Merck & Co., Inc. (MRK) Earnings Call Transcript & Summary

Good evening, everyone. Welcome to the investor event of Merck & Company, Inc. [indiscernible], New Jersey U.S.A. at the European Society of Medical Oncology Annual Meeting. Thank you to all of you who've made the effort to be with us here in Madrid, and thank you to everyone tuning in via the webcast. We're obviously, very excited to have this opportunity to speak to you about the data that was presented this weekend in our oncology program. So during today's call, a slide presentation will accompany our speakers' prepared remarks and has been posted to the Investor Relations section of our website. And before we get started, we'd like to remind you that some of the statements that we make during today's call may be considered forward-looking statements within the meaning of the safe harbor provision of the U.S. Private Securities Litigation Reform Act of 1995. Such statements are made based on the current beliefs of our company's management and are subject to significant risks and uncertainties. If our underlying assumptions prove inaccurate or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Please reference this slide in our presentation and our 2025 10-K, which identify certain risk factors and cautionary statements. So again, thank you for coming tonight. Dr. Eliav Barr, Senior Vice President and Head of Global Clinical Development and Chief Medical Officer, will begin our program with opening remarks. And then Dr. Marjorie Green, Senior Vice President and Head of Oncology, Global Clinical Development, will provide an overview of the key data updates we presented at ESMO. Eliya will then return with a few closing remarks before we get to all of your Q&A. And with that, I'm happy to turn it over to Eliav.

Sorry, it's a bit rickety up here. All right. Well, thank you, Peter, and thanks to all of you for joining us. It's a real pleasure to be here at ESMO and to have a discussion on the ongoing progress of our oncology portfolio. This has been a really amazing tremendous ESMO for our company. We've had 3 presidential symposium presentations that I think, in many ways, reflect the way in which we've been working to accomplish to accomplish across the oncology portfolio. And before Marjorie reviews the individual data sets, I'd like to take a step back and put them in context of that broader strategy. Now as many of you know, in 2021, we outlined 2 strategic objectives to sustain durable leadership in oncology. First, we sought to maximize the impact of KEYTRUDA and continue to move into earlier stages of disease, where we believe we have the greatest impact on long-term patient outcomes. We also committed to diversifying our oncology pipeline with innovative investigational candidates with novel mechanisms. And these objectives continue to guide our oncology strategy today. Now over the last several years, we've expanded KEYTRUDA's impact across tumor types and treatment settings, including through the introduction of KEYTRUDA Qlex, which may offer patients and providers a more convenient administration option compared to KEYTRUDA while providing a comparable efficacy and safety profile to KEYTRUDA. At the same time, I think we've built a broad pipeline of innovative assets designed to address important biological drivers of cancer and potentially improve outcomes for patients across a wide range of malignancies. So today, we believe that we are uniquely positioned to advance cancer care through a differentiated portfolio, spanning 3 complementary pillars of biology. The first is immuno-oncology, where we continue to build on our leadership with KEYTRUDA while advancing next-generation approaches such as enticmaran atogene and MK-2010. The second is precision molecular targeting, where we're pursuing therapies directed to key oncogenic drivers of disease pathways. The third is tissue targeting, including antibody drug conjugates, T cell engagers, designed to deliver potent therapies precisely to tumor cells. Importantly, these aren't isolated programs. Our strategy is to develop medicines that can stand on their own, but also work together through rational combinations informed by biology and clinical experience and increasingly sophisticated understanding of the disease. This approach allows us to build treatment paradigms to potentially improve efficacy while expanding the number of patients who might benefit from these medicines. Now the breadth of our portfolio and the diversity of mechanisms represented within it provide us with a strong foundation for long-term innovation. Underlying all of our developmental efforts are several core principles. First, we believe that the best outcomes are often achieved when therapies with different and complementary mechanisms are combined or used sequentially. Second, we're committed to improving therapeutic precision through biomarker-driven approaches that help identify patients who can benefit the most. And then third, we continue to prioritize earlier stage in potentially curative settings where the opportunity to change the course of disease may be the greatest. These principles have shaped our development philosophy across the portfolio, and they're reflected in the programs you'll hear today. Importantly, the data being presented at ESMO provide additional validation to this approach and demonstrate meaningful progress across several of our most important oncology programs. So without further ado, I know you want to hear about the data sets. I'll turn it over to Marjorie.

