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

Hello colleagues. My name is Hiroyuki Okuzawa and I am the President and CEO of Daiichi Sankyo. Thank you for joining our briefing session focused on the highlights of our presentations at ASCO 2024. We have been making endeavors to transform cancer treatment with DXd ADCs that are our unique and innovative technology platform. It is my pleasure to share with you another major achievement for ER HER2 today. 2 years ago, we presented DESTINY-Breast04 study data here at ASCO, which revealed that ER HER2 could contribute to breast cancer patients who were previously categorized as HER2 negative. Based on the outcome from the study, ER HER2 pioneered a new patient segment HER2 low breast cancer. Furthermore, yesterday, we presented data from DESTINY-Breast06 study, which expands the treatment opportunity for ER HER2 to earlier line of HER2 low breast cancer and moreover, to HER2 ultra low breast cancer. We are developing other DXd ADCs such as Dato-DXd, HER3-DXd, I-DXd and DS-6000. We also have known DXd-ADC internal assets including second-generation ADC. With our competitive pipeline, I am confident that we can contribute to address various unmet medical needs in oncology area. Now I hand over to Ken Takeshita. Ken will take you through our strategies around breast and lung cancers.

Thank you very much for that introduction. Next slide, please. It's a distinct pleasure for us to be able to report to you that at ASCO 2024, we had over 30 presentations across 8 assets in many, many tumor types. And we want to today, especially highlight a lot of progress we have made in our breast cancer program with our flagship drug in HER2 and also substantial progress that we have made in our lung cancer program with both our -- in HER2 program, the DESTINY series of trials in TROP2 ADC program, the TROPION series of two clinical trials. Next slide. This is our breast cancer map showing various stages, lines of therapy and types of breast cancer. And for today, we will be focusing especially on 3 different trials DB, DESTINY-Breast06, DESTINY-Breast07 and DESTINY-Breast03, and particularly notable is a clinical trial that was previously mentioned by Okuzawa-san, DESTINY-Breast06 study. This is a new study that is a major advance on top of DESTINY-Breast04 that we previously reported to you at ASCO 2 years ago. And you'll see that it is one earlier line of therapy but also an additional patient population, which we term HER2 low. And you'll be hearing more details about this from my colleague, Mark Rutstein, later on today. Next slide. This is our lung cancer map, again, showing the various different types of drugs we have in development. And here, you'll see that our major drug is in blue, that -- our data program. We also, however, have in our program in lung cancer, in orange, is in HER2, green is our HER3 directed ADC program. And finally, at the bottom in yellow is the, I-DXd program with the target antigen of B7-H3. So you can see here again that like in breast cancer, we are trying to cover all different types of lung cancers in and as many lines of therapy as we can. And today, we will be focusing especially on giving you updates to DESTINY-Lung01 and TROPION-02. Next slide. And finally, I do want to alert you to a new clinical trial that we are going to be conducting called TL-15, TROPION-Lung15, this is a new Phase III study in second-line EGFR-mutated non-small cell lung cancer for our data program in which the data with or without osimertinib is compared to platinum-based double chemotherapy in patients who have received at least 2 prior lines of EGFR TKI treatments. So this is a new study that has already appeared on the clinicaltrials.gov and you can see the details there. The study is planned to be started in fiscal year '24 in the first half. Primary endpoints and secondary points are listed there. Okay. So with this, I'm going to turn this over to my colleague, Mark Rutstein, who will go over all the many, many clinical trial data that were presented at ASCO markets.

