Okay. Good evening, everyone. Welcome to the investor event of Merck & Co., Inc., Rahway, New Jersey, U.S.A., at the European Society for Medical Oncology Annual Meeting. Thank you to all of you who have made the effort to be with us here in Madrid, and thank you to everyone tuning in via the webcast. We are obviously very excited to have this opportunity to speak to you about the data that was presented this weekend in our oncology program. 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. Before we get started, we would 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 identifies certain risk factors and cautionary statements. Again, thank you for coming tonight. Dr. Eliav Barr, Senior Vice President, Head of Global Clinical Development, and Chief Medical Officer, will begin our program with opening remarks. 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. Eliav will then return with a few closing remarks before we get to all of your Q&A. With that, I am happy to turn it over to Eliav.
Great. Sorry, it is a bit rickety up here. All right. Thank you, Peter, and thanks to all of you for joining us. It is 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 have had three presidential symposium presentations that I think in many ways reflect the way in which we have been working to accomplish across the oncology portfolio. Before Marjorie reviews the individual datasets, I would like to take a step back and put them in context of that broader strategy. As many of you know, in 2021, we outlined two 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. Over the last several years, we have 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 have 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.
Today, we believe that we are uniquely positioned to advance cancer care through a differentiated portfolio spanning three 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 intismeran autogene and MK-2010. The second is precision molecular targeting, where we are pursuing therapies directed at key oncogenic drivers and 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 are not 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 an increasingly sophisticated understanding of the disease. This approach allows us to build treatment paradigms that 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 are committed to improving therapeutic precision through biomarker-driven approaches that help identify patients who can benefit the most. Then third, we continue to prioritize earlier-stage and 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 are reflected in the programs you will 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.
Without further ado, I know you want to hear about the datasets. I will turn it over to Marjorie.
Thank you, Eliav. Hello, all y'all. I hope you have been surviving ESMO and the fun of the marathon at sprint speed. As I look across our oncology portfolio today, what strikes me is how much it has evolved over the last decade. 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. What you are 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. It is 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 are applying the lessons of the first generation of immuno-oncology to the next generation of cancer medications and combinations. Data was highlighted by three presidential symposia. INTerpath-001 demonstrates the promise of individualized neoantigen therapy, continued evolution of the treatment approaches 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.
Finally, the third presentation was KEYNOTE-C93, advancing our understanding of how to optimally use KEYTRUDA in 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. Let me start with sac-TMT, which is one of the broadest development programs currently underway in our oncology portfolio. You have heard us describe that each ADC is unique. Not all ADCs are the same. 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 belotecan-derived topoisomerase I inhibitor payload and a unique bifunctional linker that we brought in through our partnership with Kelun-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. It is not just the potency of the payload that is important, it is 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.
Based upon the clinical experience generated to date, the encouraging data presented by Kelun 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 will talk about the first global phase III data from the TroFuse development program. It is important to understand the clinical context of endometrial cancer, which remains an area of significant unmet need. It is the sixth most common cancer in women globally, and unlike many cancers, it is one of the cancers that is 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 deaths from endometrial cancer in the United States are anticipated in 2026.
Endometrial cancer is not only a growing significant health challenge, it is also associated with significant healthcare 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 recurrent were quite poor, with survival ranging between 12-24 months. Since then, we have learned a great deal about the importance of understanding the biology of endometrial cancer, biomarkers such as mismatch repair status, and 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. 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 has been presented, demonstrated a statistically significant and clinically meaningful improvement in all three clinical endpoints of progression-free survival, overall survival, and overall response rate when compared with treatment of physician's choice, which is single-agent chemotherapy. 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. What I was very encouraged by was that absolute improvement of a near seven-month improvement in overall survival for people whose lifespans had been measured in usually less than a year and in months.
We are getting up to 19 months in this end stage setting for many people diagnosed with endometrial cancer. The overall response rates doubled, going from 17.3% or almost doubled to 35%. Another thing that I would like to highlight is the duration of response of 11.1 months. It is 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. 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-1 or PD-L1-based treatment. 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 am 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 Kelun has generated an extensive body of clinical evidence evaluating sac-TMT across multiple tumor types and treatment settings.
