Hello, colleagues. My name is Hiroyuki Okazawa, 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 Enhertu today. Two years ago, we presented DESTINY-Breast04 study data here at ASCO, which revealed that Enhertu could contribute to breast cancer patients who were previously categorized as HER2 negative. Based on the outcome from the study, Enhertu pioneered a new patient segment, HER2-low breast cancer. Furthermore, yesterday, we presented data from DESTINY-Breast06 study, which expands the treatment opportunity for Enhertu to earlier line of HER2-low breast cancer, and moreover, to HER2-ultralow 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 will hand over to Ken Takeshita, and we take you through our strategies around breast and lung cancers.
Thank you very much for that introduction, and 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. We want to, today, especially highlight a lot of progress we have made in our breast cancer program with our flagship drug, Enhertu, and also substantial progress that we have made in our lung cancer program, with both our Enhertu program, the DESTINY series of trials, and our TROP2 ADC program, the TROPION series of 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'll be focusing especially on three different trials, DB, DESTINY-Breast06 , DESTINY-Breast07 , and DESTINY-Breast03 . And particularly notable is the clinical trial that was previously mentioned by Okazawa-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 two 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 of the 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 is, that, our Dato program. We also have, however, have in our, in our program in lung cancer, in orange, is Enhertu. Green is the, our HER3-directed ADC program. And finally, at the bottom in yellow is the, the I-DXd program, with, 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-Lung02 . Next slide.
And finally, I do want to alert you to a new clinical trial that we are going to be conducting called TROPION-Lung15. This is a new phase 3 study in second-line EGFR-mutated non-small cell lung cancer for our Dato program, in which the Dato, with or without osimertinib, is compared to platinum-based doublet chemotherapy who have received at least 2 prior lines of EGFR TKI treatments. So this is a new study that has already appeared on ClinicalTrials.gov, and you can see the details there. The study is planned to be started in fiscal year 2024, in the first half. Primary endpoints and secondary endpoints 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. Mark?
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 dataset, and I'm very excited to present this today, is DESTINY-Breast06, and this is a study of trastuzumab deruxtecan in HER2-low and HER2-ultralow metastatic breast cancer. And the exciting aspects of this data is the ability, again, of Enhertu to demonstrate the potential to change the way that 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. Specifically, this study were in patients who are chemotherapy naive, whereas DESTINY-Breast04 had patients that had received 1-2 prior lines of chemotherapy. In addition, including HER2-ultralo w, 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. We can see on the left that 60%-65% of that population of hormone receptor-positive, HER2 negative patients is HER2-low, and then with the ultra-low population, and we'll explain what that means in a moment, an additional 20-25 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 one endocrine-based therapy, with results consistent in the HER2-ultralow population. Next, please. This slide portrays the unmet medical need in this 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 have received endocrine monotherapy, they would have only an even less clinical outcome, demonstrating a significant unmet medical need in the patient population studied 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 ultra-low 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+, ISH 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 two prior lines of endocrine therapy, with or without targeted therapy, or one line of endocrine therapy for metastatic breast cancer and progression within six 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 endpoint 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-low and ultra-low patients. Then also overall survival in the HER2-low population and overall survival in the intent to treat population. Next, please. Here is the patient disposition.
You can see that 436 patients were included in the T-DXd group and 430 in the chemotherapy 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 a few, 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 are. 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 two prior lines of endocrine therapy. The majority of patients had received two prior lines, and only a minority had received one prior line or greater than three. As I mentioned before, approximately 90% of patients had received prior endocrine therapy with CDK 4/6 inhibition. As alluded to in the earlier slides, this patient population, therefore, 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 0.62, clear and sustained separation of the curves. If we move to the next slide, please. This is progression-free survival in the intent-to-treat population. This is a secondary endpoint, and as a reminder, this includes patients who are HER2-low and ultra-low. A very similar, statistically significant and clinically meaningful result was achieved in the ITT population as well. Here again, a median delta in 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-low population. We show on the right overall survival in ITT, which includes HER2-low and HER2-ultralow. What you can see on the slide and the title is this is approximately 40% 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. This did not cross the threshold for statistical significance, but certainly represents an early trend. 20% of patients in the chemotherapy group did receive T-DXd post-discontinuation. On the right, a very similar result. Early trend for overall survival with separation of the curves.
