Moderna, Inc. (MRNA) Earnings Call Transcript & Summary

Good evening, and thank you for joining us today. This is a very exciting day for [indiscernible] it's an exciting day for cancer immunologist, and it's an exciting day for Moderna. Today, I'm going to start by giving just some brief contextual statements on it. I'll then invite up Dr. [indiscernible], who was the lead investigator for [indiscernible] and gave a fantastic presentation today to give a reprise of that presentation. I'll conclude with concluding statements. And then we're very fortunate to have 2 world experts in melanoma, Professor Ascierto, who was the senior author of INTerpath-001 and Professor Ribas, who is a melanoma expert and a world leader in cancer immunotherapy as well Immune surveillance controls emerging cancer cells. And it does this by detecting neoantigens that form in cancer cells. These neoantigens drain or are carried to regional lymph nodes. They are processed in antigen presenting cell and then brought to the surface of the antigen-presenting cell and present it to T cells. T cells that recognize these neoantigens are activated, they circulate throughout the body, looking for the cancer and they eliminate the cancer. However, as we know, cancer can escape immune surveillance, when either the cancer lacks sufficient neoantigens and the neoantigens aren't released or aren't transported to the lymph node. The antigen presenting cells don't process them or present them on the surface. The T cell is insufficiently activated or the T cells become exhausted. Checkpoints act on T cells, anti-PD-1, PD-L1, reverse T cell exhaustion and anti-CTLA-4 lowers the threshold for T cell activation. However, they act only on T cells and are limited by whatever available neoantigens are present in that lymph node. Intismeran, as shown today by the Phase III data, has an entirely different mechanism. It optimizes neoantigen presentation. And how does it do this? Well, first, we take the tumor out of the patient and use an algorithm to select the most promising neoantigens. We package those neoantigens into an mRNA [indiscernible], and that's used to inject into the muscle of the patient. Now we know from nonhuman primate studies and from rodent studies that when an mRNA LNP is injected into muscle, it drains into the regional lymph node is taken up by antigen-presenting cells and dendritic cells. The RNA is produced into protein, and that protein in the case of neo -- in the case of our neoantigen Intismeran can be presented on the surface. So there are 3 important points to take away about why we think Intismeran is so potent first, high neoantigen expression in the cells where it's required in the antigen presenting cells and in the dendritic cells. Number two, this is in an optimal environment. It's far away from the immunosuppressive microenvironment of the tumor. And number three, because CD4 and CD8 T cells are activated, dendritic cells are activated, and cytokines are released, there's a peer's a perfect mile to create polyfunctional CD4 and CD8 T cells. And we have translational data to support some of these. Let me take you to ASCO 2026 just a few months ago, where we presented the Phase II data. I'd first like to draw your attention to the initial Phase II data that was presented a few years ago. Recall the hazard ratio at the primary analysis, which had the same follow-up as INTerpath-001 today, the hazard ratio was 0.51 to 0.61 at the primary analysis. With longer follow-up, as we showed a few months ago, the hazard ratio improved to 0.51. Now why did the hazard ratio improve? This can be seen looking at the art of the Kaplan-Meier curve. For the first 6 months, on the left-hand side, the hazard -- the Kaplan-Meiers are overlapping. And as you heard today from Dr. Long, this is in part due to the weeks required to produce entrant and then weeks or a month for the immune system to be activated. At month 6, the curve separate, and we know they'll eventually remain separated. However, in the primary analysis, that first 6 months takes up about 1/4 of the entire Kaplan-Meier curve that hazard ratio for the first 6 months takes up a quarter that -- in the longer 5-year follow-up, that 6-month haz ratio 1 is still there, but now we have follow-up to 60 months. And therefore, that initial 