At ESMO, Kelun presented encouraging results from OptiTROP-Lung06 study. This was 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 six months, and median overall survival approximately 15 months. What makes this 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. 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. 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 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. Let me then transition to the question I think you all have, is 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 evaluating MK-2010 alongside assets such as sac-TMT, WELIREG, 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 MK-2010, 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, which 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. We have learned a great deal about what the T cells need, and we use PD-L1 and scores like GEP to understand that, and we understand the importance of the tumor mutational burden in development of tumor-specific antigens. Intismeran was purposefully 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 encoding 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. 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 neoantigen 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 for recurrence despite significant advances made with checkpoint inhibitors.
Before immunotherapy, thinking back sort of 2010 and even earlier, three-year 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 II through IV melanoma, yet unmet need remains. In INTerpath-001, intismeran plus KEYTRUDA significantly reduced the risk of recurrence or death by 42% and reduced the risk of distant metastasis or death by 38% compared with KEYTRUDA alone. Improvements were observed across recurrence-free survival and distant metastasis-free survival, and results were generally consistent across subgroups. The safety profile also was very consistent with what was 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 II-B study evaluating intismeran in combination with KEYTRUDA compared to KEYTRUDA alone for patients with stage III-B, C, and IV 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 two distinct periods, and you think about when checkpoint inhibitors first emerged, that people had to be taught about non-proportional hazards in the oncology space. I think that paying attention to this is important because we are doing something that is novel in the oncology area, but is seen in other therapeutic areas. During the first six months, the curves are largely overlapping with hazard ratios of 0.99 for RFS and 1.01 for DMFS.
After six months, the curves 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 anergic or suppressed 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 five to six months after starting intismeran through those repeated doses when compared to the pembrolizumab control arm. The two 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 the cancer. The early overlap in the curves, therefore, is not unexpected. During that period, the immune system is being, and 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 six 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 immune suppression.
This is a pre-specified 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 INT is how we've built the development program. We focused first on tumor types where immunotherapy is already established, and that slide needs to probably progress, because you can't see the whole program here. Let me try and see. We focused first on tumor types that immunotherapy has 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 varying sensitivity to immunotherapy across disease types, and also in 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 TICE BCG. 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 TMB and potentially lower neoantigen expression. The positive phase III results we have seen in melanoma represent 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 in rational ways that may further improve outcomes for patients. 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. With that, I'll turn it back to Eliav.
All right. Well, thanks, Marjorie. As you've heard today, the data presented at Yeah, I know. I mean, seriously. If we fall, can someone just make sure that we get a neck brace? 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 define 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're 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 of the strategy and also the ability to continue to deliver meaningful innovations to patients. Looking ahead, we see the potential of two important oncology approvals next year. First, sac-TMT, as you heard, has now generated positive phase III data in certain types of endometrial cancer through 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 15th, 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. We're waiting for these efficacy results to really send things into a bigger trajectory. Based on these data, we're already engaging with regulatory authorities, and we look forward to hearing their thoughts. 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 extending through the remainder of the decade.
Those opportunities span all three 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 as standalone, 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 and 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. Akash?
Thanks so much. Just one quick one, then a more in-depth one. The PD-1 VEGF combo with sac-TMT, does that mean we are not necessarily going to get sac-TMT pembro first-line lung studies? I just want to make sure we clarify that. Then for maybe the cancer vaccine, are we going to look back maybe five, 10 years from now and think the analogy was not about this being a metastatic or even a post-resection drug, but maybe something more similar to GARDASIL? You are running a study in a high-risk stage I setting. You are talking about running monotherapy trials as well. We have seen monotherapy 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 will ask Marjorie to take the first one, and I will take the second, the vaccine-y type. Yeah.
Yeah. I think that the data that we have seen from our partners, Kelun, with sac-TMT and pembro is quite compelling. I see why you are answering the question, and part of it, we have not disclosed the design of what the study would look like. Because you think about contribution components, you think about potential really wonderful kind of combinations out there. We do think that the data that has been generated to date with VEGF bispecifics in regards to PFS has been really clinically meaningful and compelling and improved therapeutic index. So I say stay tuned to what the study design is going to be.
