We're gonna get started. Thank you, everybody, for taking some time out of ASCO and your time here to spend with us. I'm Stephen Hoge, I'm the President of Moderna, and I'm gonna be providing a little bit of context up front for the data we're gonna be reviewing today, which will cover our full oncology pipeline. We're incredibly excited to do that. Before I dive in, we will be making forward-looking statements during this presentation. Those are covered by the Safe Harbor Act. You can find these slides and our reference to it on our website. Over the last number of years, we have been building a pretty extensive pipeline.
Now, we're gonna spend almost all of our time today in oncology, focused on INT, because we have some exciting data, clinical data, and obviously the presentations from today, and we're looking forward to questions on that. But we did wanna take the opportunity today to give a sense of all of the other efforts that we've got advancing in clinical development, including cancer antigen-specific therapies, some novel therapeutics that have been working on actually even before IND, INT, and then some new and exciting technology partnerships that we think will translate into clinical studies very quickly here. So our agenda for the day, we're gonna try and get through relatively quickly and then get to Q&A, but we'll start off with Dr.
Kyle Holen, who will walk through our overall frame for INT and how we're thinking about how it might transform cancer. He'll hand it off to Michelle Brown, Dr. Michelle Brown, who leads our INT program, and will run through the data that was presented by Dr. Weber at ASCO this week. Kyle will come back and provide a little bit of voiceover on some of the other programs that we have in early clinical stage, and then Dr. Rose Loughlin, who leads all of research for us in the therapeutic space, including oncology, will come and share some of our work in the external partnerships and why we're so excited about those. So without further ado, I'll turn it over to Kyle.
Thank you, Stephen. So really excited to be here and particularly excited about talking about our oncology portfolio. The oncology portfolio has advanced in really exciting ways, not just our INT program, but I'll share with you some of the advancements in the checkpoint program as well as the triplet program. I'll start out by sharing with you a little bit about why we think INT is gonna be so impactful. So you all are familiar with the amazing impact that immune therapies have had across many different types of cancers. Checkpoint inhibitors have really had a dramatic impact in the cancer field. But unfortunately, despite this success, there's a clear unmet need. And I've shared here some of the response rates among these tumor types.
I'll also share with you, although there are some response rates, complete responses are very, very uncommon, and so we know that there's an unmet need, and we're excited to see how INT can help address that unmet need. So one of the things that we're doing at Moderna is first, having a focus on resectable cancers. We think that's the highest likelihood of success for INT, and so we're looking at all kinds of different adjuvant therapy treatments with INT. But there's a ton of opportunity outside the adjuvant setting. We're looking into early cancer management, treatment during patients who might have positive screening tests, and we're looking later on into metastatic settings and other lines of therapy.
So we think INT potentially has the ability to play across the entire spectrum of cancer treatment, and one of the examples of where we think this is evident is in the AACR abstract that we presented recently, where we saw really remarkable responses in metastatic and advanced head and neck cancer. Okay, with that, I'll have Michelle, Dr. Brown, come up and talk a little bit more about INT. And then I'll come back and tell you a little bit more about the rest of our portfolio. Dr. Brown?
Dr. Brown. Okay, so it's nice to see everyone, and, welcome to ASCO. We're very excited. Ooh, this is very loud. We're very excited today to be talking about the data that was presented this morning with our three-year follow-up of our randomized phase II study. And as we were reflecting about this ASCO experience, we really realized that we've been on a journey with everyone over the past year as we've been teaching and learning about what it means to have an individualized therapy and what that actually means for patients, and then also the broader development strategy. So without further ado, I'm sure a lot of you saw the press release this morning, and then this is the presentation that Jeff presented on the podium today. I'll walk you through some of the datasets and why we're so excited about it.
So this slide, when we first introduced it starting last year, we did have a substantial learning curve to teach everyone about what INT was, which is essentially an individualized neoantigen therapy that encompasses up to 34 patient-specific neoantigens, concatemerized on a single mRNA strand that's administered intramuscularly to a patient. And when that happens, that mRNA strand enters into the natural processing system, where those neoantigens are expressed on antigen-presenting cells, activate T-cells, and allow them to target specifically to an individual patient cancer cells. So we've seen this slide, and this is really where we think INT is unique, in the sense that it is, one, administered intramuscularly. Second, it's the first of its kind to design a specific therapy for each individual patient, looking at their tumor mutation profile, but also their HLA type.
And obviously, this is a follow-up to our phase II study, which I'll get into in just a second, that reported out last year, where we showcased our primary analysis that showed a clinically meaningful improvement in recurrence-free survival and distant metastasis-free survival. So after we passed that substantial endpoint last year, we had a planned follow-up for an additional year because we heard from the data set that it was early. We really needed to understand what this new class of immunotherapy would do and if it would provide long-term benefit. So we planned on watching patients for an additional year to look specifically at that durability of effect. So, you should be familiar with this phase 2 randomized study. It enrolled high-risk stage 3, 4 adjuvant melanoma patients. We randomized them to our INT plus pembro arm versus pembrolizumab.
Mind you, pembrolizumab is standard of care. This is what is used. It has set the standard, and no combination therapy in this space has ever shown a benefit above pembrolizumab. We designed the study with a very powerful and sort of aggressive hazard ratio because we wanted to see something that could be potentially transformative to patients, and we used the standard recurrence-free survival endpoint in addition to distant metastasis-free survival. Then we also really wanted to look at safety, because in this population where you're talking about potential cure, we really want to make sure that there's a good risk-benefit. Then, as we hear today, there was a couple of other exploratory endpoints looking at biomarker populations and then also overall survival. So this is the data set that we saw from Jeff this morning.