Thank you, Ken. My name is Mark Rutstein. It's my pleasure to be here to present the key data that we have at ASCO 2024. Of course, it is our intent to leverage our DXd technology to deliver potentially practice-changing medicines for patients. So with that, next slide, please. So the first data set, and I'm very excited to present this today is DESTINY-Breast06 and this is a study of trastuzumab deruxtecan in HER2 low and ultralow metastatic breast cancer. And the -- one of the exciting aspects of this data is the ability, again, of an HER2 to demonstrate the potential to change the way metastatic breast cancer patients are classified. Next slide, please. So here are the key takeaways from DESTINY-Breast06 pivotal trial. T-DXd demonstrated efficacy in HER2 low metastatic breast cancer in an earlier line of treatment to DESTINY-Breast04. And specifically, this study were in patients who are chemotherapy-naive, whereas DESTINY-Breast04 had patients that had received 1 to 2 prior lines of chemotherapy. In addition, including HER2 ultralow, the proportion of patients who could benefit from T-DXd is approximately 85% of what is conventionally called hormone receptor positive HER2-negative metastatic breast cancer after data from DESTINY-Breast06, and we can see on the left that 60% to 65% of that population of hormone receptor positive HER2-negative patients to HER2 low. And then with the ultralow population and we'll explain what that means in a moment, an additional 20 to 25 patients. So in DESTINY-Breast06, T-DXd demonstrated a statistically significant and clinically meaningful PFS benefit versus chemotherapy in hormone receptor positive HER2 low metastatic breast cancer after at least 1 endocrine-based therapy with results consistent in the HER2 ultralow population. Next, please. This slide portrays the unmet medical need in the clinical setting of this trial. Most relevant is we see the group of patients who historically have received endocrine therapy and targeted therapy particularly CDK4/6 inhibitors with a typical median PFS of 5.5 months and should those patients had received endocrine monotherapy, they would have only -- even less clinical outcome, demonstrating a significant unmet medical need in the patient population study in DESTINY-Breast06, and as we'll see, approximately 90% of patients enrolled in DESTINY-Breast06 had actually received prior CDK4/6 inhibitor. Next, please. So DESTINY-Breast06 is targeting both low and ultralow HER2-expressing tumors. We can see the graph on the bottom. We know based on DESTINY-Breast04, HER2 low are categorized as IHC 1+ or HER2 IHC 2+ is negative. And you can see on the right side of the slide, HER2 ultralow being defined as faint incomplete membrane staining in less than 10% or equal of tumor cells. So taken together HER2 low and HER2 ultralow represent the total -- intent-to-treat population of this study. Next slide, please. This is the study design. These are hormone receptor positive metastatic breast cancer patients. They are, as stated, either HER2 low or HER2 ultralow as defined previously, and also defined here on this slide in a related manner, as patients who are IHC 0, with some membrane staining of HER2. They are chemotherapy-naive, they've received at least 2 prior lines of endocrine therapy with or without targeted therapy or 1 line of endocrine therapy for metastatic breast cancer and progression within 6 months of starting first-line endocrine therapy and CDK4/6 inhibitor or recurrence within 24 months of starting adjuvant endocrine therapy, the patients were randomized to monotherapy, T-DXd or chemotherapy, chemotherapy choices being capecitabine, nab-paclitaxel or paclitaxel primary endpoints in this study for efficacy, progression-free survival in HER2 low, key secondary endpoints, progression-free survival in the ITT population, which again includes HER2 and ultralow patients, then also overall survival in the HER2 population and overall survival in the intent to treat population. Next, please. Here is the patient dispositions. You can see that 436 patients were included in the T-DXd group, and 430 in the tumor therapy group and the majority of patients randomized were treated. And you can see that on the right side, most of the patients received capecitabine and then fewer patients received nab-paclitaxel and paclitaxel. At the time of the data cutoff of the trial, 14% of patients remained on treatment, 20.5% in the T-DXd arm and 7.2% in the chemotherapy arm. And you can see median duration of follow-up of 18-months. Next slide. These are the demographics and key baseline characteristics of the patient population. Overall, they represent a very typical metastatic hormone receptor positive population. You can see that in the ITT population, the majority of patients were IHC 1+, and you can also see a large percentage of the patients had visceral disease at baseline. If we move to the next slide, please, here are the prior lines of therapy, you can see that patients received a median of 2 prior lines of endocrine therapy. The majority of patients had received -- they had received 2 prior lines and only a minority have received 1 prior line or greater than 3. And as I mentioned before, approximately 90% of patients had received prior endocrine therapy with CDK4/6 inhibition. And as alluded to in the earlier slides, this represents this patient population that represents a high unmet clinical need. Next slide, please. Here are the primary endpoint results. What we can see are statistically significant and clinically meaningful improvement in progression-free survival with a median difference of 5 months, 13.2 versus 8.1, hazard ratio of 0.62, clear and sustained separation of the curves. If we move to the next slide, please. This is progression-free survival in the intention-to-treat population. This is a secondary endpoint. And as a reminder, this includes patients who are HER2 low and ultralow, a very similar statistically significant and clinically meaningful result was achieved in the ITT population as well. Here again, a median delta and progression-free survival of over 5 months -- just over 5 months, 13.2 versus 18.1 months and a hazard ratio of 0.63 with a clear separation of the curves. Next slide, please. Here is overall survival. We show on the left, overall survival in the HER2 population we show on the left -- on the right, overall survival in ITT, which includes HER2 low and HER2 ultralow. What you can see on the slide in the title is this is approximately 40% of maturity. And what we can see is there's an early separation of the overall survival curves on the left, you can see the difference in the overall survival rates. You can also see the hazard ratio, it did not cross the threshold for statistical significance, but it certainly represents an early trend and 20% of patients in the chemotherapy group did receive T-DXd post discontinuation. On the right, a very similar results, early trend for overall survival with separation of the curves. Hazard ratio of 0.81 and approximately 18% of patients in the ITT control group with chemotherapy receive T-DXd post-treatment discontinuation. So overall, immature, but overall survival not statistically significant, but headed in the right direction. Next slide, please. Here are the results in the ultralow population. This population represents 152 patients in total. And this was a prespecified exploratory analysis, these efficacy analyses. As a reminder, the HER2 ultralow population is part of the intention-to-treat population. It is a subgroup. As we can see on the left, the progression-free survival demonstrates a hazard ratio of 0.8 and here a clinically meaningful median delta and PFS of approximately 5 months, 13.2 versus 8.3 months. And the overall survival on the right, again, an early trend Kaplan–-Meier curves are less clear because of the sample size here of the subgroup, which you can see there is separation and hazard ratio is 0.75. So the PFS improvement with T-DXd versus chemotherapy in HER2 ultralow was consistent with results in the primary endpoint population, HER2 low. Next slide, please. Here are the subgroup analysis results in the HER2 low population for PFS, and what you can see, regardless of HER2 status, prior CDK4/6 inhibitor treatment, prior lines of endocrine therapy, choice of chemotherapy and other subgroups, you can see consistency of results. Next slide, please. Here's the anti-tumor activity. You can see on the left, T-DXd, the waterfall plot and you can see on the right and on the bottom, in the HER2 low primary endpoint population, overall response rate 56.5% versus 32.2% for chemotherapy and in the intent-to-treat, which encompasses HER2 low and ultralow, 57.3% versus 31.2% and in the