On the broader question, you are right that the nature of INT really remains to be defined. The way our development program has been set up is to try to address a lot of those questions. In fact, there is a study now that is looking at earliest stage cancers. Now, of course, these studies take quite some time to read out. I think we invested right at the beginning, or the outset of that. I am eager to look at opportunities for INT outside of KEYTRUDA, simply because KEYTRUDA, while being wonderful, still has an AE profile that requires careful attention. We have already started to look at that in non-muscle invasive bladder cancer with a combination with BCG. I think that there is going to be opportunities, as you note, earlier on.
I think the most important thing that we need to address, and there is a lot of work that is being done right now, is to understand how the algorithm worked. The algorithm worked really well, there is no doubt about it, but the amount of data that we are going to be able to crunch now will really tell us a lot about what are the optimal directions that we are going to go. I anticipate that 2027 will have some really interesting studies.
Great. For the record, that was Akash Tewari from Jefferies. It's okay, Asad.
Great. Asad Haider, Goldman Sachs. Thanks for taking the question. Going back to INT on overall survival for the OptiTROP-Lung06, that demonstrated a notable trend, hazard ratio of 0.77, albeit it was still fairly immature. Do you see the potential for OS to meet stat sig given powering? The discussant said that no other adjuvant trials have shown this in melanoma, have shown an OS benefit so far. Is the level of benefit shown compelling for payers in the context of competitor neo-adjuvant regimens? Any high-level thought there?
I think they're related topics. If you look at the checkpoint inhibitor study, looking at, for example, KEYNOTE-054 and looking at the adjuvant pembrolizumab studies, significant clinical benefit has been seen, but they have not yet improved overall survival. Even though melanoma is a disease that can affect the young, about a third of patients diagnosed with melanoma are quite young at diagnosis, the median age is still around 60 or 61. This is part of why we showed the distant metastasis-free survival because that effectively indicates people who do have disease that is likely going to be fatal or has the potential to be fatal.
When that happens, there's significant burden, not only for the trauma to that individual, but thinking about it from a healthcare system, that someone has to have biopsies, and PET scans 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's 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. 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. I think that then relates to your question about payers.
I think that 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?
Yeah, I think the 0.77 number 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-054 to read out, the problem now is for the past four 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 a 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.
Yeah.
Terence.
Thanks so much. Terence Flynn, Morgan Stanley. I guess a two-part for me. Just wondering, Eliav, if you can comment on, from the melanoma data, what gives you confidence in RCC, MIBC? Those are the next two 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? Thank you.
Sure. Maybe we'll talk about the broader points and then talk about the specifics. Look, we're in a new era. This is really groundbreaking therapy. And so when we designed the clinical program, we tried to address archetype diseases that would enable us to get a certain feel about the breadth of this, almost like trying to feel our way to work at the outer limits of what INT could do. We reasoned from the beginning 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 cause long-term harm. And so with that in mind, we then looked at the KEYTRUDA data, and the KEYTRUDA data had some surprises.
The surprises in KEYTRUDA was that you didn't need to have high tumor mutational burden kind of cancers to have KEYTRUDA efficacy, in fact, RCC is that archetype. 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're all smoking-related stuff, so it's pretty high TMB. MIBC is not terribly different than that. It's a little bit less TMB, but it's also very much a carcinogen-driven disease with high responsiveness to pembrolizumab. RCC, I think, was a deliberate step to ask the question about can you be INT responsive and not be high TMB? We've been actually pretty successful in getting good neoantigens in that trial. Whether that's going to translate to efficacy, one doesn't know.
That's why we did it as phase II trials as opposed to phase III, which then speaks to your second question, which is, as the MAH, as the party of record in front of the agencies, phase II trials are phase II trials. We don't want to get ahead of the regulatory authorities and presume anything. The data, such as they are, I hope will be compelling, and then we'll see.
Daina.
You have to get your melanoma patients on enlicitide, so you [inaudible]
No kidding.