What we reported for our primary analysis essentially ran to the first hash mark at the 18-month follow-up, where we had a separation of our combination treatment arm versus the pembrolizumab standard of therapy arm with a delta of 17%. Importantly to note, what we see over time is that that treatment effect for the combination only gets better. So we have this durable, clinically meaningful treatment effect for INT plus pembrolizumab. And importantly, we now see with the pembrolizumab control arm in yellow there, that this essentially performed as we would expect it to. So it looks very similar to the KEYNOTE-054 study. It looks very similar to nivolumab's CheckMate 238 study. So what we see with this treatment effect for INT is really the powerful potential of the combination, not necessarily anything as a limitation of that control arm.
Importantly, what we see is this spreading of the curve over time to, again, emphasize that durability. And with this extra time, what we see also is a couple of really important things. The first is that the primary analysis had 44 events. This one, with an extra year of follow-up, only had 47 events, meaning in an entire year, we only had three extra patients have some kind of event, really showcasing, again, that potential treatment effect for INT. We also see that the hazard ratio has gone to 0.51, so a 49% protection in recurrence-free survival, and we see a shrinking of the confidence interval below one, really emphasizing that statistically significant p-value, which is two-sided at 0.019.
So we're very excited with the three-year follow-up data because it confirmed essentially what we saw with our primary analysis, but it also shows really what the potential and durable potential of this treatment could be. And this is true not only for recurrence-free survival, but it's also true for distant metastasis-free survival. And for those that play in the adjuvant space, distant metastasis-free survival is really important because these are the patients that have the higher risk of death or metastatic disease. Their surgeries are bigger, their outcomes are worse. So really making a profound impact on this endpoint is very meaningful for patients.
What we see again is that from the time we had our primary analysis at that 18-month mark, all the way to where we are today, we see this expansion of the INT treatment effect with 89.3% of patients not experiencing this type of distant recurrence or death. We also see that the hazard ratio is quite profound at 0.384, and that the p-value here is also very significant at 0.015. So again, both of these primary and secondary efficacy endpoints really showcase what INT can do, and this is the first time any combination has been able to show this above standard of care pembro in this setting. The other big piece that we showcased today was our overall survival.
Now, the thing to remember about overall survival is it takes a long time, so it is very early on in our days for monitoring these patients for overall survival, and most patients and most studies don't see a separation until many years later. So this is an early trend, it's a preliminary trend, but what we see is it's very positive. And what I want you to focus on is the fact that 96% of patients in the combination arm are alive at the 3-year mark, and we have a hazard ratio of 0.425. So this is the first data set of its kind.
We anticipate following these patients even longer, and we hope to see the same trend we saw with RFS and DFS, but we have a lot more work to do with the overall survival, but it's very encouraging, especially for patients today. The other piece that we showcased here that's a little bit different than what we've done before is that we looked at the different biomarker populations, and what we've reported previously is that those patients that received the INT combination do well irrespective of the type of biomarker we look at. So those with high TMB, low TMB, PD-L1 high, PD-L1 low, ctDNA positive, ctDNA negative, the combination works for all of those patients better than pembrolizumab standard of therapy. What we also have heard, though, as one of the top questions is, well, what happens with INT in relation to HLA?
Because we know HLA can be population-specific, patient-specific, and it's a mechanism of resistance for a lot of IO therapies. Just to remind everyone, INT is individualized. The algorithm that's used looks at that patient's specific tumors, but it also looks at their HLA type. We're designing a therapy that is truly specific for them, and it should work irrespective of HLA status. In addition, because of the breadth of neoantigens that we're selecting, we should have an intrinsic mechanism to get away from loss of HLA or heterozygosity. What we wanted to test with this, or show, is essentially that, one, the algorithm is working to each specific patient, and two, even if the tumor is trying to come up with a resistance mechanism, the INT combination arm does well irrespective.
As Jeff said today, the red line is higher than the orange line, and the blue line is higher than the green line, which essentially means that irrespective of HLA status, the INT combination does well, similar to everything else from the biomarker populations we've seen. The last piece I wanted to highlight, at least from the dataset that was shown today, was that we really think about risk-benefit in this patient population, right? These are early-stage patients. They're looking for a cure. They don't want these long-term adverse events that might be compounded with IO/IO combinations that have been tested or treatments that are in the metastatic setting that are marching their way down.
One of the things that's really important is that INT, when we look at it in combination with pembrolizumab, we see a very manageable safety profile where we don't see an increase in serious adverse events, we don't see an increase in Grade 3 adverse events, we don't see an increase in immune-mediated adverse events. These are all really important for patients on their long-term outcomes. Overall, what we've seen, not only in the primary analysis but with additional long-term follow-up, is the safety profile for INT is stable, and it's what we would have expected. It's really based off, you know, a little bit of fatigue, some fever, some malaise, everything that we would sort of expect from this type of therapy, but we're not seeing anything as far as increased serious adverse events go.
So as Jeff concluded today, our 3-year median follow-up data showed a clinically significant and durable improvement in RFS and DMFS, with the 49% reduction in the risk of death and a 62% reduction in the distant metastasis. We see a very positive trend in overall survival. We'll continue to watch these patients and really see how that evolves over time. We believe in this manageable safety profile and really the positive benefit-risk we have for these patients, and so far, any way we look at different populations, different susceptibility, essentially, the INT plus pembrolizumab arm does better than standard of care pembro, irrespective of what we look.
Now, obviously, we need to thank all of the folks at Moderna, all our folks with our collaborators at Merck, and then the clinical trial sites and the patients that make this possible, and we're very excited to showcase that dataset today, and we look forward to future datasets. Now, while we are thinking forward, we don't have anything yet. We did wanna reflect backwards a little bit for some of the data that we've presented at previous conferences because we think it showcases and encompasses what we're really trying to achieve with INT. One of the things that I've said about this technology overall for INT is that it really sits at this precipice and interface of technological advancement with next-generation sequencing and our understanding of cancer biology.