6 months takes up better fraction of the entire hazard ratio. And this is why we prespecified to conduct a piece-wise analysis at 6 months, and you'll hear that from Dr. Long during her presentation. But it's very important, I think, to recall in this analysis. And we do believe the Phase III data for this reason will continue to improve. Intismeran, as I mentioned, activates T cells, and we should expect to see novel T cell clones in the peripheral blood. This is a figure. The y-axis is the sum of novel T cell that we detect in the blood. And the x-axis is 4 different time points, baseline, post the pembrolizumab lead-in and just prior to Intismeran at cycle 5, so in the middle of the Intismeran regimen and then add a follow-up. And this is the Phase II Intismeran plus pembro -- versus pembro. The first portion notice the 2 arms are overlapping because patient -- both groups of patients are receiving pembrolizumab, exactly what you would expect to see. However, once Intismeran is administered. The combination curve continues to go up, more novel T cell clones are generated compared to the control arm. This leads to the question we asked with high levels of novel T cell clones be associated with clinical benefit. And in theory, this should be most evident in the combination arm. And that's exactly what we see. So the same y-axis is the number of unique loans, X-axis is the same. On the left-hand side is the combination arm. And on the right-hand side is the pembrolizumab arm. Now we've separated the patients into 2 groups. Those who had benefits, i.e., never had a recurrence and those who had, let's say, no benefit, those who had a recurrence. We did that for both arms. And you'll notice for the combination arm, patients who had no recurrence, which is the top, their novel T cell clones continue to increase during treatment, whereas the ones who had recurrence plateaued. For the pembrolizumab arm, there's an initial increase, and then there is a plateau. So this is evidence that there's an association mechanistically between the number of novel T cell phones and clinical benefit. Now these are novel T cell phones, and we don't know if they are related to the Intismeran drug product. And it is a little more complex to match T cells to neoantigens, but we were able to do it in 7 patients, which requires a lot more blood than is typically taken during the routine blood assessment. So we had -- so we consented 7 patients, and we match their T cells to the 34 neoantigens they received in their cassette. And what we found is, on average, one out of every 3 neoantigens in the 34 set is immunogenic. That is -- it induces a T cell that is novel in the blood that react specifically to that neoantigen peptide. And it ranges from about 1 to 18. And interestingly, it includes both CD4 and CD8 T cells. We then sought to further characterize the phenotype of these T cells. And we find -- this is an example. It's a CD8 T cell that recognizes neoantigen 14 from patient 3 and the CD4 T cell that recognizes neoantigen 27. And when we phenotype it using flow cytometry. What we see is that both T cell clones are polyfunctional. They make different types of cytokines, and they also have markers of a cytotoxic genotype, meaning that they're ready to go out and kill the cancer cell. Because we were able to clone out those T cells that recognize those new antigens, we had the TCR sequences, and we could go back to hold [indiscernible] and we could follow the frequency or the prevalence of those T cells during treatment. So it's the same time frame on the bottom screening, leading with pembrolizumab in the middle of the intezmeran regimen, and then at the end. And what you'll see in these 3 examples that all T cell clones only appear after Intismeran, not during pembrolizumab and most of them remain elevated for the entirety of the treatment. As a side note for the -- for those who are immunologists, one of the interesting features, which is known is that there are usually multiple T cell phones that can recognize the same neoantigen peptide. So at this point, I'd like to invite up Dr. Long to give the presentation of INTerpath-001 and then I'll return to give a few closing comments. And please come up this way so you don't fall. Okay. SP999 Thank you. SP1 You press this on advance Okay.