Daina Graybosch from Leerink Partners. One quick technical question and then a less technical one. The non-proportional hazards, you saw that also in KEYNOTE-942, the phase II. I wonder if you've talked to regulators about using statistical models as your primary analysis that reflect that. Something that's not a proportional hazard model. Then the less 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 derive more benefit. I wonder if you could talk to that and if you have any plan for using that biomarker in your gynecological development of the ADC.
Maybe starting first with the question about INT and the non-proportional hazard. I do think, again, the FDA is very familiar with these kinds of curves. We have not talked about our discussions with the FDA, and I don't want to get ahead of what might 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 in oncology about this.
Thinking back as an oncologist, I know in theory how vaccines work, and this is a therapeutic, and so you're combining these two kinds of pieces together and it's helping to introduce this to people. As we generate more data and we sell the great durability in KEYNOTE-942 of that very durable, sustained response over five years, we're imagining what's going to happen at seven years and longer, and the same thing with 001.
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, the discussant today got privy to some of the data that was there. 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. That's because you do get inherent bystander effect with this TROP2 ADC. You do get activity there. 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 hazard ratios. In both groups, though, clinically meaningful results were seen compared to control across all levels of TROP2. I think this is a drug that has benefit across all the subgroups that were studied in the trial.
Great. Chris.
Great. Thanks. Chris Schott, JPMorgan. Just on sac-TMT, just a question on the drug, maybe broadly in first-line lung, given the ASCO data, now the ESMO data, maybe specifically how you're thinking about the PD-L1 lows, the one through 49s. Should we think about Merck developing broadly, or would you want to explore that, I guess, middle group to see what the proper approach would be in that setting? 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 obviously 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 what confidence that gives you for the broader global studies. Thank you.
Yeah. No, thank you. When you look at the registration studies that are ongoing right now with sac-TMT, and remember, we started these studies about three-ish plus years ago, and we had initial data. None of the phase III data that we're seeing from Kelun was available at the time. We had a lot of phase II data that we were co-generating together and some initial data from Kelun. 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. 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 PD-L1 tumor population or an all-comer? I don't want to talk about potential future phase III's too much until they hit clinicaltrials.gov. But there's unmet need across all expression levels. There's a question about where would you get your biggest bang for your buck with a therapy. I think that when you look at all of the data sets that Kelun have generated, there has been consistent, compelling efficacy in every subgroup that has been evaluated by sac-TMT. So it's really exciting. That goes into your question of, well, how much can you trust the data and how it translates into global studies?
There was data presented at IGCS this year of the MK-2870-001 was the name of the study. It was a very large phase II study that we were working with Kelun together to help explore all of these tumors that have been formed for our 18 phase III studies. The data from the endometrial cohorts was presented, and it looked at 4 mg/ kg and 5 mg/ kg 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. 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.
Antibody drug conjugates tend to be quite consistent in similar-ish populations of response rate and duration of response. Those are the things that translate into meaningful long-term outcomes. Same thing is true about the safety. When you look across different studies, example, the breast study that was updated, the phase III, you look at the stomatitis rate that is in that 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. We are 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.
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.
Hi. Carter Gould with Cantor Fitzgerald. Maybe first a clarifying question, and I just want to make sure I'm capturing this correctly. It looked like your HR-positive breast strategy may have been updated. I believe TroFuse-010 was supposed to be a front-line and second-line study, and the slides are at least showing that only as front-line now. I just want to make sure that's correct.
It's front line.
Okay.
It is a front-line study, yes. I think that it's a front-line study.
Still same size and still data next year?
We have not. I'd say go to ct.gov for the [crosstalk]
All right. Perhaps more importantly, there was a lot of conversation with the discussant, whatever day that was, a day or two ago, on the INT regarding neoadjuvant use of PD-1s. I want to give you a chance to comment. I know I've talked to Eliav and Dean about that before, but it was a couple of years ago, and just now how you think about NADINA and SWOG potentially being a complicating factor commercially.