And not only is that showcased in what we're achieving for INT, but it's also showcased with how we're designing our studies to learn about what INT can do and how we're sitting sort of at that peak of technological advancement. So everyone that's been listening to ASCO and sort of paying attention to the early oncology space has most likely heard about ctDNA, and ctDNA is being used in a multitude of ways. First, it's to identify patients that are at higher risk for their disease coming back, but it's also being used to understand treatment effect. And so we were really excited to actually monitor ctDNA longitudinally in our studies to see what INT would do, and then also how we can use ctDNA in the future to help us identify patients or understand INT even further.
So this dataset was presented at ESMO, and this one is basically our RFS curve on the left, your left, and the DMFS curve on the right. And essentially, this is ctDNA patients that are either negative at baseline or those that had positive status. And most patients or most thought leaders at this point think that having ctDNA after your surgery is a negative prognostic factor. Those patients don't tend to do well, and that is indeed what we see. Those patients that are ctDNA positive don't do as well as those that are ctDNA negative. But what's important here is what we see irrespective of the ctDNA status, is that the INT combination with pembrolizumab does better irrespective of those high-risk patients or those low-risk ctDNA patients compared to pembrolizumab.
And then what's also really exciting about this data is that we see an early split. Because we hear with INT that, you know, it takes time to manufacture, it's only gonna maybe work for these lower-risk patient populations. And what you see in these curves is that INT can make an impact early, and it can make an impact for those that are at highest risk in this setting. So obviously, this is a small data set. We're going to continue looking at this technology, but it is very encouraging results for, again, the potential of what INT can do. The other piece we were looking at, in addition to, you know, those patients that are higher risk or lower risk, is we were looking at what INT will do for their ctDNA dynamics as a whole.
In our P201 study, we essentially found that there's three patterns for ctDNA. The first is those that basically have positive status, get treated, and then drop to negative, so showcasing that their disease is essentially was present even after surgery and got cleared with treatment. Those are the molecular responders, and that's in this number one bucket. What we have is the number two bucket, which is the polar opposite. It's these patients that were positive to start after surgery. They're high risk. They got treated. They stayed high risk, meaning that they most likely weren't responding to treatment the best way. Then we have an interesting bucket with the ctDNA negative pattern, which is essentially those that were negative the entire time.
And one of the things with the ctDNA negative is that this is very dependent on the tumor type, and we know that melanoma doesn't tend to have a lot of positive status, so even seeing these patterns was quite profound in this setting. The last piece I'll call is the, in the molecular responder category, you've got obviously different like, patterns of response, where someone could start negative, and then maybe their disease starts coming back, like what you see in the red dots, and then essentially treatment ends up taking care of that disease coming back. So it really showcases sort of the dynamics on a molecular level of what's happening in a patient. And then if you wanna translate that to clinical outcome, we essentially showed that those that had the ctDNA negative pattern, meaning they probably had very little disease left, did better.
They had less recurrence, not surprising. Those that had ctDNA positivity, that stayed positive, didn't do so well, which again, is not very surprising because obviously it means that they're not responding to what we're giving them. And then the ctDNA positive were right in the middle of the road. And what's important there is if you actually look on the bottom of the graph, what we see is that the combination essentially doubled the amount of molecular responders compared to pembrolizumab, meaning that the combination's doing something not only on the clinical side, but also on the molecular side. So this data is very encouraging. It's a highlight of what we're trying to do to understand INT as a whole, and then this will actually guide some of our development strategies as we move further along.
So I'm gonna take us a step back out of the clinical data for a minute and showcase what Stephen has already showed, which is our INT portfolio, if you will. So we have announced over the course of the year, the launch of 5 new studies. So our phase 3 in adjuvant melanoma in partnership with Merck, started enrolling back in July of last year. Our phase 3 in adjuvant non-small cell lung cancer started towards the back end of last year as well. And then in February and March timeframe, we released that the cutaneous squamous cell carcinoma, which is a phase II-III, started enrolling, followed by our renal cell carcinoma phase 2 study in the adjuvant setting and our phase 2 bladder cancer study in the adjuvant setting.
So you can really see that based off of the dataset we have showed you for the P201, that we're very excited about the potential for INT in the adjuvant space. We're very excited about the potential for patients, and in partnership with Merck, we've launched a multitude of studies to impact not only melanoma, but a broad range of tumor types. And then, basically, what I'm gonna show you in a series of slides is what the study schema is, but essentially, the theme is the same. They're adjuvant studies, they're randomized, we have the appropriate control with the standard of care, and importantly, these are all powered to show a statistically meaningful improvement for INT versus that standard of care. And that's true for our phase III study, which is currently enrolling. That's true for our non-small cell study, which is currently enrolling.
That's true for the CSCC study, which is currently enrolling. I'm sounding like a broken record. And for bladder and then for RCC. So really, this is a thank you to the entire sort of Moderna Merck team for the litany of studies that we've launched, and then I see Kyle is coming up, so I'm going to wrap this up quickly. As Kyle showcased, we've done, and as you saw on the previous slides, we've done a substantial amount of work in understanding the potential for INT in the resectable space. We have could potentially use ctDNA to start moving us towards the continuum on the right, and potentially use it for high-risk patients on the left.