Thank you, Eliav. And hello all you all. I hope you've been surviving ESMO and fun of the marathon at sprint speed. As I look across our oncology portfolio, today, what strikes me is how much has evolved over the last decade. And many of our most important scientific presentations historically centered on KEYTRUDA and rightfully so. Throughout the KEYTRUDA program, we fundamentally changed the treatment landscape for many cancers and developed a deeper understanding of how immunotherapy can benefit patients across different tumor types. Today, KEYTRUDA continues to be an important part of our strategy. We remain focused on extending benefit into earlier stages of disease, understanding long-term outcomes and identifying those patients most likely to benefit from treatment. But what you're seeing at ESMO this year is also the next chapter of our oncology story. The experience we gained through the development of KEYTRUDA has shaped how we think about biomarkers, combination approaches, earlier intervention and precision medicine. And it's directly informed our investments in areas such as individualized neoantigen therapy and antibody-drug conjugates. In many ways, the data we presented demonstrates how we're applying the lessons of the first generation of immuno-oncology to the next generation of cancer medications and combinations. So data was highlighted by 3 presidential symposia INTerpath-001 demonstrates the promise of individualized neoantigen therapy, continued evolution of the treatment approach is enhancing immune targeting of cancer and represents the first Phase III data for INT plus KEYTRUDA in the adjuvant setting for certain patients with melanoma. TroFuse-005 demonstrates the potential of sac-TMT in certain patients with advanced or recurrent endometrial cancer and marks the first global Phase III study from our broad program of 18 global Phase III trials. And finally, the third presentation was Keynote C93 and advancing our understanding of how to optimally use KEYTRUDA and certain types of endometrial cancer. Together, these studies reflect both the promise of our existing portfolio and the emergence of new platforms built upon lessons learned through KEYTRUDA development that have the potential to benefit patients across a broad range of cancers. So let me start with sac-TMT, which is one of the broadest development programs currently underway in our oncology portfolio. You've heard us describe that each ADC is unique, not all ADCs are the same, and ADCs are generally designed to deliver highly potent cytotoxic therapy preferentially to cancer cells versus normal tissue. Differences in molecular design of an ADC can have important implications for clinical performance. What particularly excites us about sac-TMT is the thoughtful design of this molecule. sac-TMT is a TROP2-directed ADC with a belatecan-derived topoisomerase 1 inhibitor payload, and unique bifunctional linker that we brought in through our partnership with Kolon Biotech. The linker includes an irreversible connection to the antibody intended to minimize payload loss in the circulation, along with a PH-sensitive release mechanism designed to facilitate intracellular and intratumoral delivery within tumor cells and supporting bystander effect. This design is also supported by a drug-to-antibody ratio of approximately 7.4. So it's not just the potency of the payload that's important, it's the totality of the structure of the antibody drug conjugate that you need to pay attention to, and we think this one is very special. And based upon the clinical experience generated to date, the encouraging data presented by Kolon and the first global Phase III from our TroFuse program we believe SAC TMT has the potential to become a cornerstone ADC across multiple tumor types. Today, we'll talk about the first global Phase III data from the TroFuse development program. It's important to understand the clinical context of endometrial cancer, which remains an area of significant unmet need. It is sixth most common cancer in women globally. And unlike many cancers, it's 1 of the cancers that's rising in incidence and mortality continues to rise. According to the American Cancer Society, there are an estimated 68,000 new cases of endometrial cancer per year and more than 14,000 [indiscernible] endometrial cancer in the United States are anticipated in 2026. Endometrial cancer is not only a growing significant health challenge, it's also associated with significant health care disparities. Mortality rates among black women remain approximately double of those amongst white women. Before the introduction of immunotherapy and KEYTRUDA had its first accelerated approval in 2019, patients outcomes who had endometrial cancer that were current were quite poor with survival ranging between 12 to 24 months. Since then, we've learned a great deal about the importance of understanding the biology of endometrial cancer biomarkers such as mismatch repair status in KEYTRUDA-based regimens and these have fundamentally changed outcome for many people with endometrial cancer. The challenge is that once the endometrial cancer has progressed after chemotherapy and an anti-PD-1 or PD-L1 immunotherapy, treatment options become very limited and survival is typically measured in months rather than in years. And that was the unmet need that TroFuse-005 was designed to address. TroFuse-005 is our first global Phase III study with sac-TMT that's been presented, demonstrated a statistically significant and clinically meaningful improvement in all 3 clinical endpoints: a progression-free survival, overall survival and overall response rate when compared with treatment of physician's choice, which is single-agent chemotherapy. And this occurred in certain patients with recurrent or advanced endometrial cancer. It reduced the risk of disease progression or death by 41% and reduced the risk of death and improved overall survival and reduced that risk by 32%. The progression increase from 3.9 to 7.2 months is important for these people. But I was very encouraged by was that absolute improvement of a near 7-month improvement in overall survival for people whose like spans have been measured in usually less than a year or months. And so we're getting up to 19 months in this end stage setting for many people diagnosed with endometrial cancer. The overall response rate doubled