Hazard ratio 0.81, and approximately 18% of patients in the ITT control group with chemotherapy received T-DXd post-treatment discontinuation. So overall, immature, but overall survival and not statistically significant, but headed in the right direction. Next slide, please. Here are the results in the ultra-low population. This population represents 152 patients in total, and this was a pre-specified exploratory analysis, these efficacy analyses. As a reminder, the HER2-ultral ow population is part of the intent-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 in PFS of approximately 5 months, 13.2 versus 8.3 months. And the overall survival on the right, again, an early trend.
The Kaplan-Meier curves are less clear because of the sample size here of this subgroup, but you can see there is separation, and the 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 the intent to treat, which encompasses HER2-low and ultra low, 57.3% versus 31.2%, and in the ultra low, 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 this safety summary, that T-DXd was overall well tolerated. There were modestly higher increases of grade 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.
The most common AEs associated with dose reduction included nausea for T-DXd and a type of rash for chemotherapy. If we would 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 the adverse events of special interest. We know that adjudicated drug-related 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 two at 8.3%. For example, there were three grade three events, 0.7%, and there were three grade five events, 0.7%. Considering these results, we believe these are consistent with what would have been seen with T-DXd in breast cancer. If we look to the bottom, left ventricular dysfunction, there were three events of grade three ejection fraction decreased in the T-DXd arm and one 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 ultra-low population consistent with those in HER2-low, and the confirmed overall response rate was 57% with T-DXd versus close to 31% with 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 establish T-DXd as an effective new treatment option for patients with hormone receptor- positive, HER2-low and ultra-low metastatic breast cancer following at least one line of endocrine-based therapy. And so overall, and as stated at the outset of 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 we're gonna turn to HER2-positive metastatic breast cancer, and we're gonna 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. Here, if we move to the next slide, we see updated efficacy results for both progression-free survival and overall survival. This includes overall survival at greater than three years of follow-up. We'll start with overall survival and the result. At this point, with this analysis, what we can see is the median overall survival has been reached. There are no tests of statistical significance for either endpoint because the study has already resulted in 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 curves 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 two treatment arms. There were modestly higher rates of serious drug-related AEs.
There were higher rates and of adverse events associated with dose, dose reduction and discontinuation, and perhaps, wouldn't be a surprise that there would, there would be a difference in some of these rates, especially over time. 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 efficacy and the safety with 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 1b 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, the first-line therapy in this setting or frontline HER2 metastatic breast cancer is THP. That's trastuzumab, pertuzumab, and also taxane. Based on the CLEOPATRA study, which reported a median PFS of 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 1b study, DESTINY-Breast07, presents the first data set of first-line T-DXd, with or without pertuzumab, in the frontline 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 two 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 endpoints. And so for this interim analysis, we'll look at data from the Module 0 and the Module 2 of this phase 1b/2 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%-40% of patients, depending on which arm you look, who were recurrent. And you can see on the right, the prior treatments that they had received, including prior 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 due to adverse event in the combination arm compared to the monotherapy arm. And there was 24-25 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 that 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 for the combination 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 CAM 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. 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 or grades greater than or equal to 3 adverse events in the combination arm. Also, interruptions in addition to discontinuation. There were no Grade 4 or 5 ILD events. We can see down bottom on the left table, there was one 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. 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 two diarrhea in the combination arm compared to the monotherapy arm. There was one 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 at 12 months, but they're listed here.
In addition to that, the majority of patients in both arm 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. Importantly, this data set supports the ongoing global phase 3 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 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 that 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-to-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 one prior anticancer therapy, so really second line plus. 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 is 56%. And here again, 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 survivals there and the curves. They overlap to a great extent.
The median in the 5.4 lower dose arm was 19 months. The median in the higher dose arm was 17.3 months. So overall, very robust clinical benefit, despite either dose or at both doses. But 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 for various adverse event categories that for 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 for the higher dose at 6.4 compared to the lower dose at 5.4.
There was one drug-related interstitial lung disease event leading to death in either arm. So overall, when considering the efficacy, comparability across the two 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, at which patients received less than or equal to two lines of prior therapy, and then it went into a dose expansion phase.
And in that phase, patients received one or fewer lines, less than or equal to one line, of prior 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, this study explored 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, of the frontline subgroup, the 1L subgroup, 42 patients in the doublet arm, 54 patients in the triplet arm. What you can see, the majority of patients had adenocarcinoma, the minority squamous, and this is typical and consistent with the patient population.