And then, as Kyle alluded to, we were very encouraged by our AACR data in advanced squamous cell carcinoma of the head and neck, which potentially shows the potential for INT in the metastatic setting. I'm not going to go over all of that data. This was showcased at AACR. It essentially was part of the P101 study, which was our phase 1 study and showcased an expansion cohort. The thing I will say is that this population was truly representative of advanced metastatic population. They didn't have the best performance status. They had burned through a number of treatment options. Overall, their prognosis was relatively poor. What we saw in this sort of later stage population is that INT safety was the same as what we would expect across the board.
Importantly, what we saw from the spider plot at the AACR presentation, and showcased by the very nice flat lines on the bottom of the screen, is that we had patients that when INT was on board in this metastatic setting, we got a deepening of their clinical response, we got increased disease control, and we had patients that were very advanced, have complete responses. So that shows that we're doing something right in the adjuvant setting for doing all of these clinical studies, but there is potential and promise to potentially make an impact in these later lines. So obviously, we're very excited about the P201 data today. We're using it as fuel for the litany of studies we're doing for tomorrow, and then we've got a lot of work to do for where we would wanna go beyond now.
All right, with that, I will hand this back to Kyle.
Thank you. Yes, thank you, Michelle. We're really excited about INT, but equally excited about the rest of the oncology portfolio, which we haven't spent a lot of time talking to you about, so I'd like to share a little bit of those thoughts, right now. I'll start with our checkpoint engine-specific therapy, 4359. So 4359 works a little bit differently than what you'd think of as a checkpoint antibody. So whereas a checkpoint antibody takes off the brakes, if you will, for a T cell activation, what 4359 does is it directs those T cells, directs them specifically to IDO or PD-L1. And the reason why that's important is because it has a direct tumor effect, and it allows the T cells to have a specific activation against the tumor.
We are excited about the possibility of the checkpoint vaccine, and therefore, we've included on here this slide, the schema for the phase 1 trial, which includes expansion cohorts. So we're currently enrolling in combination therapy with a checkpoint inhibitor in the metastatic setting. And these, there's two cohorts here in this expansion. There's a cohort in non-small cell lung cancer and first-line non-small cell lung cancer that are PD-L1 positive, over 50%. And then we also have a frontline metastatic melanoma study that's enrolling. So both of these studies should give us a really good idea of what additional benefit the checkpoint vaccine will have over pembrolizumab alone. The other asset in our portfolio is our triplet therapy, also known as mRNA-2752.
So 2752 is a combination of OX40, IL-23, and IL-36. These mRNAs are injected directly into the tumor and elicit a very robust immune response. That immune response is really exciting because part of the mechanism of action for this combination is it induces tumor cell killing that unleashes antigens, which train the T cells then to go out and attack those specific antigens. And so because of that, we've seen abscopal effects, meaning that we've injected the tumor, and we've seen lesions distant to the injected tumor have tumor responses. This is a schematic of our phase 1 trial, so we've had multiple different types of tumors enroll into this study, including some lymphomas, and we're expanding into a melanoma CPI refractory setting.
And then the other study that's been pretty exciting to see is an investigator-sponsored study in DCIS, where we've seen really robust immune responses in injecting these DCIS tumors. And this is ongoing work that's being done by, Dr. Laura Esserman. She presented some of these data at the San Antonio Breast Cancer Conference, and we hope to have updated data coming up, at this year's, San Antonio Breast Conference. That was a real quick overview of some of our other pipeline assets. Now I'm going to pass things over to Dr. Loughlin, who's gonna talk to you about some of our external engagements. Thank you.
Thank you. All right. In addition to the clinical pipeline that we walked you through today, we wanted to share just a little bit about some of our early efforts, which are really looking to diversify the oncology pipeline that we have with our platform.
So we recognize that our platform is well suited for multiple therapeutic approaches in immuno-oncology, and we also recognize that there's a depth of expertise in each of these types of approaches that can really be critical to success. So we have identified partners in different areas who can really bring that design and biology expertise to our platform through collaborations. So we'll give you a preview of each of these different product concepts. Starting with TCR bispecifics. So these are a form of T cell engager, and like many T cell engagers out there, they do have a CD3 binding domain that identifies the T cell and helps activate it. What's unique about this format is the other binder. Instead of recognizing cell surface proteins, like your CD19 or your BCMA, it's actually a TCR mimetic.
So what it recognizes is a specific peptide presented on an MHC by the cancer cell. Now, this really opens up a new target space for a T cell engager. You can look for intracellular proteins as cancer antigens. So not only can you look at a bigger target space, but you can also pick targets that are more specific to cancer cells. And so this can let you open up that therapeutic index as you're developing your T cell engager. Now, what's important to also recognize about this format is that it is HLA restricted, so that bispecific is specific to a certain HLA type.
So much like you think about INT being individualized and being able to help any patient with any HLA, we look at our platform and the advantages we have in manufacturing, speed, and costs, and know that we can pursue additional HLA types once we understand that a cancer antigen is a good target, has a good therapeutic index, and is starting to show that clinical signal. Our platform also has the ability to combine different bispecifics, so we call it multiplexing. You might think of it as a combination, but they're actually just one therapeutic in our eyes. You can actually pursue multiple cancer antigens in one therapeutic. So through our collaboration with Immatics, we're bringing these forward.
They also have two bispecifics that are already in the clinic in recombinant protein form, so we're very much looking forward to those data and what it teaches us about this field. So the second concept is actually an enhancer for T cell therapies. So engineered T cell therapies have been transformative in certain spaces, particularly the hematological malignancies, but in other spaces, you can see limited persistence of the engineered T cells once they're infused. You can see, partial responses or exciting responses, but limited durability. And so what we're looking to do is, after you have infused an engineered T cell therapy, then we provide an mRNA enhancer. And what that does is, within that patient's body, it's presenting the same antigens that those engineered T cells are designed to recognize.