going from 17.3% or almost double to 35%. And what -- another thing that I'd like to highlight is the duration of response of 11.1 months. And it's that duration of response, combined with that overall response rates that really translates to that clinically compelling efficacy that was seen. Equally important, the responses were very deep and the durability I just talked about. So I think that this data represents a meaningful advance for these people with advanced endometrial cancer who have received a platinum-based therapy and a PD or PD-L1-based treatment and treatment options are quite limited for them. So this is exciting information for us to see and potentially gives hope to people with this disease. The safety profile of sac-TMT is very consistent with previous studies of sac-TMT and no new safety signals were noted. Discontinuation rates were quite low. It was 3.1% in the sac-TMT arm and 4.9% in the treatment of physician's choice arm, and quality of life was maintained over time. These findings represent the first and only positive global Phase III data for a TROP2 ADC or any ADC in endometrial cancer and reinforce our belief that sac-TMT has the potential to become an important treatment option for certain patients with advanced or recurrent disease. Now I'm going to turn from endometrial cancer in the TroFuse-005 study to sac-TMT of lung cancer. As many of you know, our collaboration with Kolon has generated an extensive body of clinical evidence evaluating sac-TMT across multiple tumor types and treatment settings. At ESMO, Kolon presented encouraging results from OptiTROP-Lung06 study. This is conducted in China in patients with first-line advanced non-squamous, non-small cell lung cancer whose tumors have a PD-L1 TPS below 1%. These are the patients who have the worst outcomes with the KEYNOTE-189 regimen and have the need for new therapies. While pembrolizumab and chemotherapy has improved outcomes, prognosis for this population remains challenging. Median progression-free survival is approximately 6 months and median overall survival approximately 15 months. And what makes the study particularly interesting to me is that it evaluates sac-TMT plus pembrolizumab against a very active control arm, which is the KEYNOTE-189 control arm of pembrolizumab and chemotherapy. And the combination demonstrated a statistically significant and clinically meaningful improvement in progression-free survival, reducing the risk of progression or death by 51%. Median progression-free survival improved from 5.7 months to 15 months and the duration of response was approximately doubled. Overall survival remains immature, but we observed a favorable trend with a hazard ratio of 0.58. Safety profile also very consistent with the known safety profile of the individual agents and no new safety signals were seen. This study adds to the growing body of evidence supporting the activity of sac-TMT in non-small cell lung cancer across different PD-L1 expression levels. Importantly, these findings, along with the other data sets evaluating sac-TMT in lung and in other tumors provide additional confidence as we continue advancing our global TroFuse lung cancer and broader TroFuse studies. And it supports our ambition to establish sac-TMT as a cornerstone asset and therapy across a broad range of tumors recognizing that most oncologists in the community setting see people with multiple different kinds of cancers. Our TroFuse program currently includes 18 ongoing global Phase III studies and represents the broadest range of disease settings being explored for a TROP2-directed ADC. Approximately 10 of these studies are focused on women's cancers, including endometrial, ovarian, cervical and breast cancer. We are also pursuing data -- excuse me, opportunities across lung, bladder cancer and gastric cancer, where TROP2 biology may provide a compelling opportunity for intervention. Just as KEYTRUDA development taught us where immunotherapy could have its greatest impact, every sac-TMT study provides insights that shape future development decisions. These lessons are already informing for additional studies, novel combinations, biomarker strategies and earlier-stage development opportunities. And we expect the program will continue to evolve as new data emerges. So let me then transition to the question I think you all have, so let me talk about MK-2010. When I think about our overall oncology strategy, it begins with developing medicines that demonstrate meaningful activity individually and then thoughtfully combining them in ways that may improve outcomes for patients. We believe that Merck is uniquely positioned to evaluate this biology given our extensive experience with KEYTRUDA, our history of developing VEGF containing regimens and the breadth of assets available for the combination development within our portfolio. Today, multiple Phase II combination studies are underway about MK-2010 alongside assets such as sac-TMT, [indiscernible] and other therapies. As we have said in the past, MK-2010 is a Phase III-ready asset. We have had productive discussions with the FDA regarding our Phase III plans. Based on those discussions and the totality of data generated to date, we anticipate initiating Phase III development for MT-2010 and including combinations with sac-TMT in the first-line non-small cell lung cancer setting in the first half of 2027. We will provide further updates on these plans in due course. Turning now to Intismeran, our individualized neoantigen therapy with our partners, Moderna, but I believe this is one of the most exciting scientific advances in oncology today. One of the most important lessons we learned is that durable clinical benefit depends upon effective immune recognition of tumor-specific antigens. So we've learned a great deal about what the T cells need and we use PD-L1 and [indiscernible] like GEP to understand that. And we understand the importance of the tumor mutational burden in development of tumor-specific antigens. Intismeran was purposely designed around the principle that using a patient's own tumor sample we can identify the unique mutational fingerprint of their cancer and generate a personalized mRNA-based therapy and coding up to 34 neoantigens specific to that individual patient. The goal is to create and expand tumor-specific T cell responses and complement the immune activation