Yeah. The neoadjuvant studies were initially designed. The patients with the tumors, they tended to have macroscopic sort of bigger melanomas that had lymph node involvement. Both SWOG 1801 and the NADINA study did have these larger tumors. The SWOG study also included potentially resectable stage IV disease. They are a selected subgroup of melanoma. It's very hard with these Mohs microsurgery and the lymph node surgeries sometimes to get good negative margins. One of the questions was, could you do this and make the surgery easier and then be able to have your benefit? Then they were looking at efficacy as well. The studies you're looking, it's a little apples and oranges between these trials a bit. I say that when you're looking at the NADINA study, these were well-conducted studies, both of them.
In the experimental arm where people received two cycles of ipi-nivo, there was 6%-7% of people didn't make it to surgery. Then in the adjuvant setting, you had about 10% of people receive monotherapy nivo. You had people receiving BRAF-directed therapy, and you had a lot of heterogeneity in your post-adjuvant treatment. It makes it really hard for us to look at that trial and compare what does that mean versus what does INTerpath-001 mean. People really anchor on the 83% data, and that was data with a median follow-up of about 9-point-something months compared to the two-year data that has also been published on the NADINA study that showed that that benefit, the original hazard ratio, had been the 0.3 something range, had dropped into the 0.4 something range, and then maybe it stabilizing.
It's hard to tell, but there was some loss of efficacy. I think it's an important study and it's something that's really helped to show that for people who do have these bulky kind of diseases, that you're able to do this approach, but there is risk of progression. We saw in the SWOG 1801 study, about 10% of people didn't make it to surgery because of progression in that period as well. That study had more consistent adjuvant therapy, and we do see a drop in efficacy over time in the adjuvant setting when you look at the first two-year event-free survival and then going into later data sets. I can't compare them, not because I don't want to, but they are very apples and oranges in their approach.
What I can do is look at the KEYNOTE-942 study, which did have a higher risk population than we see in the INTerpath-001 study, and I see very consistent two-year data. In KEYNOTE-942, it's staying stable over time. We'll need time to see what this happens over time here. Are we going to see those continued durable benefit? The number of people who have neoadjuvant therapy, we think it's about 20% of the population who are really candidates for the neoadjuvant approach, and there's a lot of heterogeneity about where it's used. We also need to remember that for the NADINA study, about 30% of people get very significant grade III or higher toxicities, and there were people who were unable to either undergo surgery or receive any adjuvant therapy when they needed it because of potentially residual disease due to significant toxicity.
Whereas when we look at the toxicity with INTerpath-001, there are no increase in immune-related AEs and the therapy was generally deliverable and well-tolerated.
All right. Alex.
Alex Hammond, Wolfe Research. The discussion for the OptiTROP trials mentioned dose attenuation and pulsing dosing will be part of ADCs in non-small cell lung cancer. I am wondering if and how you guys are planning to implement those strategies into your development with sac-TMT.
I am sorry, could you rephrase the question for me?
I could not hear.
I had a hard time hearing you.
Yeah [inaudible]
If you are going to utilize dose pulsing with sac-TMT in small cell lung cancer.
Dose pulsing in non-small cell lung cancer. I am not certain what they mean. I missed that presentation. I hate to tell my partners, Kelun, that I missed that presentation. So I am going to need to listen to the discussant to understand what they intended by that. There is dose modification that occurs, because this is a cytotoxic therapy, and depending upon the AE profile, sometimes you can hold a dose or you can modify the dosing if needed. There is not a current prospective plan to look at some kind of induction and maintenance. We think that we have with our 4 mg/ kg dose that we are using in our global studies, either as monotherapy and combination the optimal kind of dosing for benefit and risk, and that is spoken to by the duration of response.
If you look at the endometrial study, the TroFuse-005 study, the duration of therapy there is over 30 weeks for the experimental arm compared to 15 weeks for the control arm. Despite that doubling of therapy exposure, the number of people who had to discontinue drug due to toxicity was numerically higher in the control arm. I think that having to modify doses is not unexpected with a cytotoxic therapy. I think that it's more important to think about, can people stay on treatment in a very tolerable way? That duration of response shows it, and the quality of life being maintained is another thing that really is very reassuring. You never want treatment to be worse than the disease. People who've got recurrent cancer, they're not going to take therapy that's making them miserable.