ultralow and remarkably, a consistent result, with an overall response rate of 61.8% versus 26.3%. Next slide, please. Now we turn to safety. What you can see of the safety summary that T-DXd was overall well-tolerated. There were modestly higher increases of greater than 3 treatment-related adverse events, serious adverse events, events associated with discontinuation. On the other hand, dose reduction was higher in the chemotherapy arm. And in addition to this, you can see on the right side of the slide, the most common adverse events associated with treatment discontinuation was pneumonitis for T-DXd, peripheral sensory neuropathy for chemotherapy. And the most common AE is associated with those reduction included nausea for T-DXd and type of rash for chemotherapy. If we could go to the next slide, please. Here are the most common drug-related adverse events in 20% or more of patients in either treatment group. Overall, what we see is a consistent safety profile for T-DXd relative to other breast cancer studies. The most common adverse events being nausea, fatigue, alopecia and neutropenia are consistent with what we expect for this drug. So no surprises and no new safety signals encountered. If we would turn to the next slide, please. Here, importantly, are adverse events of special interest. We know that drug-adjudicated interstitial lung disease is an adverse event of interest. We can see any grade rate of 11.3%. The majority of ILD was low grade. You can see grade 2 at 8.3%. For example, there were 3 grade 3 events, 0.7% and there were 3 grade 5 events, 0.7%. Considering these results, we believe these are consistent with what have been seen with T-DXd in breast cancer. If we look to the bottom left, ventricular dysfunction, there were 3 events of grade 3 ejection fraction decreased in the T-DXd arm and 1 in the chemotherapy arm. There were no cases of cardiac failure in the T-DXd arm. Next slide, please. So in conclusion, T-DXd demonstrated a statistically significant and clinically meaningful PFS benefit versus chemotherapy in hormone receptor positive HER2 low metastatic breast cancer in an earlier line of treatment in the DESTINY-Breast04. As I showed results in the ultralow population, consistent with those in HER2 low, and the confirmed overall response rate was 57% with T-DXd versus close to 31% of chemotherapy. No new safety signals were identified. Interstitial lung disease does remain an important safety risk for T-DXd, and this study and these results established T-DXd as an effective new treatment option for patients with hormone receptor positive HER2 in ultralow-metastatic breast cancer following at least 1 line of endocrine-based therapy. And so overall, and as stated the offset in the presentation, T-DXd in this study continues to demonstrate the capability to potentially reclassify the categorization of breast cancer patients and represent a potential new standard of care in this setting. Next slide, please. Now I'm going to turn to HER2-positive metastatic breast cancer, and we're going to show the updated results of DESTINY-Breast03. As people are likely aware, trastuzumab deruxtecan is approved in second line plus HER2-positive metastatic breast cancer in many countries. And here, if we move to the next slide, we see updated efficacy results for both progression-free survival and overall survival, and this includes overall survival at greater than 3 years of follow-up. And we'll start with overall survival in the results. At this point with this analysis, what we can see is the median overall survival has been reached. There are no test of statistical significance for either endpoint because the study has already resulted and readout. So these results are descriptive. Nonetheless, we can see the median overall survival in the T-DXd arm is a remarkable 52.6 months compared to 42.7 months for T-DM1, hazard ratio 0.73, and we can see the separation of the curve sustained with a longer follow-up. If we look on the left, again, a descriptive follow-up analysis of progression-free survival, 29 months for T-DXd versus 7.2 for T-DM1 with a hazard ratio of 0.3. If we move to the next slide, please. This is the safety summary I'm glad to report that there was no cumulative toxicity. T-DXd safety profile remains manageable. If you look at the upper graph, you can see that drug-related grade equal to 3 adverse events was very similar between the 2 treatment arms. There were modestly higher rates of serious drug-related AEs. There were higher rates of adverse events associated with dose reduction and discontinuation and perhaps wouldn't be a surprise that there would be a difference in some of these rates, especially over time. And if we look at the ILD down bottom, so we can see overall with further follow-up, an ILD rate of 16.7%, notably no grade 4 or 5 events, 2 grade 3 events, and there were no additional new grade 3 events since past analysis. There were an additional 4 grade 2 events since the last follow-up time. So overall, when we look at the safety -- the efficacy and the safety of this trial, this follow-up data now confirms the superiority of T-DXd over T-DM1 and supports the approved and current indication in second-line plus metastatic HER2-positive breast cancer. Next slide, please. Then we turn to DESTINY-Breast07. So this is a Phase Ib trial of T-DXd monotherapy or T-DXd plus, the anti-HER2 agent pertuzumab in patients with previously untreated HER2-positive metastatic breast cancer. Next slide, please. So as background, T-DXd -- I'm sorry, the first line therapy in this setting for frontline HER2 metastatic breast cancer is THP, that's trastuzumab, pertuzumab and also taxane. Based on the CLEOPATRA study, which reported a median PFS at 18.7 months in that frontline setting, T-DXd monotherapy, as we showed in the previous slide, has demonstrated impressive efficacy in the second-line plus setting. This Phase Ib study DESTINY-Breast07 presents the first data set of first line T-DXd with or without pertuzumab in the front line of HER2-positive metastatic breast cancer. Next slide, please. This is the study design. As mentioned, this is a frontline patient population with no prior therapy for metastatic breast cancer. Patients were HER2-positive, they're randomized to 2 arms. You can see module 0, T-DXd monotherapy with 75 patients, and then you see module 2, 50 patients, T-DXd plus pertuzumab, primary endpoint safety and efficacy as key secondary end points. And so for this interim analysis, we'll look at data from the module 0 and the module 2 of this Phase Ib/II study. Next slide, please. Here are the baseline characteristics. And you can see this would be a fairly typical frontline HER2-positive metastatic breast cancer population. You'll notice what's highlighted is that most of the patients were de novo, but there were about 36% to 40% of patients, depending on which arm you look who are current. And you can see on the right, the prior treatments that they had received, including trastuzumab, pertuzumab, T-DM1. If we would move to the next slide, please. Here is the patient disposition. You can see the majority of patients are still ongoing therapy, 63% versus 56% across the arms, and there were a greater number of patients and higher percentage who discontinued treatment with adverse events in the combination arm compared to the monotherapy arm. And there was 24 to 25 months of median duration of follow-up. Next slide, please. Here are the efficacy results. On the left is T-DXd monotherapy with a confirmed overall response rate of 76%. You can see the median duration of response was not reached and indeed, the responses are durable. If you would move to the right, you would see T-DXd plus pertuzumab and you can see the confirmed overall response rate is 84%. Note that the complete response rates for the monotherapy were 8%, the complete response rate with a combination of 20%. And again, for the combination, median duration of response not reached with durable responses. If we move to the next slide, here is the duration of response and the KM curves speak to durability with a number of patients remaining in response. And so if we move to the next slide, please. Here are some efficacy subgroup results both by disease status, including de novo and also the recurrent population that I mentioned in the baseline characteristics and also hormone receptor status. And you can see regardless of disease status and hormone receptor status. The response rate is robust. Next slide, please. Here is the safety overview. Overall, either T-DXd or T-DXd plus pertuzumab were well-tolerated. You can see that there were some modestly higher grades, excuse me, rates grades greater than or equal to 3 adverse events in the combination