that already is generated by KEYTRUDA. This represents a fundamentally individualized approach to cancer therapy. Rather than targeting a single shared antigen, each therapy is designed to be tailored to the specific biology of an individual patient's tumor. And at ESMO on Saturday, we presented results from INTerpath-001, which represents an important milestone both for us and excitement for what our research program can mean for the broader oncology field. This is the first positive Phase III study of an individualized neoantrogen therapy and the first positive Phase III study of an mRNA based cancer therapy for certain patients with melanoma. Patients with high-risk resected melanoma remain at risk recurrence despite significant advances made with checkpoint inhibitors. Before immunotherapy, thinking back sort of 2010 and even earlier, [indiscernible] recurrence rates exceeded 65% for many people with high-risk melanoma. KEYTRUDA and other checkpoint inhibitors have improved outcomes for people with resectable high-risk Stage 2 to 4 melanoma, yet unmet need remains. In INTerpath-001, Intizmaran plus KEYTRUDA significantly reduced the risk of recurrence or death by 42% and reduce the risk of distant metastasis or death by 38% compared with KEYTRUDA alone. Improvements were observed across recurrence free survival and distant anthesis resurvival and results were generally consistent across subgroups. The safety profile also was very consistent with seen in KEYNOTE-942 and no new safety signals were identified. What we are seeing in Phase III builds upon the body of evidence previously generated in KEYNOTE-942, our Phase IIb study evaluating Intismeran in combination with KEYTRUDA compared to KEYTRUDA alone for patients with Stage IIIb C and 4 resected melanoma. The sensitivity analysis that were done help us understand the shape of recurrence-free survival and distant metastasis-free survival curves. There are 2 distinct periods. When you think about when inhibitors first emerge that people had to be talked about non-proportional hazards in the oncology space. And I think that paying attention to this is important because we are doing something that's novel in the oncology area, but as seen in other therapeutic areas. During the first 6 months, the curves are largely overlapping with hazard ratios of 0.99 for RFS and 1.01 for DMFS. After 6 months, the curve separate with hazard ratios improving to 0.42 for RFS and 0.50 for DMFS. This pattern is biologically consistent with what we understand about therapeutic vaccines. Unlike a directly cytotoxic therapy, an individualized neoantigen therapy requires time to prime and boost and repeatedly boost the immune response, expand neoantigen-specific T cells and overcome the energic or suppress state created by the tumor microenvironment. In the Phase II KEYNOTE-942 study data presented an exploratory analysis of a random subset of patients at AACR at 2025 and then at ASCO in 2026, show a rise in T cells in the first 5 to 6 months after starting Intismeran through those repeated doses when compared to the pembrolizumab control arm. The 2 components of the regimen are intended to play complementary roles. Intismeran is designed to generate and expand the T cells directed against neoantigens unique to an individual patient's tumor. Pembrolizumab removes the PD-1 mediated inhibition, enabling those T cells to remain active against cancer. The early overlap in the curves, therefore, is not unexpected. During that period, the immune system is being -- the immune response is being primed and boosted. Once a sufficient immune response is developed, the event pattern changes meaningfully with hazard ratios in the 0.4 to 0.5 range beyond 6 months. We have seen the importance of priming and boosting with preventative vaccines, including GARDASIL. While this is a therapeutic cancer setting and the biology is more complex, the underlying principle is similar, repeated exposure may be needed to generate a sufficiently robust immune response, particularly when trying to overcome pre-existing immunosuppression. This is a prespecified sensitivity analysis and does not replace the ITT analysis, which is so important in oncology studies. However, it strengthens our confidence that combination is generating a meaningful immune-mediated treatment effect. INTerpath-001 is only the beginning. One of the things we've been very deliberate about with I&T is how we built the development program. We focus first on tumor types where immunotherapy is already established, and that's why needs to probably progress. You can't see the whole program here. Let me try and see. We focus first on tumor types that immunotherapy is already established, and we believe an earlier intervention provides the greatest opportunity because I lost my place. We now have multiple late-stage studies underway across melanoma, lung cancer, bladder cancer and renal cell carcinoma with multiple studies already enrolled. These trials will be important for signal detection to help us understand the role of INT across tumor types with different biological characteristics, including tumor mutational burden and bearing sensitivity to immunotherapy across disease types and also in the settings as we have studies in the metastatic setting ongoing as well. We are also looking at INT as monotherapy and in combination with other drugs such as [indiscernible]. As examples, melanoma is a tumor that has high tumor mutational burden and is highly sensitive to IO therapy, whereas renal cell carcinoma, which is IO-sensitive, has lower TMV and potentially lower neoantigen expression. The positive Phase III results we have seen in melanoma represented a proof point for the platform. As additional studies mature, we look forward to sharing more data and further defining the potential of individualized neoantigen therapy across oncology. As we think about the future of oncology, we increasingly see opportunities to combine complementary mechanisms and rational ways that may further improve outcomes for patients. So when you step back and look across our data presentations at ESMO this year, you begin to see the future taking shape. Together, these programs represent the next chapter of our oncology program and our continued commitment to bringing innovative therapies to patients with cancer. And with that, I'll turn it back to Eliav.

