FDA has granted us a breakthrough therapy designation, it's a very good sign about our submission plans and probably successful regulation. We also talked a little bit today, but not too much, but a little bit about the fact that we have data in other cancers already, esophageal cancer and prostate cancer. Those are where we have already initiated various randomized studies. I think we are ahead in terms of other B7H3 drugs from a timeline perspective. I also want to point out that we have a second drug intended for use in small cell lung cancer. This is a drug that was referred to in our presentation as MK-6070. That is a T-cell engager that we are co-developing with our collaboration partner also for I-DXd. Between the two, we have actually two drugs very active in small cell lung cancer. MK-6070 has already reported on a single agent activity in small cell lung cancer. You also just now saw our data in small cell lung cancer. We have two drugs in small cell lung cancer. I think you also heard that we are already doing a phase I study combining the two drugs, two drugs with a very high activity in small cell lung cancer. This allows us to very quickly do combination studies because we don't have to work with another company to create this combination. Because these are two internal drugs, it is much faster for us to be doing these combinations. Of course, once we start to see some clinical data with the combination, we do intend to develop a combination program, not just in a relapsed refractory setting, but hopefully, if the data supports, we intend to advance the combination in the frontline setting to replace the current standard therapy in the frontline setting for small cell lung cancer. Okay. That's clear. Thank you. The next question is from Sogi-san from Bernstein. Please go ahead. Thank you very much. I also have two questions. First question is about B7H3 as a target. As we have learned from Dr. Wei, the targets behave quite differently. Therefore, some targets require the specific patient selection strategy, such as in the QCS. I just wanted to see how do you see B7H3? Do you see it looks like in small cell lung cancer, maybe such an elaborated patient selection strategy may not require it. What do you understand as B7H3 as a target? What kind of activities or what kind of plan do you have in place for the future patient selection strategy? Okay. It looks like the B7H3 as a target is a very different situation than the TROP2 target, where in lung cancer, we are using a very fancy digital pathology technology as a biomarker. The data you saw today in small cell lung cancer, we can see that the drug activity is quite wide and pretty much in the non-selected patient biomarker. We continue to do the standard immunohistochemistry, i.e., CSA, to see whether or not there are any trends or patterns in the response between B7H3 positive versus negative expressing cancer patients using this IHC, the standard technology. At least in small cell lung cancer, we don't see a need for a biomarker. Eventually, we're going to have to go through all the details of the data. I think in the other cancers, we are, I think, in the exploratory stage right now for the biomarker. Hopefully, if a biomarker is needed, IHC, etc. Great. Thank you very much. In that question, my second question about combination with the MK-6070, I understand the rationale is that both the mechanism of action of these molecules are very distinct. Therefore, it's targeting a kind of different approach. Is there any synergy, rather than just 1 + 1 = 2, is there any possibility of 1 + 1 = 3 type, the synergistic expectation? Okay. I can just give you a biological answer right now because we don't have any clinical data yet. From a biology standpoint, what you can imagine is that I-DXd would go directly to the tumor cells, lyse the tumor cells, and the lysis results in the release of tumor antigens and tumor-associated antigens. These are mostly intracellular antigens and some extracellular antigens that are being released. The second drug, the MK-6070, is a drug that is intended to enhance T-cell response, anti-tumor T-cell response. When we talk about anti-tumor T-cell response, we're really talking about T-cell recognition of these tumor antigens that have been released by dying cancer cells. From a biology standpoint, theoretically, this is a great combination. You know that one drug releases the tumor antigens and the other drug brings all the T-cells into the tumor bed and causes the T-cell immunity and response, I guess. Hopefully, we'll see that in action in patients as well. Great. Thank you very much for the clarity. You know that sounds very exciting. Thank you very much. Okay. The next question is from [Murawka-san] from Morgan Stanley. Please go ahead. [Foreign language] Murakawa from Morgan Stanley. Thank you very much for this opportunity. The first question is that on slide 33. [Foreign language] Let's see the timeline for the study going forward. [Foreign Language] First line? [Foreign language] Can you hear my voice? [Foreign Language] The timing for IDeate-Lung03 is that it is coming to this landscape sometime next year. At this time, first line and third line coinciding with the approval timing, the outcome will be read out. Then IDeate-Lung03 is also coming out around that time. Is my understanding correct about this landscape? Okay. Let me ask Dr. Laadem to answer your timeline questions. Are you talking about the I-DXd in combination with atezolizumab and carboplatin? We're talking about I-DXd Lung01, or can you repeat the question, please? [Foreign language] Yes, IDeate-Lung03's outcome is expected to come out next year. I just wanted to confirm that. This is a phase I/II trial. We're trying to combine I-DXd with either amrubicin plus or minus