arm, also interruptions in addition to discontinuation. There was -- there were no grade 4 or 5 ILD events. We can see down the bottom on the left table, there was 1 grade 3 ILD event in the T-DXd plus pertuzumab arm. Overall T-DXd and the combination were well-tolerated. If you move to the right, you can see the most common adverse events, and the list of adverse events here and the rates are more or less what you would consider and expect for T-DXd and consistent with the known safety profile. Perhaps one thing to point out is a higher rate of grade 2 diarrhea in the combination arm compared to the monotherapy arm. There was 1 AE leading to death, and this was not related to study treatment. Next slide, please. In conclusion, in this first data set of T-DXd monotherapy and T-DXd plus pertuzumab, there were robust response rates. These response rates were durable. I did not show PFS rates of 12 months, but they're listed here. And in addition to that, the majority of patients in both arms and either arm are still ongoing. Overall, encouraging activity was observed and the safety profile was consistent with what we know about these drugs, T-DXd and pertuzumab. And importantly, this data set supports the ongoing global Phase III trial DESTINY-Breast09 of T-DXd or T-DXd plus pertuzumab in frontline HER2-positive metastatic breast cancer. Next slide, please. Now we will turn to lung cancer, a few data sets in lung cancer that were presented at the ASCO meeting. The first is a final analysis and therefore, a follow-up of T-DXd in patients with HER2 mutant metastatic non-small cell lung cancer, DESTINY-Lung02. Now T-DXd is approved in this indication in many countries based on the clinical benefit it was observed and the positive benefit risk profile and this is the final analysis. Next slide, please. Here is our study design. In this trial, patients were randomized 2:1 to T-DXd at 5.4 milligrams per kilogram or 6.4 milligrams per kilogram. You can see all these patients had a HER2 mutation, and they received at least 1 prior anticancer therapy. So really second line plus, the primary response rate was overall was the -- primary efficacy endpoint was overall response, but as we'll see there's also an overall survival analysis. Next slide, please. So here are the updated results. You can see the overall response rate in the 5.4 milligram per kilogram group is 50% and the duration of response at 12.6 months, you can see the overall response rate in the 6.4 milligram per kilogram arm, it's 56%. And here again, a median duration of response is quite similar at 12.2 months. There were patients in both arms who also achieved complete response. If you look to the bottom right, you can see overall survival. And of course, considering that there are only 102 patients in the 5.4 milligram per kilogram arm and 50 patients in the 6.4 milligram per kilogram arm, but nonetheless, you can see the median overall survival there and the curves, they overlap to a great extent. The median in the 5.4 lower dose arm is 19 months, the median in the higher dose arm was 17.3 months. So overall, a very robust clinical benefit despite either dose or at both doses. If we move to the next slide, please. The differentiation occurs in the safety. And here you see the overall safety summary at the lower dose 5.4, and then at the higher dose 6.4. And you can see where various adverse event categories that were grade 3 and greater adverse events, serious adverse events, events associated with discontinuation and events associated with reduction as well as interruption. Those rates were higher, but a higher dose at 6.4 compared to lower dose at 5.4. There was 1 drug-related interstitial lung disease event leading to death in either arm. So overall, when considering the efficacy, comparability across the 2 doses and then the higher adverse event rates at the 6.4. This data, this final data does confirm the currently approved dose of T-DXd in HER2 mutation positive non-small cell lung cancer at 5.4 milligrams per kilogram. Next slide, please. So the last data set we'll discuss together is TROPION-Lung02. This is an update of Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy as first-line therapy for advanced non-small cell lung cancer. Next slide, please. The study design is at the top, this study included an escalation phase in which patients received less than or equal to 2 lines of prior therapy and then went into a dose expansion phase. And in that phase, patients received 1 or fewer lines -- less than, equal to 1 line of platinum therapy. And this analysis that we'll focus on today is the cohort of patients that are frontline or 1L patients. You can see in the study design above the study explore the doublet of course of Dato-DXd in combination with pembrolizumab. It also includes the triplet of Dato-DXd with platinum-based chemotherapy, either cisplatin or carboplatin and also pembrolizumab. Importantly, in the demographics and baseline characteristics of these -- the frontline subgroup, the 1L subgroup, 42 patients in the doublet arm, 54 patients in the triplet arm where you can see the majority of patients had adenocarcinoma, the minority squamous and this is typical and consistent with the patient population. And what I want to point out, especially at the bottom of the table, is the PD-L1 expression. This here, you can see a larger -- a fairly significant percentage of the population actually had PD-L1 expression of less than 1%. You can see 43% of the doublet arm, 30% in the triplet arm, 1% to 49%, 45% versus 43% and only a minority of patients had PD-L1 greater than equal to 50%. And I mentioned this because I think it helps us characterize some of the response rates that we see. So on the next slide, please. So here, we can see subgroup analyses. First thing you observe on the left column is in the doublet in the frontline setting there, overall response rate of [Audio Gap] 52% and durable responses with a median duration of response not achieved in the triplet. You can see overall response rate of 56% and also median duration of response 12.9 months. And considering that a significant percentage of these patients in either arm, and particularly the doublet, have low expressing for PD-L1, these results are encouraging. And you can see that the doublet and the triplet -- with both the doublet and the triplet, you can see their responses across different cohorts of PD-L1 expression level. So overall, evidence of antitumor activity and evidence of some robust antitumor activity, with durable responses across both doublet and triplet and across lines of expression of PD-L1 expression levels. If we would move to the next slide, please. Here are the safety summaries. You can see on the upper left, the rates of grade greater or equal to 3, treatment related adverse events were higher in the triplet arm. The majority of this was due to chemotherapy-related cytopenias. And you can see serious treatment-related adverse events about 12% in the doublet, 22% in the triplet, there were discontinuations as well. Dato-DXd discontinuation is 21% of the doublet and then 13% in the triplet, discontinuation of any drug, you can see 29% in the doublet. In addition to that, on the bottom right, we show adverse events of special interest in this population. There was the occurrence of stomatitis, which of course, is a known adverse event of Dato-DXd. You can see the majority of events were low grade with a few grade 3 events. In terms of adjudicated drug-related ILD, you can see all grades of 24% and 26%, respectively. There were no grade 4 or 5 ILD events. And there were 2 grade 3 ILD events with the doublet and one with a triplet. So in summary, what we see overall with this updated analysis of TROPION-Lung02 is that there are evidence of antitumor activity and significant response rates as well as durability and manageable safety profile. And these data support the ongoing frontline pivotal trials of Dato-DXd with pembrolizumab, TROPION-Lung08 in the 50% higher PD-L1 population and TROPION-Lung07. So Dato-DXd plus pembro with or without chemotherapy in the frontline non-small cell lung cancer population. To the next slide, please. So I'm pleased then to have presented this data to you. Our intent is, of course, to leverage our pipeline and our DXd technology to deliver practice-changing -- potentially practice-changing results. We're very excited by the DESTINY-Breast06 results, already -- also excited by all the results that we presented across breast cancer and lung cancer today and absolutely continue on our mission to do the best we can to deliver innovation and to deliver medicines to patients who are waiting and have significant unmet needs. So with that, we'd like to now open the Q&A.