All right. Well, thanks, Marjorie. So as you've heard today, the data presented at -- yes, I know, I mean, seriously. If we fall, can someone just make sure that we don't have -- we get a [indiscernible]. anyway. So anyway, back to business. As you've heard today, the data presented at ESMO reflect meaningful progress on several of the programs we believe will help to find the next chapter in our oncology portfolio. Whether it's sac-TMT, Intismeran, MK-2010 or the broader portfolio, we really remain focused on advancing therapies that have the potential to address important unmet needs and improve outcomes for patients living with certain types of cancers. The data you've seen today are not isolated achievements. They are the results of a deliberate strategy we established several years ago, maximizing the impact of KEYTRUDA, extending our leadership into earlier stage of disease, building a diversified oncology portfolio spanning multiple biologic pathways, modalities and mechanisms of action. The progress highlighted today reinforce our confidence in the strategy -- of this strategy and also the ability to continue to deliver meaningful innovations to patients. Looking ahead, we see the potential of 2 important oncology approvals next year. First, sac-TMT, as you heard, has now generated positive Phase III data in certain types of endometrial cancer TroFuse-005. It's exciting that this is the first global Phase III study within the TroFuse development program, an important milestone in what we believe could become a cornerstone ADC across multiple tumor types. The FDA has granted a PDUFA date of June 15. And of course, we look forward to continuing to work with regulatory authorities to bring sac-TMT to patients as quickly as possible. Second, Intismeran autogene has delivered the first positive Phase III for an mRNA-based individual neoantigen therapy in melanoma. And that's really strengthened our belief in the potential of this approach and further supports ongoing expansion of the INTerpath program, and we're waiting for these efficacy results to really send things into a bigger trajectory. Based on these data, we are already engaging with regulatory authorities and we look forward to hearing their thoughts. Now beyond these near-term opportunities, what really excites us most is the breadth and depth of the oncology pipeline that continues to advance behind these lead assets. We see a substantial and diversified set of registration-enabling opportunities, enabling through -- extending through the remainder of the decade. Those opportunities spent all 3 strategic pillars, the immuno-oncology pillar, the tissue targeting pillar and the precision molecular targeting pillar. They include multiple potential first or best-in-class approaches and encompass a broad range of modalities, including ADCs, antibody drug conjugates, individual neoantigen therapies, T cell engagers, targeted small molecules and then next-generation immunotherapies. What's particularly important is that many of these programs are being developed not only a stand-alone, but also as rational combinations, informed by the more than decade of experience that we've had with KEYTRUDA and a growing understanding of tumor biology. That approach continues to guide how we think about maximizing benefit for patients and creating the next generation of oncology treatment paradigms. Taken together, we believe the data presented at ESMO and the development opportunities ahead reinforce our confidence in our oncology strategy, in our ability to continue to deliver meaningful innovation for patients over many years to come. With that, I'll turn it over to Peter for Q&A, and will gingerly walk back to my chair.