And outside of that suppressive tumor microenvironment, it's actually looking to present that antigen to those T cells to help them activate, to help them proliferate. Now, we have two collaborations right now in this space. These are clinical combinations. So we're looking to combine with Immatics IMA203, which already has phase 1 data out there in metastatic melanoma. And so we have designed an enhancer that presents the specific epitope and frame that that TCR T cell therapy is designed to identify. We also have a collaboration with CARsgen on CT041, which has phase 1 data in gastric and pancreatic cancers. And similarly, our enhancer encodes for claudin 18.2, which is what the CAR in their CAR T is designed to recognize.
Now, this type of combination is a relatively new application and a new field, and so we're really looking forward to getting data and looking and seeing if we think this application could work across different types of cell therapies, regardless of target, regardless of format, and really enhance the performance of those cell therapies in settings where it's been a little bit challenged, particularly solid tumors. And then finally, we're working on our own cell therapies, but with an in vivo approach. So this is in the CAR- M space. So with our mRNA in an LNP, we can infuse those into patients and actually transfect a patient's myeloid cells in vivo with a CAR- M. So we're transfecting monocytes they might be trafficking around. We can transfect macrophages, which might already be in the target organ.
With that CAR, you can help those monocytes and macrophages if they are circulating, once they reach the tumor, stay there and actually change their state. This is where our collaboration with Carisma really comes in, because the design of that CAR is very specific to myeloid cell biology, and they've been working on this for quite a while. Once it's in that environment, recognizes that antigen, it moves into a pro-inflammatory M1 state. It stays present there. It starts releasing cytokines and other proteins that help it make that suppressive environment a little bit more inflammatory, and it also starts to phagocytose cancer cells.
Now, the myeloid cells do not have to eat the entire tumor, but by eating cancer cells, they actually turn into an antigen-presenting cell themselves, and so they are showing those antigens from the cancer cell to all of the other T cells in that microenvironment. And so what we're really excited to see is in Carisma's clinical programs, which are ex vivo, whereas ours are in vivo, but they follow the same principles, their translational data is showing this multifaceted MOA. So we hope this gives you a sense of the diversity of different approaches we're looking at in the early oncology pipeline. And I think I'm handing it over to Lavina or Stephen for Q&A.
A little bit of both. Thank you very much, Rose. And I'll ask maybe Kyle, Michelle, and Rose to come stand near Lavina, and we'll try and answer as many questions as we can in about the 20 minutes we have. So, please, and Lavina has the wand, and we'll approach people. So Lavina?
If I can please ask that you identify yourself and your affiliation before your question. Thank you.
Oh, great. Thanks so much. Luca Issi, RBC Capital Markets. I have three quick questions. So first, maybe, how do you think about the impact of the NADINA trial that we've seen at ASCO? Implication for your study feels to me that, you know, new standard of care is PD-1 plus CTLA-4 in the neoadjuvant settings now. So, do you still have space to potentially amend the protocol and maybe explore your INT as add-on in that settings? Any thoughts there are much appreciated. Two, how should we think about potential for an interim look for the phase three? Is the phase three designed to have an interim look, and if so, after how many events, and how much alpha are you spending there for the interim look?
And then quickly on the accelerated approval and potential for accelerated approval, in your mind, is that less or more than 5% chance? Thank you.
I'll take that question first, and then I'll maybe hand it off to Kyle-
NADINA
Michelle to handle the NADINA and the phase 3. So on the accelerated approval, as we've said before, you know, we think the data is pretty compelling. When the hazard ratios are getting to the numbers we're talking about here, and when there's a trend on overall survival, it's an appropriate question to ask. We have not yet because we wanted to show diligence in rolling the phase 3 and completing the manufacturing site, activities that we are well underway on this year. We wouldn't be asking if we didn't think it was a reasonable public success, but I wouldn't dare to assign a number to it. At the end of the day, it's not our call. It'll fall for regulators, both in the US and Europe, to make that decision.
Maybe I'll respond to the NADINA question. So any treatment that's gonna help patients, we're all for. And so it was exciting to see that hazard ratio of 0.32. I mean, that was incredible. But I have some concerns about NADINA. First, it was an investigator-initiated study. We don't know if it would meet any type of regulatory bar. Secondly, they only have 9 months of follow-up. I think they really do need to do a further follow-up on that study. Third, 47% of those patients, after 2 cycles of ipi/nivo, had grade 3 or worse side effects. So it can be challenging to try and administer that therapy. And lastly, as Dr.
Weber said today during the session, a small percentage of patients would be eligible for that type of treatment based on the eligibility criteria for NADINA. He said in his practice, he likely only sees about 15% of his patients that'd be eligible for that therapy. So despite the fact that Christian mentioned that all studies should stop and amend immediately to change their control arm, that's not part of our plan. The current standard of care, we believe, is pembrolizumab adjuvantly, and so we're continuing with that plan. And then for the phase 3, maybe I'll just quickly mention, yes, we do have interim analyses planned. We have not disclosed how much alpha we're spending or the timing of those interim analyses. And is there anything else you wanted to add on the phase 3?
Yeah. No, we're very excited about the phase 3. As Dr. Weber said, it's enrolling. We're very excited about the support for the patients, the support from the sites, and then obviously, the sort of continued data sets like we're showing with the 3-year, only uplift the momentum we see for the phase 3.
It's just amazing enthusiasm that we're seeing for the phase 3, and it's just really heartwarming to know that people are so invested in that study.
Gena Wang from Barclays. So maybe follow up, you know, two questions. One also maybe ask about the market opportunities. You know, a few doctors we talked to, they talk about there could be a niche market opportunity for melanoma. Maybe you can help us understand why that comment is wrong. And then second question is also for accelerated approval path, you know, why manufacturing readiness is important? We haven't seen any other therapy like they have to have a manufacturing ready, even cell therapy, before they were able to submit for accelerated approval.