What I want to point out, especially at the bottom of the s- of the table, is the PD-L1 expression. Because 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% in the doublet arm, 30% in the triplet arm, 1%-49%, 45% versus 43%. And only a minority of patients had PD-L1 greater than or equal to 50%. And I mention this because I think it helps us characterize some of the response rates that we see. So on the next slide, please. So here you can see subgroup analyses.
First thing you'll observe on the left, on the left column, is in the doublet, in the frontline setting there, overall response rate of 52% and, durable responses, with 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, in particular 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 that there are 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 is the safety summaries. You can see on the upper left, the rates of grade greater than or equal to three. 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, 12% in the doublet, 22% in the triplet. There were discontinuations as well. Dato-DXd discontinuations, 21% in 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 three events. In terms of adjudicated drug-related ILD, you can see all grades of 24% and 26% respectively. There were no grade four or five ILD events, and there were 2 grade three ILD events with a doublet and 1 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, and significant, response rates, as well as durability and manageable safety profile. And these data support the ongoing, frontline pivotal trials, of, of Dato-DXd with pembrolizumab, TROPION-Lung08, in the 50% and higher PD-L1 population, and, TROPION-Lung0 7. So Dato-DXd, plus, pembro, you know, 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. Thank you.
Please raise hand if you have questions. The first question is from Yamaguchi-san from Citi.
Hello, can you hear me?
Yes.
Oh, great. Thank you. Thank you for taking my questions. So this is Yamaguchi from Citi. First question regarding DB06. Did you have any kind of preview or pre-expectation on what kind of data is expected for Enhertu? And I was surprised to find out there are ultra low and low are almost the same, but are you surprised as well or not? Thank you, the last one.
So thank you for this question. I believe we had relatively high expectations for DESTINY-Breast06, based on the results of DESTINY-Breast04. What we can see so far, you know, within HER2, is the ability to demonstrate efficacy and transform our results in different lines of current therapy and across lines of therapy. Now we've moved, in HER2, into an earlier line of hormone receptor- positive disease. We had high expectations, certainly, you know, for the HER2-low population. Now, when it comes to the ultra low population, the consistency of the results across HER2-low and ultra low 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 a dataset produced by a group in France and with the Hospital of Gustave Roussy, 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 Enhertu to demonstrate efficacy across a range of HER2 expressions in hormone receptor-positive patients, including that HER2-ultralow population, which has not been historically considered a candidate for HER2-targeted therapy. So overall, I do think the consistency between the two patient populations is remarkable.
However, we did have proof of concept, and therefore, have expectation based on both the DB-04 results and the DAISY results to address these two 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.
Thank you. A quick follow-up, which was discussed at the conference as well, is that, because it is relatively difficult to diagnose ultra low from the pathologist's point of view, and it already covered 80% of the patients, do we still need to make a HER2 diagnostics or not in the future?
Thank you for this additional question. Indeed, there was, and of course, I was at that discussion as well, at the conference around the pathological assessment of the ultra low. I would point out that Daiichi Sankyo and our partner AstraZeneca we do have experience 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, 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. Now, you also asked the question, whether or not we think there'll come to a time that no HER2 IHC testing is required. Also, at this point, I believe what we would say is we, we would follow the evidence.
So to date, what we can see is that Enhertu 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 Enhertu 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 will continue to build the evidence, and we will guide the use of Enhertu and suggest the guidance of the use of Enhertu based on the data that we have. Therefore, we would continue, at this point, to recommend the immunohistochemistry testing in accordance with the way that the trial was designed.
If this regimen should be approved, we would absolutely call for use of a immunohistochemistry assay.
Great. Thank you. The second very quick question on regarding Dato-DXd. Dato-DXd is relatively in the competitive position compared to Enhertu at the moment, and we see some sort of a same sort of data generating from the SKB front, and also there are some setback on the therapy front. So can you give me a quick update on what your competitive landscape on that?
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 cell lung cancer. Could you please repeat?
Yes. So we see some kind of same sort of data generated from the SKB product, and also there are some setback on the therapy front. So competitive landscape on the Trop2 is getting complicated from our side, but how do you see this competitive, what, what is the, what are your competitive advantage you have? You have it, but, in order to, to win this race, what, what is important from your side? Thank you.
Yeah, so I, I think one, I do see the competition, certainly, and we saw it this ASCO. We saw data from the SKB. We also did see, you know, the EVOKE-01 results. We know that, you know, several Trop-2s 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 the studies have been ongoing for quite some time, with, I think, a temporal advantage then. AVANZAR, conducted by our partner AstraZeneca, also TROPION-Lung07 and TROPION-Lung08. In addition to that, of course, we do now have a positive pivotal trial in TROPION-Lung01.