Okay. Questions. Haley and Ann from my team have microphones. So if you please wait for a mic. And when the mic comes to you, if you could state your name and firm, that would be really helpful to all of us here and online. So Akash.

Just 1 quick 1 and a more in depth one. The PD-1 VEGF combo with sac-TMT, does that mean we're not necessarily going to get sac-TMT, pembro first-line lung studies? I just want to make sure we clarify that. And then for maybe the cancer vaccine, are we going to look back maybe 5, 10 years from now and I think the analogy was not about this being a metastatic or even a post-resection drug, but maybe something more similar to GARDASIL? Like you're running a study in a high-risk Stage 1 setting. You're talking about running monotherapy trials as well. We have seen monotherapy kind of durable neoantigen responses. So are we too focused on renal and we really should be looking about going in a precancerous maybe polyp-like setting with this drug?

So maybe I'll ask Marjorie to take the first one, and I'll take the second the vaccine type. Yes.

Yes. I think that the data that we've seen from our partners, Kolon with sac-TMT and Pembro is quite compelling. And so I see why you're answering the question and part of it. We haven't disclosed the design of what the study would look like because you think about contribution components, you think about potential like really wonderful kind of combinations out there. We do think that the data that's been generated to date with VEGF bispecifics in regards to PFS has been really clinically meaningful and compelling and improved therapeutic index. And so if your goal is really to to displace KEYNOTE-189, you want to make sure you're optimizing your chances. And so I'd say stay tuned to what the study in is going to be.

And on the broader question, I think it's really -- it is -- you are right that the the nature of I&T really remains to be defined. And the way our development program has been set up is to try to address a lot of those questions. And in fact, there is a study now that's looking at earliest stage cancers. Now of course, these studies take quite some time to read out. But I think we invested right at the beginning, at outset of that. I do -- I am eager to look at opportunities for I&T outside of KEYTRUDA simply because KEYTRUDA, while being wonderful, still has an AE profile that requires careful attention. And so we've already started to look at that in non-muscle invasive bladder cancer, our combination with BCG. But I think that there's going to be opportunities, as you note, earlier on. I think the most important thing we need to address, and there's a lot of work that's being done right now is to understand how the algorithm worked. The algorithm worked really well. There's no doubt about it. But the amount of data that we're going to be able to crunch now will really tell us a lot about what we need, what is -- what are the optimal directions that we're going to go? And I expect -- I anticipate that 2027 will have some really interest studies.

Great. And for the record, that was Akash Tiwari from Jefferies. It's okay. Asad.

Great. Asad Haider at Goldman Sachs. Just going back to INT on overall survival for the IptiTROP-06, that demonstrated a notable trend hazard ratio of 0.77, albeit it was still fairly immature. So do you see the potential for OS to meet [indiscernible] paring the discussant said that no other adjuvant trials have shown this in melanoma I've shown in has benefit so far. And then just is the level of benefit shown compelling for payers in the context of just competitor new adjuvant regimens? Just any high-level thought there.

I think they're related topics. So if you look at the checkpoint inhibitor study. So looking at, for example, KEYNOTE-54 and looking at the advent pembrolizumab studies, significant clinical benefit has been seen that they have not yet improved overall survival. And even though melanoma is a disease that can affect the young, about 1/3 of patients diagnosed with melanoma are quite young at diagnosis, the median age is still around 60 or 61, and this is part of why we showed the distant metastasis-free survival because that effectively indicates people who do have disease that has -- is likely going to be fatal or has the potential to be fatal. And when that happens, there's a significant burden, not only for the trauma to that individual but thinking about it from a health care system that someone has to have biopsies and PET scan and CAT scans and additional therapies and loss of productivity and just everything horrible that happens with recurrent cancer, and that's a very strong surrogate. In the curative setting, our goal is to get people survival to where it matches age-related survival. Unfortunately, our cancer therapies can't keep things like heart disease and Alzheimer's and motor vehicle accidents from happening. And so I hope that we will see overall survival and us seeing DMFS at the first interim analysis is quite interesting and compelling, but it's going to take time to know whether we are going to see that for certain. And I think that then relates to your question about payers. I think that it's -- there is a significant burden by having recurrent disease and that distant metastasis-free survival, I think, is the compelling reason when you think about what would happen if somebody did develop liver metastasis or lung metastasis and the downstream consequences of that. Anything else you'd like to add, Eliav?