Okay, thank you for that, Gena. So I'll, I'll take that—the second part of that first, because it is really important. This, as an individualized treatment, is unlike anything we've ever done in our platform before. It is sort of like cell therapy, but we're gonna be trying to do it at a much larger scale, particularly as we move into histologies like lung. And so for that reason, in order for us to be able to license a facility, at the end of the day, it'll be a facility, not just the concept of an INT that will be the subject of a review and a license from a regulator like the FDA. We have to establish that facility so it can be inspected. And so we, we certainly could, in our clinical trial right now, rely,
We're manufacturing INTs, about 1,000 this year for the ongoing phase 3s, if you just do the math. And you could rely upon those facilities, which are Norwood, for the manufacture of commercial scale INT, but we really think that wouldn't be the optimal overall long-term plan from a commercial perspective. It's not the right economics, as you know, from Norwood. Yours and others who've been there. It's got a phenomenal number of programs that are running through it. It's our R&D site. We also do our large-scale commercial manufacturing for other vaccines. And so for a whole host of reasons, we don't actually think it makes sense to establish INT personalized manufacturing there, and we'd rather dedicate a separate facility.
That's a facility that we've been building in Marlborough, Massachusetts, for almost a year now, and we're well down the path to establishing that. That would be the facility that we would expect to be a part of our submission, and that ultimately would be inspected as a part of that submission and licensed to manufacture INTs. It is because it is such a unique manufacturing challenge. We're not scaling out to billions of doses. We're scaling down to 9 or 10 doses for an individual, but scaling out to thousands of different medicines every year that we're making in that facility. Because of that engineering, it is unlike anything else we're doing, and really do think it's gonna be best served long term by a purpose-built facility.
In terms of the niche market, we don't believe this is a niche market. Look, there's thousands of patients that are eligible in the U.S. alone for INT, and then you think globally, there's clearly a high unmet need. As you saw from the curves that Michelle had presented, almost half of the patients recur with pembrolizumab. So there's a huge unmet need in this space, and we think that INT can fit it. But the other important component of this is that we don't believe that INT is relegated to just melanoma. It should be histology agnostic, and so that's why you see such a broad range of different tumor types that we're expanding into bladder, renal, lung, melanoma. There's head and neck cancer data.
So far, we don't believe that there's any reason why any tumor type should not respond to INT, so that doesn't sound very niche to me. But of course, our first step out of the gate is gonna be in melanoma. Anything you want to add to that, Michelle?
No. I think you guys covered it nicely.
Hi, this is Dina from Jefferies on behalf of Mike Yee. In terms of the metastatic setting with INT, you had really good results for the head and neck, but you've started a lot of adjuvant studies, so just thinking about your strategy there, given this positive result, do you plan on moving into the metastatic settings? And if so, which specific tumor types would you be able to do that first? Thank you.
Yeah. So I, I think that you can see, based off all the studies that we've had, that we're definitely invested in the adjuvant space, but we're also making biologically rational, driven decisions, right? So we're still learning about INT. We're still making sure that the manufacturing is up in time. We're still making sure that those patients are getting their treatment in an upfront manner as quickly as possible. So we really believe and are following the data from the P201 study, and what it set forward is that litany of studies. Now, we know that the metastatic setting is just a larger hurdle as a whole, right? We know those patients are sicker, they move faster, they have bulkier tumors.
So the hurdle for a mechanism of action like INT and an individualized therapy, where you need their sample to sequence and then generate their individual medicine to get delivered to them, it has a whole litany of different questions than the adjuvant space. But as Kyle showed, that we really are thinking about making rational decisions today to make those learnings and then open the door to find out where those boundaries are for INT. We believe in the head and neck data from the P101 study, so we really are thinking about exploring that. We also really believe in the safety profile for INT and the risk-benefit that could be for earlier stage patients, so we're really thinking about that. What you also see in our adjuvant space is very warm tumors, very high TMB tumors, right?
But we also know that we have a pancreatic cohort in our P101 study, and so we're starting to sort of expand not only that warm tumor environment, but also out into those colder TMEs. So what you're seeing is a solid foundation for learning and then an expansion out for the opportunities for INT.
The other thing I'll just add real quickly is the other thing that gives us confidence in potentially moving into the metastatic space is what Michelle had showed previously with the ctDNA-positive patients. Those essentially are behaving just like metastatic patients, the ctDNA-positive melanoma patients. And if they're responding as well as they are to INT, I think we've got a pretty good shot at metastatic, but only the studies will tell us whether or not we'll have efficacy. But those studies are currently being planned, and we will let you know what those studies are in due time.
Thanks. Terence Flynn, Morgan Stanley. I know you guys had made an effort to rename the vaccine from PCV to INT, and you've done a lot of initial dose-ranging work, but maybe just talk to us about, you know, that decision and also some of the decisions on doses for some of the subsequent trials, how you're kind of choosing dose and confidence there. And when you think about, you know, frequency of dosing, obviously, with the durable data you're seeing here, how does that factor into, to longer-term decisions? Thank you.
Sure. Yeah. I'll- You want to take the dose stuff? I was gonna take the PCV to INT, but maybe I'll let you take the dose question. But anyway, let me start with PCV to INT. So, one of the reasons why we decided that INT made more sense in this setting is because we're not really using INT as a preventative therapy. And most people think vaccine is a preventative therapy to make sure that they don't get COVID or RSV, as some two prime examples of other products in our pipeline. And so we're not using this as a preventative therapy, we're using it as a treatment.