[Operator Instructions] The first question is Yamaguchi-san from Citi.

Yamaguchi Hidemaru from Citi. First question regarding D-B06. Do you have any kind of preview of your pre-expectation on what kind of data is expected for ultralow. And I am surprised to find out ultralow and low are almost the same. But do you have -- are you surprised as well or not?

So I believe we had relatively high expectations for DESTINY-Breast06 based on the result of DESTINY-Breast04. What we can see so far within HER2 is the ability to demonstrate efficacy and transform the results in different lines of therapy and across lines of therapy. And now we've moved in HER2 into an earlier line of hormone receptor positive disease and we had high expectations certainly for the HER2 low population. Now when it comes to the ultralow population, the consistency of the results across HER2 low and ultralow are indeed remarkable, yet we did have proof of concept for the efficacy of T-DXd in HER2 ultralow hormone receptor positive metastatic breast cancer on the basis of the data set produced by a group in France and with the hospital of Gustave Roussy where called DAISY, D-A-I-S-Y, where there were a cohort of patients with a fairly robust response rate as proof of concept in this patient population. Upon seeing that proof of concept that then provides confidence in the ability of HER2 to demonstrate efficacy across a range of HER2 expression in hormone receptor positive patients, including that HER2 ultralow population, which has not been historically been considered a candidate for HER2-targeted therapy. So overall, I do think the consistency between the 2 patient populations is remarkable. However, we did have proof of concept and therefore, had expectation based on both the D-B04 results and the DAISY results to address these 2 subpopulations of the ITT population within DESTINY-Breast06. I would lastly conclude that we're very happy and very pleased with these results for patients.

A quick follow-up, which was discussed at the conference as well is that because it is relatively difficult to diagnose ultralow from the pathologist point of view? And it already covered 80% of the patients. Do we still need to make -- hard to diagnostics or not in the future.

So indeed, it was -- and of course, I was at the discussion as well at the conference around the pathological assessment of the ultralow. I would point out that Daiichi Sankyo and our partner AstraZeneca, we do have experience educating, educating the community pathologists included, on the reclassification of the treatment of metastatic breast cancer patients based on DESTINY-Breast04. So I think with those learnings and with those tactics, we think that -- and we feel comfortable that we'll be able to engage with educational campaign and continue on this course -- assuming the regimen gets approved, continue on this course of reclassifying breast cancer patients and with an educational campaign and guidance that will support pathologists, in the diagnosis of HER2 ultralow patients. And fundamentally, this would require looking for any expression at all, any expression versus the absence of expression. And so we believe this is feasible. And you also asked the question whether or not we think they'll come to a time that no HER2 IHC testing is required. And so at this point, I believe that we would say is we would follow the evidence. And so to date, what we can see is that HER2 is capable of producing efficacy across a very broad range of HER2 expression, including very, very low -- patients with very, very low levels of expression in their tumors. But at this point, we do not have a confirmation that in HER2 would produce efficacy in patients who do not express any HER2 receptor at all. On this basis, we'll continue to follow the data and the science. We'll continue to build the evidence, and we will guide the use of in HER2 and suggest the guidance of the use in HER2 based on the data that we have. And therefore, we will continue at this point to recommend the immunohistochemistry testing in accordance with the way that the trial was designed and if this regimen should be approved, we would absolutely call for use of a immunohistochemistry assay.

Just second very quick question regarding Dato. Dato-DXd is relatively in the competitive portion compared to HER2 at the moment. And we see some sort of the same sort of data generating from the SKB front. And also, there are some setback on the Trodelvy front. So can you give me a quick update on what your compared to...

Sorry, just to repeat the question. I heard your observations, I think about -- yes, thank you so much. I apologize that we lost you for a moment. I'd like to ask if you could repeat your question, I believe it had to do with the TROP2 landscape in non-small lung cancer. Could you please repeat?

Yes. So we see some kind of same sort of data generated from the SKB products. And also, there are some setback on the Trodelvy front. So competitive landscape on the TROP2 is getting complicated from our side. But how do you see this complicated? What is the -- what competitive advantage you have that in order to win this race, what is important from your side?