Yes. I think the 0.77 number is -- was really is exciting. It's small numbers, and so we really have to have those data mature. As somebody who's been sitting around waiting for Keynote-54 to read out, the problem now is for the past 4 years, all the deaths have been heart disease and that kind of stuff. So no secondary malignancies, but it's all been sort of deaths and death is death, but it's not cancer death. So we're going to look at cancer-free survival as kind of a surrogate. But I think the DMFS is probably the best way to look at that. And so time will tell, but it's very encouraging.

Terence.

Terrence Flynn, Morgan Stanley. I guess, 2 parts for me. I was just wondering, Eliav, if you can comment on -- from the melanoma data, what gives you confidence in RCC, MIBC? Those are the next 2 readouts that we're going to see here. And then maybe I thought the PDAC poster was pretty interesting, particularly given low TMB. So what are the implications of that for the next set of tumors? And then can RCC and MIBC be registration-enabling could you file on those potentially?

Sure. Maybe we'll talk about a broader points and then talk about the specifics. I mean, look, this is -- we're in a new era. This is really groundbreaking therapy. And so when we designed the clinical program, we tried to address architype diseases that would enable us to get a certain feel about the breadth of this almost like trying to feel our way to work the outer limits of what INT could do. We reasoned from the beginning that this was all -- that the most important thing was to have a relatively intact immune system and to try to do this in a curative setting, where the patients haven't yet received strong anticancer therapies, which in and of themselves can be -- can cause long-term harm. And so with that in mind, we also -- we then looked at the KEYTRUDA data and the KEYTRUDA data were surprised had some surprises and the surprises in KEYTRUDA was that you didn't need to have high tumor mutational burden of cancers to have KEYTRUDA efficacy and in fact, RCC is at archetype. And so you can take the tumors that are high or relatively high TMB. And you look at non-small cell lung cancer and melanoma, and they've got pretty high -- they're all smoking-related stuff. So it's very pretty high TMB. And MIBC is not terribly different than that. I mean, it's a little bit less TMB, but it's also very much a percentage and driven disease with high responsiveness to pembrolizumab. RCC, I think, was a deliberate step to ask the question about what is -- can you be INT responsive and not be high in TMB. We've been actually pretty successful in getting good new antigens in that trial. Whether we're going to be -- whether that's going to translate to efficacy, one doesn't know. And that's why we did this Phase II trials as opposed to Phase III, which then speaks to your second question, which is as the MAH -- as party of record in front of the agencies, Phase II trials are Phase II trials. And we don't want to get ahead of the regulatory authorities and presume anything. The data such as they are, will be -- I think will be -- I hope will be compelling and then we'll see.

Daina?

You have to get your melanoma patients on [indiscernible]. So you [indiscernible] Daina Graybosch from Leerink Partners. One quick technical question and then a less technical one. So the nonproportional hazards, you saw that also in KEYNOTE-942, the Phase II. And I wonder if you've talked to regulators about using statistical models as your primary analysis that reflect that. So something that's not a proportional hazard model. And then the last technical question on TroFuse-005, very interesting in the subgroup that you saw an association of TROP2 expression with the TROP2 medium and high seeming to drive more benefit. I wonder if you could talk to that, and if you have any plan for using that biomarker and your gynecological development of the ADC?