We've issued a press release explaining that there was a clinically meaningful overall survival in the non-squamous subgroup, and we do have a submission process and a 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 that would be critical for us to continue to advance our program and to be able to complete enrollment in these studies and read out as soon as possible.
In addition to that, I would say that we do look at a translational program and a biomarker program, certainly, for the TROP2, for our TROP2 ADC, Dato-DXd. Our partner, AstraZeneca, and they can answer more questions of that than we can, but our partner, AstraZeneca, has announced, you know, they're focused on, a TROP2 assay, and TROP2 analytics, you know, 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.
Great. Thank you. Sorry for weak Wi-Fi. Thanks.
Yeah, and I think, you know, 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 Enhertu, is also shared by Dato-DXd. We're confident in the data that we've produced so far by Dato-DXd, and we also wanna point out that these, these drugs are actually different drugs as well. And we can probably see that, you know, as an example, you know, 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. Thank you.
Sure. Thank you very much.
The next question is from Hashiguchi-san, from Daiwa Securities .
I am Hashiguchi. I have two questions. My first question is, in the ASCO meeting, clinical data were presented for Trop-2 ADCs other than the DXd, and the data showed that there was no difference in efficacy between squamous versus non-squamous. Multiple datasets indicated such results, but it seems the antitumor effect of Dato-DXd in TROPION-Lung01 study is limited to the non-squamous. How do you explain the result from your perspective?
So, thank you for the question. And so, it is true that the early data that we see with SKB-264, you know, suggests a 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 you did 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've presented, and we've also communicated via this 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 TL01 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 rates 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, perhaps, differential sensitivity to our payload by histology. Perhaps there are a different rate of uptake of ADC in one 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. I think, I think it's important, though, however, that we continue to build the database, continue to investigate and understand, but I do think it is notable that the trend in efficacy according to histology is seen not only in TROPION-Lung01, but also outside TROPION-Lung01 with Dato-DXd.
... Thank you. I have another question. In EVOKE-01 study for Trodelvy, in the group with the prior PD-L1 antibody , SD and PD patients show higher efficacy. Is this trend observed with Dato-DXd? Do you have data which indicates 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.
Thank you very much, Ijo de su.
The next question is from Wakao-san, from J.P. Morgan.
Hi, thank you for taking my question. This is Wakao from J.P. Morgan. First question about the scientific reason for the efficacy of ultra-low population regarding DB-06. So as you commented, you are gathering the data. We'd like to know about the scientific factors and mechanism which Enhertu show the efficacy in ultra low as well. So I'd like to know your hypothesis, and can this be considered as bystander effect? And we'd like to know the potential of HER2-low and ultra-low in other cancer types. If it's effective only for breast cancer, we'd like to know this reason. Thank you. This is the first question.
Yes. So, in terms of a rationale or an understanding of how Enhertu could be effective and consistently effective in HER2-low and ultra-low, I think this really relates to this point, to the DXd mechanism of action, our ADC mechanism of action, and the efficiency of that. And it is the case, it is an empirical observation, that as long as patients have at least some HER2 expression, that the antibody of Enhertu can bind 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 the efficiency of the mechanism of action, that could explain the efficacy in the HER2-low population. Now, 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 ultra-low HER2 HER2-low potential for other tumor types, for example, in pan-tumor trial or 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 ultra-low population, as we've done in metastatic breast cancer, hormone receptor- positive in these other tumors. In terms of plans to further assess ultra-low population, that lower HER2 expressing population in other tumors, we have not disclosed anything. As soon as we would, we would let you know.
Okay, thank you. Second question about, regarding, DB-06, chemo, chemotherapy cohort. In DB, DB-06, chemotherapy has shown better efficacy compared to previous trial. For example, on page 40, what's your thought on this? Do you think that this result has any impact on the difference between chemotherapy and Enhertu? This is second question.
Yes, sorry, can you? Oh, okay.
Yeah, I think you're referring to the chemotherapy arm in DB-06 versus controls. Is that correct?
Yes, that's right.
Yes. Okay. And, you know, it's always very difficult to compare across clinical trials, and we just have to assume that the patient population we enrolled in our 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, you know, ultimately, it's really not the control on performance, but really the hazard ratio and the P value that are very important for us when we interpret the DB-06 clinical trial data.