Okay. Thank you. Thank you. It's a pleasure to present these data again to a smaller, more cozy audience. So -- and it is a true honor to be able to present results on something so transformational for cancer. So this is a Phase III randomized clinical of Intismeran combined with pembrolizumab. We refer to intesiran as an type of IT therapy versus pembrolizumab alone for the adjuvant treatment of Stage IIb up to stage melanoma. Now I don't have my glasses, but I can see this slide I'm not that blind, but so -- and I do present this on behalf of my co-investigators, 7 global sites and all of their teams. These are my disclosures. So we know that there is a clinical benefit for the adjuvant treatment of melanoma patients with anti-PD-1 monotherapy alone. That's clear. But shown here are the 2 curves for Stage III resected melanoma and Stage II resected melanoma Stage IIb. The red curve is placebo. The blue curve is pembrolizumab alone. And yet, despite their significant clinical benefit and absolutely changing the field, we still have 44% and 33% of patients recurring or dying at 5 years. So in the melanoma field, we see that there is a big -- a lot more work to do in terms of getting to 0 deaths and to curing cancer. Now it's not that we haven't been working at it. These are 3 landmark Phase III clinical trials combining anti-PD-1 with 3 different checkpoints, CTLA-4, LAG-3 and anti-TIGIT all negative. And so we have not had any improvement in the adjuvant setting over and above anti-PD-1. Sorry, go back again. And what I presented today was really asking the oncology world, how did we get here to reflect on how we got here in 2026. And there really is over 100 years of work in immunology, cancer biology and the technological innovation that's happened, particularly in the last 60 years. And so if you're looking at where we are today with Intismeran, there are 3 really important scientific advances. First of all, the discovery that neoantigens exist back in the 1980s. These are unique mutations that are only found in an individual tumor. They are not found in their normal cells, and they are not found in anyone else's cancer. And that begs the question if they're so unique, could they be seen as foreign to that patient's immune system. Then the second biggest scientific advance is really built on next-generation sequencing, and that's the ability to rapidly sequence the tumor and also use the computational algorithms to identify and rank which neoantigens we think or we predict will give us the most robust antitumor response. And then the third is a platform that really is built for speed, and that's the fact that mRNA, you can include many multiple antigens in a single strand of mRNA. And there's a demonstrated robust CD4 and CD8 tumor response or responses to these proteins. That's wrapped in a lipid nanoparticle injected into the patient. So altogether, that is a very rapid individualized manufacturing process, giving us Intismeran. Intismeran, as you heard before, encodes up to 34 neoantigens, and this is based on the patient's individual what we call, tumor [ mutanome ] and their HLA type. The workflow for Intismeran is standardized from collecting the tumor tissue and blood right around to administration of -- to the patient takes 6 to 8 weeks. In terms of the mechanism of action, this is now a busy slide without the animations. But -- so it's injected intramuscularly. The mRNA is then taken up by nearby cells, all sorts of cells. Antigen-presenting cells take this up as well. They process the protein, present the protein as neoantigens in this case and elicit a T cell response, clonal expansion migration to the tumor and then tumor cell kill. And it is hypothesized that with the release of more epitopes as the tumor is killed, but this enhances that cycle of immune activation. [indiscernible] here. You've just seen the data for the Phase IIb trial. Just to reiterate that the clinical benefit is durable out to 5 years. Left is relapse-free survival. So this was the proof of concept. Right is distant metastasis-free survival, hazard ratio of 0.41 at the last analysis and 0.51 and [indiscernible]. But most importantly is that there is translational data, which you've just seen, which linked the T cell clonal increase to the lack of relapse and that, that was mapped precisely to the neoantigens in the Intismeran. So I won't go through that in any more detail than as we've already heard, so this is the design. This is a standard adjuvant trial design in terms of eligibility, resected cutaneous melanoma, [ AJCC 8 ] addition. Stage IIb right up to Stage IV, these are high-risk patients recurrence. Each patient had to have formal and fixed paraffin-embedded tissue that was of sufficient quality and quantity for Intismeran manufacturer, which required next-generation sequencing and then no price systemic therapy. Patients were randomized 2:1 to the active arm of Intismeran 1 milligram intramuscular every 3 weeks for 9 doses plus standard dosing of pembrolizumab every 6 weeks versus placebo and standard pembrolizumab. The pembrolizumab was started first