Even though they do have this very high unmet need. I've been very reassured, and you're seeing that consistency across multiple studies in the Kelun studies as well as now in the global trial as well. I may not specifically answer your question, but that's how I think about the dosing of sac-TMT in our global trials.
Courtney.
Hi there, Courtney Breen from Bernstein. Two questions. The first one's hopefully a quick answer. The sac-TMT PDUFA date that you mentioned is June 15th. Can you just clarify if you're using the CNPV for that date? Could the CNPV pull that further forward? It doesn't seem fast enough based on the previously historical, I guess, proposed timelines that that might be possible with the CNPV. The other question that I had was just about the combination potential phase III's that could start in the first half of next year. You've obviously got phase II's ongoing.
They appeared on clinicaltrials.gov last month, I think it was, but perhaps popped up a little bit earlier as well. Can you just tell us about the burden of data that you will have to inform that decision? Are you relying on data from Kelun combinations with other PD-1, VEGFs, and sac-TMT internal modeling? How are you getting conviction about the dosing and the combination selections you're making?
I think as stated, I'll address the second part first, is that we've had very productive conversations with the FDA and which is why we're just telling you that we're starting our phase III's next year. We're really excited about that. Phase II studies are done for multiple reasons. Some of them can be signal finding, but they also can be used to get greater understanding of combinations and inform for ongoing phase III trials. We have multiple combinations that we're looking at with MK-2010, not necessarily just with sac-TMT in these studies. I don't want to say anything more specific than that because of the hyper-competitive landscape that we're in. There are a lot of reasons for us to have phase II studies ongoing while concurrently thinking about a phase III development program with our phase III-ready asset, MK-2010.
Lots of excitement there. Kelun does have its own bispecific that it is working with. We have data that they have done with Avastin combined with a checkpoint inhibitor and sac-TMT. We do have data sets that already have helped to inform for information that we are using for our global studies. Lots of stuff that is ongoing to inform for potential future for that combination. We have had really productive conversations with the FDA. I never want to get ahead of them. When you submit something, whether you are using the CNPV or not, you get the PDUFA date. I think that we are all very excited about the potential to accelerate. Anything else you would like to add on that?
Yeah. I would say that our discussions with FDA to date have been incredibly productive and speedy. We have had good experience with their very robust, very in-depth, but more accelerated reviews. We are hopeful that we can bring this drug for patients as quickly as possible. I would also want to point out for MK-2010, that it is not just sac-TMT in MK-2010. MK-2010 will have friends with benefits with different parts of our pipeline. We look forward to being able to get started with that next year as well.
That is part of why we have several studies, because there are different INDs.
Yeah.
Yeah.
[Deena]
Hi, thanks. This is [Deena] from UBS on for Mike Yee. I guess, to Daina's point on the biomarker strategy, in the OptiTROP-Lung06, we actually saw, while it is very stunning and great data, we did see that there was a better benefit in the TROP2 low patients, which was kind of opposite of what we saw in the endometrial. So there is a bit of a difference in the TROP2 expression and the benefit that we see across cancer types. I guess maybe just thinking about what is your strategy for the biomarker testing. I saw on one of your slides that in lung that you are not focused so much on the biomarker strategy, but you are in other indications. Just want to talk through how you are thinking about that.
Maybe to clarify, we have a broad biomarker plan across all of our sac-TMT studies. Every tumor is going to be different about expression and response. During the presentation today with the TroFuse-005, it referenced the testing that is being done with RTD and IHC testing. We have very similar kinds of approaches in our studies. We have not talked about where we might have a primary hypothesis about a biomarker enrichment or not in particular studies. Part of it has to do with how antibody drug conjugates, particularly this one that does have very robust bystander effect as well, and different tumor types may need to have more consideration than others. So it is there. It is also meant to be scalable for global usage. So it is there and we are thoughtful about it, but that is all I can really tell you at this time.
All right, so it has been a long four days. We are just over the hour mark, so maybe time for two more questions. Will.
Hi, [Will Vang] here for Mohit Bansal, Wells Fargo. I know you alluded to going against KEYNOTE-189 with a potential sac-TMT and MK-2010 combo. I guess based on the data we have seen from the PD-1x VEGF class and then also the old PD-1 plus VEGF combo trials, do you see a specific histology that such a combo would make more sense? Also, I guess in squam, do you see a rationale for MK-2010 plus sac-TMT as well?