Okay, understood. Finally, I'd like to know first-line potential for Enhertu, HER2-low and ultra-low settings. So we believe that the result of DB-06 will encourage development in first line, so earlier treatment on DB-06 . I'd like to know what you currently think about the development strategy for first line.
Yeah. So fundamentally, I mean, we haven't announced, a, a front-line study, or an earlier line study in general, in the hormone receptor-positive HER2-low or ultra-low population. Of course, we do have the, very extensive and comprehensive, early line program, DESTINY-Breast09, in the front line, DESTINY-Breast05 in high-risk adjuvant setting, DESTINY-Breast11 in the neoadjuvant setting for the hormone receptor-positive population. We are indeed discussing and are interested in earlier lines of therapy for the hormone receptor HER2, HER2-low, population, but nothing, nothing to disclose, just yet. But we're certainly thinking about it. We certainly want to optimize, the use of Enhertu, and we wanna make sure that as much as possible, we can address, we can address unmet needs, including in earlier lines.
So as soon as we have something to share, we will.
I also want to add that we have other drugs actually that is maybe active in a similar patient population. And I want to remind you of our other Dato program in TROPION-Breast01 as being an important Dato that we would like to have you think about. We have multiple drugs that are possibly available for front-line setting in hormone receptor- positive cancers.
Okay, understood. Thank you.
The next question is from Muraoka-san from Morgan Stanley.
Good morning, Morgan Stanley, Muraoka speaking. Thank you for taking my questions. On page 23, there are PFS and OS charts in HER2-ultralow, and my question is about OS data. In short, it's a great data. Around months 27, OS curves of the both arms dropped dramatically. What happened? Please explain.
Yes, so thank you for the question. 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, you know, in the study, there are still patients there, you know, who are censored. And so every time you see these little hash marks on the KM curve, this represents, you know, a censored patient. So the bottom line is this data set is still immature, and I think that drop-off in the curves is a reflection there.
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 up for overall survival. And that basically explains the morphology of the curves.
Thank you. Next question is regulatory related, future-oriented, again, about DB-06. When DB-04 results were made available, they were so good that FDA approval was given in an accelerated manner through the so-called Real-Time Oncology Rev iew. Likewise, DB-06 results will pave a similar approval pathway. Is it a fair expectation?
I think it's a possibility. We have not yet had a definitive yes or no on this question, so please wait for that decision. We'll announce that when we have the information.
Understood. Thank you. That's all from me.
The next question is from Mamegou-san, from BofA.
This is Mamegou from BofA Securities. Hello, can you hear me?
Yes.
Again, about DB-06. Very impressive data. Congratulations. My question is about OS. The company's attitude 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. If significant, of course, it's better. Even if OS is not significant, is it still not a problem? Please tell me.
Yes, 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 achieve 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, by precedent, in the earlier lines of the metastatic breast cancer, we believe that progression-free survival is a very important representation and endpoint for demonstrating clinical benefit. 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 it has the potential to change the clinical practice.
Thank you. Next question is also about DB-06 , 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 DB-04 . People might behave stronger concerns about the side effects. It seems to me this is troublesome. With this DB-06 study 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?
Yeah. So first of all, I would say, based on the results as they're taken, 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 the study. We believe that if the regimen is approved, that it would be an important potential regimen for patients to address an unmet medical need. And we've also explained in the presentation of DB-06, we've showed, you know, what the efficacy results historically, you know, 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, you know, for us to conjecture. Indeed, I could only guess. But I would say, based on what we've seen with Enhertu in other settings, both HER2-positive and also in the hormone receptor-positive later setting, I believe we would expect, if the regimen is approved, we would be expecting a significant uptake. I'm not able to conjecture and to guess upon a quantification.
Thank you.
The next question is from Wada-san, from SMBC Nikko.
This is Wada from SMBC Nikko. Can you hear me?
Yes.
Thank you. 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 that drug is approved to treat the HER2-ultralow population based on the results of DB-06, and diagnosis is well established. According to you, HER2-low and HER2-ultralow accounts for 80%-90% of HER2-negative population. The remaining 10% is HER2-zero patients. As the diagnosis become more precise, HER2-zero population will be smaller. In other words, the drug will be used for a larger number of patients. IHC-zero patients are being studied in DB-15 study. Please explain the company's strategy.