Yes. So I think one, I do see the competition, certainly, and we saw at this ASCO, we saw data from the SKB. We also did see the EVOKE-01 results. We know that several TROP2s are advancing into the pivotal trial setting, already advanced, but also advancing. I would say one key consideration, of course, would be operational efficiency and speed. And of course, we have -- between ourselves and AstraZeneca, we have 3 ongoing and studies have been on going for quite some time, but I think a temporary advantage then, events are conducted by our part and AstraZeneca also TROPION-Lung07, TROPION-Lung08. In addition to that, of course, we do now have a positive pivotal trial on TROPION-Lung01. We've issued a press release explained that there was a clinically meaningful overall survival in the non-squamous subgroup, and we do have a submission process and regulatory process there. So I think the first thing that we can say is that in terms of time, we are at this point a front-runner. I would also say, however, and I mean we certainly take the competition seriously, but we then would focus on the operational delivery. I think it would be critical for us to continue to advance our program and to be able to complete enrollment on these studies and read-out as possible. In addition to that, I would say that we do look at a translational program and biomarker program, certainly for the TROP2 -- for our TROP2 ADC Dato-DXd, our partner AstraZeneca, they can answer more questions on that than we can. But our partner AstraZeneca has announced they're focused on a TROP2 assay and TROP2 analytics for their program. And I think we will continue, as a partnership to continue to advance biomarker efforts in order to optimize benefit risk in order to promote the potential for differentiation. And I think in addition to that, I think it's important to remember that we do have a leading DXd technology. And we're very confident in that technology, of course, the linker payload system is shared by HER2 and is also shared by Dato-DXd. We're confident the data we produce so far by Dato-DXd. And we also want to point out that these drugs are actually different drugs as well. And we can probably see that as an example, when we look at the DXd technology versus as an example, Trodelvy, which is a different drug, SKB-264, which is a different drug. So I thought I'd mention that as well.

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

[Interpreted] I'm Hashiguchi. I have two questions. My first question is, in the ASCO meeting, clinical data were presented for TROP2 ADCs other than the DXd, and the data showed that there was no difference in efficacy between squamous versus non-squamous, multiple data sets indicated such results but it seems the antitumor effect of Dato-DXd in TL-01 study is limited to the non-squamous. How do you explain the result from your perspective.

And so it is true that the early data that we see with SKB-264 suggests similar efficacy across histology. In addition to that, we all -- many of us saw at ASCO, the presentation of the EVOKE-01 results, which of course, the trial was negative. But we [indiscernible] results. And within the subgroups, there were similar efficacy parameters and results across histologies. Now for Dato-DXd, as we've shown, as we've explained, as we presented and we've also communicated this in press release, there is differential pathology. At this point, we don't have a clear answer for that. However, we do see that this result is actually consistent even outside the TL-01 study, for instance, at this ASCO, there was the presentation of the ICARUS-LUNG01 study. This was an academically run study from Gustave Roussy. And this was in a very similar patient population, second-line plus of non-small cell lung cancer. And actually, the response rate separated, again, higher for non-squamous non-small cell lung cancer versus squamous. So even though we can't explain clearly the observation, we're working on it. And indeed, multiple hypotheses, I mean, could include, for instance, perhaps a differential sensitivity to our payload by histology. Perhaps there are a different rate of uptake of ADC in 1 histology versus another as example, but this is only conjecture. What I can tell you is these ADCs, as I've stated previously, are not the same. These are not the same drugs. And actually, you could probably see that in the performance of the EVOKE-01 trial. And I think it's important, though, however, that we continue to build the database, continue to investigate and understand, but I do think it's notable that the trend in efficacy according to histology is seen not only in TROPION-Lung01 but also outside TROPION-Lung01 with Dato-DXd.

[Interpreted] I have another question. In EVOKE-01 study for Trodelvy, in the group with the product PD-L1 antibody, is the NPD patients show higher efficacy? Is this trend observed with that Dato-DXd, do you have data? Would you indicate that?

So we did see that with the EVOKE-01 results and indeed, interesting finding, not sure what the biological rationale would be. But we do -- we actually don't have such data to share for Dato-DXd at this time.

The next question is from Wakao-san from JPMorgan.

This is Wakao from JPMorgan. First question about somatic reason for discussing of ultralow operation regarding D-B06. As you commented, you were gathering data, we'd like to know about the somatic factors in mechanism, which had to show the efficacy in ultralow as well. So I just [indiscernible] your hypothesis. And can this be considered bystander effect. And we'd like to know the potential of high to low and ultralow in other cancer types. If it's effective only for breast cancer, we'll be drafting this liaison? This is the first question.

So in terms of a rationale or an understanding of how an HER2 could be effective and consistently effective in HER2 low and ultralow, I think this really relates to this point to the DXd mechanism of action, our ADC mechanism of action and efficiency of that. And it is the case, it is an empirical observation, as long as patients had at least some HER2 expression that the antibody of HER2 and by to the receptor on the tumor cell, take up the ADC and cleave the payload and destroy the tumor cell. I do think and you alluded to that, I do think mechanistically, another component to this, which is logical, is the cell permeability of the DXd payload and its ability to promote a bystander effect, yes. So fundamentally, we believe it is the mechanism of action of our DXd technology, including its bystander effect and including to the efficiency, the mechanism of action could explain the efficacy in the HER2 low population. You also asked about other tumors. And I believe, maybe can you repeat that part? Do we see such a result in other tumors. Is that correct?

Yes. So do you have any plan to explore the ultralow, high to low potential for other tumor parts, for example, in PanTumor trial, something.

So we have published some data with lower HER2 expression and higher HER2 expression in diseases like, for instance, colorectal cancer. We have not published data with the ultralow population as we've done in metastatic breast cancer, hormone receptor positive, in these other tumors. In terms of plans to further assess ultralow population that lower HER2-expressing population in other tumors. We have not disclosed anything as soon as we would, we would let you know.

Second question about the -- regarding D-B06 chemotherapy report. In D-B06, chemotherapy has shown better efficacy compared to previous trial. For example, on Page 40, what you saw on this? Do you think that this result has any impact on the difference between chemotherapy and in HER2. This is second question.

Okay. Yes. I think you're referring to the chemotherapy on the D-B06 versus HER2. Is that correct?

Yes. It is right.

It's always very difficult to compare across clinical trials. And we just have to assume that the patient population we enrolled in non-clinical trial was somewhat different from those patients who had enrolled in the earlier clinical trials with chemotherapy in a similar line of therapy. But ultimately, it's really not the control and performance that really would be hazard ratio and a p-value that are very important for us when we interpret the D-B06 clinical trial data.