at randomization within 13 weeks of recession. The Intismeran was started as soon as it was available to the site, the earliest was [indiscernible] in day 22 and the latest was Cycle 4 day 1. The primary endpoint was the relapse-free survival as per the investigator. The secondary endpoints are shown here, the key one for today is a distant metastasis-free survival. The statistical considerations are very important because, first of all, we had hierarchical testing, which is pretty standard for these large Phase III trials. If the relapse-free survival is positive, you then move on with power to the distant metastasis-free survival than to the overall survival. The treatment differences, just to see if they are significant was tested by the [indiscernible] test. That doesn't tell you the size. It just tells you that it's statistically significantly different. The size or the magnitude of the treatment difference is measured using the hazard ratio for the primary end point. It was the COGS model, which is a standard approach in the intent-to-treat population. However, because of that delay in the separation that we saw in the Phase II, there were preplanned sensitivity analysis to look at the robustness of these results. And one is called the piece-wise hazard ratios. And I really do think that this trial will be the first to sort of set this as one of the first standards for immuno-oncology because this is not a new phenomenon that you may have a little bit of a later separation. And then the other thing is the modified intent to treat. And that is all people who actually got the placebo or the Intismeran. The interim analysis was conducted when we reached at least 240 recurrence events and at least 18 months since the last patient was randomized, and this is 24.6 months of median follow-up at the data cut. So 1,749 patients were randomized -- sorry, worth screened, 1,137 randomized the biggest reason, the most common reason for screen failure was due to inadequate tissue supplied by the site. And I'll talk about that in a minute because I was one of the sites, how did we learn from that experience so that we became very efficient at getting the right amount of tissue. 757 patients were randomized to the combination, 380 to pembrolizumab alone. In both arms, one patient didn't receive treatment, the rest [indiscernible] did. Then when you move to the addition of the placebo Intismeran that was equal in both arms, 96% of patients received placebo or their Intismera in each arm. 70% completed treatment, similar in both arms, but the reason was different for discontinuation in the combination arm, it was adverse events. But in the pembrolizumab arm, it was due to recurrence that they didn't continue to treat. So 91% of all patients in the trial had the maximum of 34 neoantigens identified for the Intismeran design. Over 99% of those randomized to the combination, we were able to, when I say we, Moderna, we're able to successfully manufacture the Intismeran. The median time, and this is really important to describe those curves, the median time to first dose of Intismeran with 64 days. Baseline characteristics is what we would expect for this population and similar in both arms. The most common stage with Stage III, which is what we would expect and the least common Stage IV, which is also what we would expect. So this is the Kaplan-Meier analysis for the recurrence-free survival. In the green is the combination. The combination of pembrolizumab with Intismeran significantly improved the recurrence-free survival over pembrolizumab alone. And the hazard ratio for overall was 0.58 with a p value of less than 0.001. So this represents an overall 42% reduction in the risk of recurrence or death with the combination of a single agent. I've also got the 2-year landmark relapse-free survival with 82.2% and 70%. Now looking at the piece-wise hazard ratios. As expected, in the first 6 months, the hazard ratio was 0.99. And then after 6 months, the hazard ratio was at 0.42. So a 58% reduction in risk of recurrence or death after 6 months. And the reason this was done, as I'll reiterate -- I said it before, is the mechanism of action. I know David said it as well, the mechanism of action of Intismeran is at the early stage of antigen presentation. So that requires time for the T cells to get activated. But secondly, the medium time to injection of Intismeran was 9 weeks. This is the modified intent to treat. So this is all patients who actually received placebo or the vaccine or Intismeran, and the hazard ratio was 0.51, so a 49% reduction in the risk of recurrence or death. Now looking at the distant metastasis free survival. One of the key secondary endpoints. This was the second in the hierarchy. It was significant as well with the combination hazard ratio of 0.62 and a p-value of 0.002. So a 38% reduction in the risk of distant metastases or death with the combination. Similar sensitivity analysis, hazard ratio in the first 6 months, 1.01 hazard ratio after 6 months, 0.50, so a 50% reduction in the risk distant metastases or death. And the confidence intervals