And that comes with a very different profile and consideration of perhaps a toxicities that you might not expect from a very aggressive chemotherapy or IO agent. So that led us to change the nomenclature to INT, an Individualized Neoantigen Therapy, as opposed to having a vaccine as part of the nomenclature.
The only thing I'd add to that is that there was at least one regulator, major regulator, outside the U.S., where the use of the word vaccine was actually a problem for them in terms of classification of how they would regulate the product. And so there were even regulators who said: Look, you're really doing this with a therapeutic intent. The word vaccine will create more problems than it is. So it wasn't just that interpretation. We were actually advised externally as well.
And you're correct, we've done some dose exploration. We think we have a pretty good dose, as clarified by the 201 data, so we don't really wanna fix what isn't broke. So we're moving forward with the same dose and schedule with our future studies, with some minor modifications based on how the chemotherapy is administered and how the IO agents are administered. But we strongly believe in the dose that we've been using for the 201 study, and that we're currently using for 101. Anything else you want to add about dose and schedule?
Yeah. So with, with dose and schedule, I think the key is that we wanted to manage that risk-benefit and then also patient convenience, right? We know that the IO agents, when we're paired with pembro, are every Q three weeks or Q six weeks. We think from a biological perspective, from a priming and reexposure perspective, that we think the Q three week makes the most sense to allow for the T cell mobilization. As you saw with both the P101 and P201 study, we're very encouraged by the, the data we're seeing, and we also believe that with the 9 doses, what we're doing is appropriately mobilizing T cells and training and activating them, but we're not exhausting them. And so we're standing by the dose, dose and schedule that we see, and you see it throughout all of the future studies that we have.
We have looked at immunogenicity to understand if that's the case, and yes, we're seeing activated T cells long after the last dose of INT, so we feel pretty confident that they're not getting exhausted from the current schedule.
Great. Hey, guys, Jessica Fye, J.P. Morgan. I had three. Coming back to NADINA and its relevance in the comment that less than 20% of patients would meet those criteria. Can you talk conceptually about why or why not neoadjuvant treatment, like, wouldn't benefit other subgroups who are otherwise candidates for adjuvant melanoma treatment? And I'm just thinking about even if it were like the SWOG S1801 regimen, that might dovetail a little bit more with kind of what you're already working on versus full-on ipi-nivo. Second, regarding the phase 3 in adjuvant lung, I know you said there's lots of enthusiasm to enroll the phase 3 for melanoma, presumably because you have this phase 2 data. So how's enrollment going for adjuvant lung?
And then lastly, following up on Terence's question, I guess, if you're seeing those activated T cells and good kind of durability, is there any consideration to maybe like spacing out dosing frequency at least a little bit farther into treatment?
Great questions. So let me first tackle the NADINA question. So, I think that based on SWOG S1801 data, neoadjuvant approach does make sense. But there hasn't been any efforts to change any labels globally or really significantly change the, the standard of care. And so when we go out and talk to melanoma doctors, there hasn't been a big shift to a neoadjuvant approach, and so we believe that it's still relevant for us to continue on with our current plan, which is giving INT in the adjuvant setting. Now, sometime in the future, down the road, maybe that will continue to shift at some point, but right now, we think we have the best strategy to continue with INT in the adjuvant setting with pembro, adjuvant. The next question was about, the, the lung enrollment. Early days, very early days.
We can't really comment too much about enrollment. We're still getting countries open. We're still getting sites up and running, and we might be able to give an update sometime in the future, but right now, we don't really have a good sense of what that enrollment's gonna look like. And then the last question was about the spacing out the administrations. It's a really interesting question. I think that might be something that we could explore in other studies. The challenge right now is that we believe that the schedule that we have is effective, and I wouldn't want to compromise that efficacy by exploring that in another indication. So we're sticking with the current schedule, but it may be something that down the road we could explore in a translational study.
Yeah, and I think the only thing I'll add is, you know, with the even the neoadjuvant space, everything we hear about is what is the risk-benefit, how do you identify those truly high-risk patients? And so even with SWOG S1801, they still had a very narrow population where you could have the palpable tumors, right? So you're really trying to identify the appropriate patient population, and I think the data is still early days, as Kyle alluded to. I think we're all excited about this, like, treatment effect from metastatic, to adjuvant, to neoadjuvant, and we see more and more of that creep. But what we're also still hearing is, where is your risk-benefit? Who are the patients that really need this? Who are the ones that can watch and wait? And I think we're still early on in those days.
So for what we see, we really believe in where INT is sitting in the adjuvant space. But that's not to say that we wouldn't explore it earlier on. We're seeing that with our cutaneous squamous cell study. It's in the perioperative space, and even in P101, we have a perioperative gastric cohort and perioperative non-small cell lung cohorts. So we are definitely exploring it, but we're just not there yet for melanoma because it's just so novel at this point in time and understanding those patients. Lung, the one thing I will add is that we see enthusiasm across the board for INT across the tumor types that we have. We really aren't hearing, "Oh, you have metastatic or you have melanoma data.
We're only really excited about melanoma." That's just not the case, because INT is so individualized to the patient, that we see that level of engagement and enthusiasm really across all of the studies we're seeing.
The other shift that has to happen to make S1801 a reality is the practice patterns have to change. That means a medical oncologist has to see these patients before the surgery happens, and that's not happening yet. There hasn't been that shift in practice patterns, and that's hard to do. We've seen that in breast cancer, where it took a long time for that neoadjuvant approach to really take hold because they had many, many multidisciplinary clinics, and they had a very, very aggressive patient advocacy organization that tried to push that to happen. I'm not seeing that shift happening yet, and it may take a long time to get there.