Okay. Understood. Finally, I'd like to know first-line potential for HER2 at low and with the ultralow settings. So we believe that the result of D-B06 will increase development in first-line. So how do you keep demand in D-B06 and I'd like to know what you currently think about the development strategy for first-line?

So fundamentally, I mean, we haven't announced a frontline study for an earlier line study in general in the hormone receptor positive HER2 or ultra low population. Of course, we do have the very extensive and comprehensive early line program DESTINY-Breast09 in the frontline, DESTINY-Breast05 in high risk adjuvant setting, DESTINY-Breast11 in the neo-adjuvant setting for the hormone receptor positive population. We are indeed discussing and are interested in earlier lines of therapy for the hormone receptor HER2 low population, but nothing to disclose just yet. But we're certainly thinking about it. We certainly want to optimize the use of in HER2. And we want to make sure that as much as possible, we can address unmet needs, including in early lines. So as soon as we have something to share, we will.

And I also want to add that we have other drugs actually that may be actually in a similar patient population. And I want to remind you of our other data program and PD-L1 as being an important data that we would like to be -- how do you think about. We have multiple drugs that are possibly available for frontline setting in hormone receptor positive cancers.

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

[Interpreted] Morgan Stanley, Muraoka speaking. On Page 23. There are PFS and OS chart in HER2 ultralow. And my question is about OS data, in short, it's a great data, around months 27, OS groups of the both arms dropped dramatically. What happened, please explain.

I think when you look at the KM curves for the ultralow population, it's important to remember that this is a 150 patient population, right? So it means that the sample size is lower. And therefore, the morphology of the curves can be a little bit less clear. And you'll notice in the study, there are still patients there who are censor. And so every time you see these little hatch marks in the KM curve, this represents a censored patients. So the bottom line is this data set is still immature. And I think about dropoff in the curves is a reflection there. And over time, we'll continue to follow these patients as the maturity increases, the curves will probably become more clear because there are a number of patients there who are still censored, that are still being followed for overall survival and that basically explains the morphology of the curves.

[Interpreted] Next question is regulatory related, future-oriented. Again, about D-B06, when D-B04 results were made available, they were so good that if the approval was given in an accelerated manner through the so-called real-time oncology review. Likewise, D-B06 results will pave a similar approval pathway. Is it a fair expectation?

I think it's a possibility. We have not yet a definitive yes or no on this question. So please wait for that decision. We'll announce that when we have information.

The next question is from Mamegano-san from BofA.

[Interpreted] This is Mamegano from BofA Securities. Again, about D-B06. Very impressive data, congratulations. My question is about OS. The company is headed toward OS. For testing alpha is defined as 3.5%. And you will continue following up for OS. Is it okay, even if OS is not significant? Second line and after means crossover within HER2. It's significant, of course, it's better. Even if OS is not significant, is it still not a problem? Please tell me?

So indeed, overall survival is immature, and we said 40%. And the way that we're characterizing the data is it requires more follow-up but there is an early trend. As you pointed out, there is some crossover. It's hard for us to predict based on the accrual of additional events and the proportion of the crossover over time, exactly sort of what will happen to the overall survival and how it will evolve. But we do think these results are encouraging, and we will continue to follow them up and report the updated results as soon as we can. You asked, I think, without overall survival statistical significance, should overall survival not achieved statistical significance, would this be a problem? I think you asked. So of course, this would be a question for the regulatory agency to decide. However, my precedence, in the earlier lines of the metastatic breast cancer, we believe that progression-free survival is a very important representation and endpoint of -- for demonstrating clinical benefits. So hard for us to say exactly how the regulatory agency will consider the overall survival, but we believe the data that exists today, including with the immature overall survival, represents a positive benefit risk profile and has the potential to change clinical practice.

[Interpreted] Next question is also about D-B06, particularly adverse reactions. There were 5 grade 5 events reported. This is post endocrine therapy setting, and so less lenience about side effects. More AEs means less acceptable to my understanding. It is a treatment line earlier than D-B04, people might have stronger concerns about the side effects. It seems to me this is troublesome. With this D-B06 result, how much market share does this antibody can earn according to your estimate with this safety profile, what percentage of market share does this ADC can take?

Yes. So first of all, I would say, based on the results that they're taking with the safety profile that's consistent with what we know about in HER2 and no new safety signals. That in association with what is a very clinically meaningful PFS result in this population, with a delta of 5 months and median progression free survival that exceeds a year. We believe it's a favorable benefit risk profile in this study. We believe if the regimen is approved, but it would be an important potential regimen for patients to address an unmet medical need. And we've also explained in the presentation of D-B06, we've showed what the efficacy results historically, with some of the standard of care. So we think this regimen has the potential to address an unmet clinical need. Now in terms of projecting market share and uptake, I think it's very difficult for us to conjecture. Indeed, I could only guess. But I would say, based on what we've seen within HER2 and other settings, both HER2-positive and also in the hormone receptor positive later setting, I believe we would expect if the regimen is approved, I believe we would be expecting a significant uptake. I'm not able to conjecture and to guess on quantification.

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

[Interpreted] This is Wada from SMBC Nikko. Because we are running out of time, I will ask only one question. It is about Page 14, perhaps. It is about diagnosis. Let's assume the drug is approved to treat the HER2 ultralow population based on the results of D-B06, and diagnosis is well established. According to you, HER2 low and HER2 ultralow accounts for 80% to 90% of HER2-negative population. The remaining 10% is HER2 0 patients. As the diagnosis become more precise, HER2 0 population will be smaller? In other words, the drug will be used for a larger number of patients. IHC 0 patients are being studied in D-B15 study. Please explain the company's strategy.