Yeah, so I think in terms of your assessment of the prevalence of HER2 absolute zero versus or HER2-ultralow, you may be correct that there is an under-diagnosis of all HER2-ultralow, because up until now, for the breast cancer pathologist, it was not important to make a distinction between HER2- zero versus HER2-ultralow. And I remind you that the ultra low definition can include any patient with any trace staining in a tumor field. So it may be that what you're suggesting is correct, that it's an underdiagnosed patient population. Having said that, I think we, as a company, need to formally prove that there's activity or not in the HER2- zero patient population, and that's really the reason, one of the reasons why we're conducting this additional study, DB-15 .
I understood. Thank you.
The final question is from Sogi-san from Sanford C. Bernstein.
Thank you for taking my question. I have three. So first of all, regarding the Enhertu, the DESTINY-Breast07 study. So this is the first-line HER2-positive. So actually, if you look at the response rate, this is pretty similar to, you know, CLEOPATRA data of, you know, Perjeta and, you know, the Herceptin and the chemo. But if you look at the PFS rate at 12 months, it's quite encouraging for the Enhertu. So, you know, in terms of, you know, predicting what's going to happen, you know, the ongoing phase 3 study for this setting, should we actually rather look at this in a PFS rate at 12 months, rather than, you know, the overall objective response rate?
Yeah. So, thank you for the question. I mean, I think the DESTINY-Breast07 trial is a phase 1b, and it, and it's an interim analysis, and I think, you know, there's more data to come. I think it is the totality of the data. So I mean, we see, we see response rates, I mean, 76%-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 median progression-free survival in this descriptive follow-up analysis, with the hazard ratio 0.3 in breast, in DESTINY-Breast03 for progression-free survival, the median PFS there is, I believe, 29 months.
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 when 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 the DESTINY-Breast03 results, and we think they're supportive of DESTINY-Breast09.
Great. Thank you very much. So second question is TROPION-Lung02 for Dato-DXd. This is the first-line, non-small cell lung cancer in combination with pembro plus minus platinum. And so in terms of, you know, the response rate, you know, it's quite encouraging when compared against the Keytruda trials. However, you know, the AE-related discontinuation rate is significantly higher. So I think always the question is this study, you know, the ongoing TROPION-Lung07, Lung08 may, you know, hit in a positive in terms of efficacy, but always, you know, when it comes to actual clinical use, you know, the safety might be in question. So what is your view on this?
Oh, so safety is certainly important, and I think, you know, we're always learning, of course. Now, when we design the protocols and the pivotal trial protocols for TROPION-Lung07 and TROPION-Lung08 as an example, we take great care in designing 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 of 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.
Overall, we think the TROPION-Lung02 data suggests that Dato-DXd does have potential in the frontline setting. 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, you know, the including DB-06, now you started having, you know, those phase 3 trials with the PFS as a primary endpoint, or PFS, or OS as a dual endpoint rather than more conventional, you know, the PFS OS co-primary endpoint. What is, yeah, 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, you know, those, you know, the sole, dual, versus co and co primary endpoints.
Yeah. So, right. So, in our trials, we either have a single primary endpoint or a dual primary endpoint. So a dual primary endpoint is when either one can be positive and then have a positive study, as opposed to when both have to be positive actually to have a positive study. So we do look at both single primary endpoints and dual primary endpoints, 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, you know, we might consider the timing of readout of the endpoints, where progression-free survival might read out earlier, as an example, than overall survival.
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, you know, so that probably, you know, you have already pre-aligned with, you know, broadly, pre-aligned with the regulators, you know, the primary endpoint. But there's always question of, you know, that even though, you know, for those study with the sole primary endpoint, so what about in the overall survival? So, you know, What is the current, the sort of state of mind of regulators on this, you know, the PFS only versus, you know, in the end, they also want to see the OS positivity?
Yeah, again, I think, here, it depends on the disease setting completely. Because, you know, if you have, like, a very earlier line, let's say, in certain disease states, like breast cancer or colorectal cancer, right? There may be, maybe, overall survival may be historically more difficult to demonstrate. And so maybe there'd be more of a potential to look at the PFS endpoint. But it really does depend on the disease state. And, you know, just to mention also that you can still look at overall survival in the context, you know, of a single primary endpoint of overall survival, where, the statistical power is placed on that endpoint. But you could 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 could have a PFS primary endpoint, and if that is positive, then you can test the overall survivals. 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 if PFS is the primary endpoint, and then you're able to test overall survival for significance hierarchically, if PFS is positive. I hope that helps explain as well.
Thank you.
Yes, very much so. Thank you very much.
Thank you, everybody. We'll now conclude Daiichi Sankyo's ASCO 2024 highlights. Thank you very much for joining today.