Myles Minter from William Blair. I think going back to AACR, when we looked at the head and neck cancer data, there was about 23% of patients that actually had detectable T cells that were activated against your vaccine. So I'm just wondering whether you've learned anything across your trials that can help boost that response. And in the
ctDNA positive patients that have responded in the melanoma study, like, what did their T-cells look like in terms of percentage of responses? Just coming back to the comment that that ctDNA positivity might be a surrogate for more metastatic indications.
Yep. So, first things first, in the P201 study, because it was so focused on establishing INT as far as the clinical efficacy goes, we did not sample a lot of patients in for apheresis for T-cell responses. That was not the priority. Now, we are launching what it's called a Part B of that study, where we are enrolling additional patients for additional translational analyses to really understand that lens of the neoantigen presentation, more of the immunogenicity work, more about recurrences and all of those pieces. So there is a translational arm that is now enrolled on that study. So we'll know more with that. With the P101 across the board, anytime we've looked at the translational data, we showcase that we are mounting T-cell responses to approximately about a third of the neoantigens that we're including, but these are pretty high T-cell responses.
Currently on the literature, we don't know how many neoantigens need to mount a T-cell response to be able to drive a clinical benefit, right? That is a magical number. It could be just one.
That's all you need.
But what we believe in is that what we're doing with our algorithm is that we are selecting the ones that we think are going to be more robust. They're having multiple shots on goal, allows us to minimize tumor escape, increase neoantigen cross-linking, you know, elicit more T-cells into that milieu, which then will help with, like, clonal escape and those pieces. So it's a synergistic mechanism, and I don't think it's just gonna be this one for one. Like, you get one T-cell, one neoantigen, and that's going to do it. Nor do I think having a magical number up to 34 is going to be. It's somewhere in there and what happens in that individual patient. But we are in all the studies that you see, collecting a lot of samples for these patients to really understand what INT can do.
And the beauty of it is that it is based on a computer-based algorithm, so that gives us the latitude to take those learnings from clinic, put it back onto the algorithm, and then move that forward to iterate on itself. Now, the novelty is that we don't want to break it, we believe it. And so there's always this balance of learning and application that we're also going to be thinking through with the development.
I'm also really excited about some novel techniques that we're using, including T-cell receptor sequencing. Looking at that T-cell repertoire, I think, will be really informative. More to come in that space, but we're learning a lot about how INT works.
Mani from Leerink Partners. I struggle to add on to some of the excellent questions that have already been asked.
But I do want to follow up on Luca's question. I don't think it could be quite as quantitative as set a 5% line, but let's talk about timing, which I think you can talk about.
Yes.
Let us presume that we get to all the various manufacturing questions and discussions that you're having with the FDA and other regulators, which we're not entirely privy to, but you certainly are. Those are resolved in a satisfactory fashion. You have regulatory feedback, letting you know those are resolved in a satisfactory fashion. At some point this year, I would guess. What is the process from that point, presuming the phase 3 is fully enrolled, which I would guess it is, should we expect a press release? Should we expect commentary at ASH, SITC, J.P. Morgan next year? Like, what would be your philosophy and timing on when you tell us, "Oh, we've decided to, to file. We've made a decision based on these phenomena, these analyses." Like, when might you tell us, and what metrics will you use to decide, we should file, we shouldn't file?
So it's a fair new approach. I won't say 5% or not or anything. But let me do the best to characterize how we're thinking about it. Obviously, I won't break any new ground in giving a date or a specific time. We've said pretty clearly the three things we think are necessary: durability, a manufacturing facility, and enrollment in the phase 3. We feel like with the data we have right now, we've got the first, in terms of durability, and it's pretty compelling hazard ratios, and we're pretty set on that. The manufacturing facility, we're well down the path. We hope to give tours in the future.
But, we would assume that our ability to establish the right operational cadence in that manufacturing facility will happen soon. We are obviously in the phase 3, already manufacturing at a scale that's almost commercial for an individualized treatment, you know, 1,000+ patients this year.
So we have some line of sight to that, some confidence to it. When it comes to the phase 3 enrollment, we're well down that path as well. I think one of our investigators may have said and made some news on that recently. So I won't confirm or deny, but we're really happy with the brisk pace of enrollment in that study. In many ways, we feel ahead of schedule. The next announcement we would make will be with our partner, Merck, when we're completed that enrollment. At that point, we would know, we would all know that we've kind of satisfied at least those three criteria. Now, the question of how we would approach regulators, obviously, there's— we're, breakthrough designation, PRIME designation. We have the opportunity to engage in those conversations.
We'll keep those confidential while we're having them, because there'll be some back and forth. It's likely not a one and done. If we did get to the point where we were gonna proceed with submission because we got an indication that that was an appropriate thing to do at this point, we would talk to our partner, Merck, and it would be a joint decision on public disclosure. Obviously, it's a significant one for us, and so we would lean into wanting to make sure people were aware of that because it would start to become a big part of our activities and work for the short term. So I can't give you a date when that'll happen.
We're getting real close to all the pieces being there, but the next step for us is to finish this enrollment in the phase 3.
Great. It looks like we've exhausted all questions. I'll hand it back over to Stephen just for real, and the team for concluding remarks.
Yeah. Well, I just wanna, first of all, thank my colleagues for the excellent presentation and Q&A, and obviously, thank all of you for taking the time. It's an exciting moment for us. It's our second chance to do this at ASCO. We hope to Mani's and others' questions, that maybe next year we're talking about even more specifics on the progress of the INT program and and some of these milestones being behind us. But we also hope to be able to share some of the progress and the clinical data on some of those other programs, because we really do believe that we're just the beginning of showing the potential of our platform to impact cancer and help cancer patients across the world. So thank you for being here.
Thank you for your time, and hopefully, we'll see you again next year.
Thank you.