So I think in terms of your assessment of the prevalence of HER2 absolute 0 versus our HER2 ultralow, you may be correct, that there is an under-diagnosis of our HER2 ultralow because up until now, for the breast cancer pathologist, it was not important to make a distinction between HER2 0 versus HER2 ultralow. And I remind you that ultralow definition can include any patient with any trace staining in the tumor field. So it may be that what you're suggesting is correct. That brings an under-diagnosed patient population. Having said that, I think we, as a company, need to formally prove that there's activity or not in the HER2 0 patient population. That's really the reason of the reasons why we're conducting this additional study D-B15.

The final question is from Sogi-san from Sanford Bernstein.

I have three. So first of all, regarding the ENHERTU of the D-B07 study, so this is the first line HER2 positive. So actually, if you look at the response rate, this is pretty similar to CLEOPATRA data of, you know Perjeta, Herceptin and the chemo. But if you look at the PFS rate at 12 months, it's quite encouraging for the ENHERTU. So in terms of prediction what's going to happen, the ongoing Phase III for the setting. Should we actually rather look at this PFS rate at 12 months rather than the overall objective response rate.

I mean I think the DESTINY-Breast07 trial is a Phase Ib and it is in interim analysis, and I think there's more data to come. I think it is the totality of the data. So I mean, we see response rates, I mean 76% to 84%, and as you say, progression-free survival rates are encouraging DESTINY-Breast07. But I think we would also consider as well what I showed for DESTINY-Breast03 because the progression, the median progression free survival in this descriptive follow-up analysis with the hazard ratio of 0.3 in DESTINY-Breast03 for progression-free survival. The median PFS there is, I believe, 29 months and the median PFS for CLEOPATRA, of course, it is a cross-trial comparison with many caveats, but the median PFS for CLEOPATRA historically is 18.7 months. So I think when we consider the response rates that we see in DESTINY-Breast07, when we can see the evidence of durability in the form of that early progression-free survival rates that you referred to and what we consider the median PFS in the second-line plus setting of HER2-positive metastatic breast cancer of approximately 29 months in DESTINY-Breast03, we think that this data overall is supportive of DESTINY-Breast09. Of course, we can never project the results of the pivotal trial. But we are encouraged by the DESTINY-Breast07 and DESTINY-Breast03 results and we think they're supportive of DESTINY-Breast09.

So second question is T-L02 for Dato. This is the first line in non-small cell lung cancer in combination is pembro plus minus in the platinum. And so in terms of -- the response rate is quite encouraging when compared against the KEYTRUDA trials. However, the AE related discontinuation rate is significantly higher. So I think always the question is this study, the ongoing the T-L07, 08 may hit a positive in terms of efficacy, but always when it comes to actual clinical use in the safety might be the question. So what is your view on this?

So safety is certainly important. And I think we're always learning, of course. Now when we design the protocols and the pivotal trial protocols for T-L07, T-L08 is an example, we take great care in design and dose modification criteria. Of course, we also have a close surveillance of the safety, and indeed, I mean, with what we have in terms of dose modification criteria and training and guidance for investigators, we feel encouraged by the conduct of the studies in Dato-DXd in frontline non-small cell lung cancer, and we learn, of course, from the early phase study, including, as you referred to, the TROPION-Lung02. So overall, we think the TROPION-Lung02 data suggests the Dato does have potential in the frontline setting, and we believe is supportive, including the ability to have a potentially favorable benefit risk profile and a tolerable regimen in the frontline setting.

A high level question. So on the -- including D-B06, now you started having those Phase III trials with the PFS as a primary endpoint or PFS or OS as a dual endpoint rather than more conventional PFS, OS co-primary endpoint. When do you see on the strategic and also scientific background of this.

So you're asking in general why we might have a sole primary endpoint versus a dual primary endpoint? Is that your question?

No, versus -- rather than dosing a sole, dual, versus, co and primary endpoint.

Yes, right. So in our trials, we either have a single primary endpoint or a dual primary endpoint. So dual primary endpoint is when either one can be positive and then have a positive study as opposed to co and both have to be positive, actually to have a positive study. So we do look at both single primary endpoints and dual primary end points. And there are multiple considerations. I mean, first of all, we consider the disease state and the expectation of what might be the most important regulatory endpoint as an example. In addition to that, we might consider the timing of readout of the endpoints where progression-free survival might read out earlier as an example, an overall survival. And so we take multiple considerations, look at different study designs, which has an impact on the timing of our endpoint results, our interim analyses. Also, we have discussions with regulatory agencies about the most appropriate endpoint structure. So I'm not sure we can say that there is a one size fits all to our approach, depending on the disease, depending on the line of therapy, depending on regulatory feedback, we might consider having a single primary endpoint or having a dual primary endpoint.

So I understand that probably you have already pre-aligned -- been broadly pre-aligned with the regulators the primary endpoint. But there's always a question of the -- even for those study with the sole primary endpoint, so what about the overall survival. So the how -- what is the current -- the sort of state of mind of regulators on this the PFS only versus in the end, they also want to see the OS positivity.

Again, it clearly depends on the disease setting completely because if you have like a very earlier line, let's say, in certain disease states, like breast cancer, colorectal cancer, right? Maybe overall survival may be historically more difficult to demonstrate and so maybe they'd be more of a potential to look at the PFS endpoint, but it really does depend on the disease state. And just to mention also that you can still look at overall survival in the context of a single primary endpoint of overall survival, where the statistical power is placed on an endpoint, but you can also look at overall survival in what we call hierarchy -- sorry, if you can have overall survival in a dual primary endpoint structure, so it's always the primary endpoint in the dual endpoint structure with PFS or in addition to that, you could test overall survival and hierarchy. So what I mean by that is you can have a PFS primary endpoint and if that is positive, then you can test the overall survival. So having a primary PFS endpoint doesn't rule out your ability to show a statistically significant overall survival. I just wanted to point that out that you could look for statistical significance of overall survival, either when overall survival is the sole primary endpoint or the PFS is the primary endpoint and then you're able to test overall survivals of significance hierarchically if PFS is positive. I hope that helps explain as well.

Thank you, everybody. We'll now conclude Daiichi Sankyo's ASCO 2024 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.]