No. It was a very leading question saying that we're going to go against KEYNOTE-189 broadly. We're doing a study in first-line, just stay tuned to next year. I can't speak more specifically about it.
I think we're very confident. I have to say that the Kelun data
Works across all histologies. Yeah.
I mean, seriously, it's pretty important for us. Kelun gives us a harbinger of what to look for and what to do and not do. What's been super cool about the OptiTROP lung program is that it's active here, it's active there, it's active everywhere. I think that it provides Marjorie and her team with a lot of optionality to do smart trial design.
Yeah.
I'm grading them and we'll see what happens next year.
All right, last question, Richard.
Thank you for the question. Richard Wagner, Bank of America for Jason Gerberry. I wanted to return to the neoadjuvant question setting for intismeran. What is the state of the technology now with regard to the ability to turn around doses quickly? In order to understand what are the practical considerations with intercepting a patient undergoing neoadjuvant treatment? I know that you are putting forward some fairly ambitious studies where you intercept patients after three cycles of preoperative chemotherapy and bladder cancer. With that technology state now, does that open a neoadjuvant melanoma study? Would you do it, if you can? Then indirectly, but still within the neoadjuvant versus adjuvant paradigm, the result failure to show overall survival with KEYTRUDA in the adjuvant lung cancer setting, the PEARLS study, KEYNOTE-091, what does that mean for the intismeran study with KEYTRUDA in the adjuvant setting?
Is adjuvant KEYTRUDA essentially a practice that will go away by the time the results are available?
There are lots of different questions in those two points. Maybe let me start with talking about survival and lung cancer. I think the presentation that was done this afternoon about the updated data from KEYNOTE-91, they talked about the lung cancer-specific survival in the same way that we were talking about the distant metastasis-free survival. When you have an early lesion , you have competing causes of death. They highlighted some of the death imbalances that occurred in KEYNOTE-91. We do think that our goal always with therapy in the curative intent setting is to reduce the risk of death from cancer being what takes someone away prematurely compared to what would normally happen to them if all things were created equal.
I wish that these therapies would cure heart disease and cure strokes and other things that happen, but they are not able to do that. It is really important to think about the totality of burden of cancer and recurrence and outcomes when thinking about benefits of therapy. That is how I generally view that. Our phase III studies cannot answer every clinical question that is out there. Just the registration studies, the way that we do them is I cannot answer them all at one time. This is an open question about would there be something for someone who has residual disease after a neoadjuvant approach? It is not used as much in the community setting. It tends to be done much more in the academic setting because of the need. You have to really carefully map the tumor and the lymph nodes.
I think that there are some questions that we just do not have answers to today. Again, the majority of people do not receive neoadjuvant therapy for melanoma at this time. The turnaround time for generation of INT, it is a complex but well-oiled machine. Moderna has been amazing partners to work with on the manufacturing and getting things up to scale. We have had to do this in multiple global studies to get this going in a very consistent way so we are ready for commercialization. There is a huge orchestration process that has been done that is complex but is very scalable to get this out there. Right now, we are saying the turnaround time is around six weeks. If you have a neoadjuvant regimen, that is a six-week regimen. Right now, those two things are not necessarily compatible.
There are things you could consider for a study concept that could introduce a neoadjuvant approach. I think that the data is quite consistent in INTerpath-001 across multiple stages, across multiple subgroups. Again, if I go back to the SWOG study and 10% of people had progression before they got to surgery in the neoadjuvant setting, I think that the data you have is quite compelling in INTerpath-001.
Yeah, I don't see neoadjuvant becoming the rage. That's not what we're hearing from our melanoma experts. It's a very specific set of patients where they really want to be able to debulk the tumor before they do the surgery. I think that the 1801 regimen is relevant for specific narrow group of patients. I think adjuvant is going to be the way to go for most of the patients.
Okay. Thank you all again for your--
Safe travels.
Thank you, guys.
Thank you all again for your time and attention and the really good questions, and safe travels home.