So maybe starting first with the question about INT and the nonproportional hazard. So I do think, again, the FDA is very familiar with these kinds of curves. And so we have not talked about our discussions with the FDA. I don't want to get ahead of what may end up in a potential label or how this would show up in there. But we wanted to really help to start to educate the broader community and oncology about this. Then you back as oncology, I know in theory how vaccines work. And this is a therapeutic. And so you're combining these 2 kinds of pieces together, and it's helping to introduce this to people. So as we generate more data and we sell the great durability in Keynote-942 of that very durable sustained response over 5 years, we're imagine what's going to happen at 7 years and longer and the same thing with 001. So I think it's stay tuned, would be my answer, Daina, on that as we talk to health authorities, but this is something the FDA and other health authorities, I think, are going to be familiar with. In terms of the biomarker subgroup in TroFuse-005, and the discussed today got privy to some of the data that was there. And endometrial cancer is a tumor type that has very high expression of TROP2 Responses were seen across all expression level of TROP2, even people who had minimal or no detection. And that's because you do get inherent bystander effect with TROP2 ADC. And so you do get activity there. And the way that the histology worked out is that carcinosarcoma tumors tend to have lower TROP2 expression than those tumors that are not carcinosarcoma and those tumors are biologically quite aggressive. The response rate was higher in carcinosarcoma with sac-TMT than it was with the control arm, but that does impact those results between the higher TROP2 expression and the lower TROP2 expression on those hazardous ratios. In both groups, though clinically meaningful results we're seeing compared to control across all levels of TROP2. And so I think this is a drug that has benefit across all the subgroups that were studied in [indiscernible].

Great. Chris?

Chris Schott, JPMorgan. Just on sac-TMT, just a question on the drug made broadly in first-line lung given the ASCO data and now the ESMO data, specifically how you're thinking about the PD-L1 kind of lows, the 1 through 49? Should we think about Merck developing kind of broadly? Or would you want to explore that, I guess, middle group to see what the proper kind of approach would be in that setting? And maybe just a quick second one, which is the translation of some of the China data we've seen on sac-TMT to global studies, I think we say saw the first one of these today, but just talk a little bit about on endometrial, how that played out versus what you'd seen from China? And just as that, what confidence that gives you for the broader global studies?

Yes. Thank you. When you look at the registration studies that are ongoing right now with sac-TMT, remember, we started about 3-ish plus years ago. And we had initial data, on the Phase III data that we're seeing from Kolon was available at the time. We have a lot of Phase II data that we are cogenerating together and some initial data from Kolon. And so we went into some settings where we really thought as a maintenance approach that we would be able to have tremendous benefit, and that includes those people who have higher PD-L1 expression in their tumors as well as those who don't necessarily. And so we do have maintenance approaches for -- across all of the ranges in KEYNOTE-189. I think the question you're getting to is if we were going to do a replacement strategy, would we focus on a higher tumor -- PD-L1 tumor population or an all-comer? And I don't want to talk about potential future Phase IIIs too much until they hit clinicaltrials.gov, but there's unmet need across all expression levels. There is a question about where would you get your biggest bang for your buck with a therapy. And I think that when you look at all of the data sets that Kolon have generated, there has been consistent, compelling efficacy in every subgroup that has been evaluated by sac-TMT. And so it's really exciting. And that goes into your question of, well, how much can you trust the data and how it translates into global studies? There is data presented at ICGS this year of the TroFuse, I am not sure it was 2070-001 was the name of the study. It was as a very, very large Phase II study that we were working with Kolon together to help explore all of these tumors that have been formed for 18 Phase III studies. And the data from the endometrial cohorts was presented, and it looked at 4 milligrams per kilogram and 5 milligrams per kilogram because we wanted to understand fully where was the best benefit/risk for something that we thought had the potential to go broadly and understand the efficacy. And the data presented there, it was a slightly different patient population than in the Phase III study, but you see very generally consistent response rates and duration of response and antibody-drug conjugates tend to be quite consistent when in similar-ish populations of response rate and duration of response. And those are the things that translate into meaningful long-term outcomes. Same thing is true about the safety. And so when you look across different studies, for example, the breast study that was updated the Phase II, you look at the stomatitis rate that the NAT study is very similar in that trial to what we see in TroFuse-005, whereas in the Phase II, the stomatitis rate was a little bit lower. So we're seeing consistent data in the disease studied in the Phase II China study that has translated into global Phase III endometrial study. The thing about global studies is that you do have heterogeneity of populations. You have heterogeneity of AE management. You have subsequent therapies that are different across the globe. And so each trial will be its own experiment. But I think that consistency and seeing that positive data and what really makes me excited is that durability of being able to deliver it for a long time makes me very optimistic about the program broadly.

Great. Carter?

Carter Gould with Cantor. Maybe first, a clarifying question, and this may be, I just want to make sure I'm capturing this correctly. It looks like your HR positive breast strategy may have been updated. I believe the trophy use 10 was supposed to be a frontline and second-line study and slides are at least showing that only is frontline now. I just want to make sure that's correct?

It's front line. It is the frontline study. yes. I think that tech if you -- it's a frontline study.