carboplatin. Basically, we're replacing etoposide with I-DXd in the first line therapy. As you know, the study is a dose escalation, and your understanding is correct. The dose escalation is ongoing, and we're going to go to the dose expansion after that. [Foreign language] Thank you very much. The second part of my question, dose escalation. For this IDeate-Lung03, including that, I-DXd dose, perhaps maybe more than 12 mg, like 16 mg or more, in all likelihood, is there a possibility or no? No, it's not a possibility to go to 16 mg. 16 mg was discontinued during the phase I single agent, phase I. The dose escalation, we're talking about doses between 8 mg and 12 mg. We try to combine doses between 8 mg up to 12 mg with an immune check inhibitor, atezolizumab, plus or minus carboplatin. The timelines shown here are correct. [Foreign language] Okay, thank you very much. For clarification, that's all for myself. Thank you. The next question is from [Bufanasan] from Pathology Associates. Please go ahead. Excuse me. Thank you for taking my question. We spoke previously about the differentiation from tarlatamab, and I wonder if you can just say a couple of words regarding the position with brain mets and in platinum resistance against tarlatamab. Thank you. As you point out, the brain metastasis activity that we're seeing with I-DXd is actually very interesting, a bit surprising, because I-DXd is a fairly large molecule. It's a biological agent, actually. This kind of drug is not typically associated with brain metastasis activity because these are large molecules that do not cross the blood-brain barrier. However, in all of our DXd ADC series, starting with HER2 originally, then TROP2 and other ADCs now, we are seeing very good brain metastasis activity, including I-DXd in today's presentation. I think it's a very important point. We can also see that our drug is active in patients previously treated with platinum that you mentioned, but also active in patients previously treated with a T-cell engager such as tarlatamab, and also, very interestingly, active in patients previously treated with a systemic TOP1 agent such as topotecan, the same class of drug as the payload for I-DXd. I hope that answered the question. Yes, indeed. Thank you very much. The next question is from Michael Nedelcovych-san from TD Cowen. Please go ahead. Hi. Thank you for the question. I have one. To what do you attribute the activity in patients who have experienced a TROP1 inhibitor in earlier lines of therapy? It's an interesting finding, and it seems to have broader implications than just this trial. Maybe you could discuss that. A related question, while there is activity, it does appear to be lower in that subgroup. Do you think there is any risk that those patients are excluded from the label should I-DXd ultimately achieve accelerated approval in this setting? Thank you. Okay. In terms of why this drug is active in topotecan-treated patients, I have to say I don't have a good answer for you. Maybe Dr. Laadem has some ideas, but the only thing I can imagine happening in these patients is that perhaps I-DXd has this ability to focus and concentrate the drug delivery into cancer cells as opposed to just systemic exposure. Possibly, we are able to deliver much more drug into cancer cells compared to systemic exposure to topotecan. That's just my speculation, but perhaps that is what's happening. Now, in terms of the eventual label, and is the FDA going to exclude those topotecan-pretreated patients? I'm not the FDA, so I can't tell you. I'm just going to speculate. I hope you don't mind. I hope you understand I'm just speculating. The topotecan-treated patients, there's no other available therapy, really. I would think that the data is sufficient for the FDA to consider that the drug is active in topotecan-treated patients. That's number one. Number two, as you know, the FDA typically is looking at the ITT patient set, and they prefer not to do the subgroup analysis and make approval decisions based on various subgroup analysis. For these reasons, I'm just going to speculate now that the eventual label point will not exclude topotecan-pretreated patients. We'll have to see. We'll see what happens. Okay? All great points. Thank you so much. Okay. The next question is from [Yamaguchi-san] from Citi. Do you have additional questions? Yes, I do. Can I? Yes, please. Thank you. Just one question. Regarding breakthrough therapy designation, I understand breakthrough therapy designation is one of the most, I would say, powerful sort of variations from the FDA so far. Given there are so many trials going on and the phase III is also already going on, I understand probably the success may be higher. Can you give me some example where you can, how to say, extend the shortened timeline of approval where you can find out the time value of breakthrough therapy designation of your whole I-DXd program? Thank you. Okay. I think you're asking really what kind of advantages do you get by having a breakthrough therapy designation? In this case, yes. Yes. Eventually, we have to go through the process with the FDA to know exactly what this translates into, but possibly the review time will be short. Possibly, we may get a priority review instead of standard time review. These are kind of speculations, but we just have to see what happens. Once they get the dose in and they look at it, then they give us a deeper. Okay, thank you. If you have questions, please raise hand. [Bufanasan] from Pathology Associates, do you have additional questions? If so, please go ahead. No other questions at the moment. Thank you very much. Okay. If you have any questions, please raise hand. Okay. I do not see any hands being raised. We would like to now conclude the I-DXd WCLC 2025 highlights. Thank you very much for joining.