after 6 months do not cross 1. The sensitivity and the modified intent-to-treat population hazard ratio of 0.55. That's a 45% reduction in the risk of distant metastases or death in the 2-year landmarks for distant metastases are showing there. In the prespecified subgroups, nearly all of them favored the combination over pembrolizumab alone. There are some groups that are very small numbers when you have very small numbers and you have very small numbers of events, the confidence interval is very wide, but it also means the estimate, so the diamond can switch like this with one patient. So you really have to be careful at looking any information with wide confidence intervals, we don't at this early juncture at this first interim analysis. Also, what was really very nice to see was in the risk stratification by stage. So it's risk based. We saw both groups benefit from the combination. In terms of adverse events, the left of what we call all-cause adverse events. So as per trial protocols, there are a lot of things that we call adverse events that have nothing to do with the actual treatment. And then on the right are the treatment-related adverse events. And so I'm going to focus in on those. There was a slight higher rate of all-grade treatment-related adverse events in the combination, which is what we'd expect, Intismeran does cause local adverse events. But importantly, when we look at Grade 3 to 5 or serious adverse events, they were broadly similar in both arms. In terms of adverse events that led to discontinuation, this was higher in the combination arm compared to pembrolizumab. And the deaths, the 2 deaths due to treatment in the combination arm all occurred before Intismeran was commenced, so they were due to pembrolizumab. The 8 deaths due to all cause adverse events, not related to treatment. Only the 2 I just explained, 5 of them occurred for the Intismeran started and 3 after and were not related to either treatment. These parts are really nice because they quickly visualize where you're seeing the adverse events. So this is all cause adverse events in more than 10%. And what we've boxed there are those that are greater 10% incidents in the combination because that's what we want to know, well, what is this doing. Well, what was really interesting is they're very low grade, they all grade 1 or 2. They're very transient injection site pain, chills, pyrexia or fever injection site reaction. And these were of no concern to the investigators looking after these patients. When we look at the pembrolizumab or checkpoint inhibitor adverse events, you can see they're broadly similar in both groups. So what we can say is that it does not appear that [indiscernible] is potentiating pembrolizumab adverse events. So the conclusions focusing in on the efficacy first. The primary endpoint and the key secondary endpoints demonstrated that the combination did reduce the risk of recurrence or death over pembrolizumab alone by 42% overall and 38% for distant metastases in death. If we look at the sensitivity analysis, the combination reduced the risk of recurrence or death by 58% after month 6. The benefit was observed in almost every prespecified subgroup. The overall survival is immature, and so a follow-up. This trial is ongoing. We are continuing to collect data on our patients who continue to remain blinded as are we. Safety was consistent with what we've seen before in the Stage II, no potentiation of pembrolizumab toxicities or adverse events. Intismeran was reliably delivered at a global scale. The trial is evidence of that. And there are ongoing trials in many cancers in the neoadjuvant adjuvant and metastatic setting. So this is not as bold as it could be, but into INTerpath-001 really does set the new benchmark for melanoma. But critically, it is a huge advantage. It is a landmark for the advanced in personalized cancer medicine. Thank you. I just want to also make note of all of the people, all the work that goes into this trial, lots of sites, a data safety monitoring board, the support from the sponsors. And as well, [ Jeff Weber ], we always mention him, he was a huge supporter, had a leading role in the Phase II. And he actually contributed patients and enrolled them right up to his [indiscernible], and this will be published in the New England Journal of Medicine. Thank you.

Thank you very much, Dr. Long. One group I also want to thank and note is Merck. I've been at 2 large pharma companies that have had intense competition with Merck. And I can say it's been absolutely fantastic to be collaborating with Merck rather than competing with them. They're absolutely excellent partners. So just a couple of words in conclusion. Beyond melanoma, there still remains an unmet need across many different adjuvant settings, as you can see here. And we have Intismeran clinical trials in all of these tumor types. Now one of the common questions that is frequently asked is will Intismeran work outside of melanoma. And we have the trials ongoing. But here are the reasons why I walk away believing that it does work. First, there's the science. All of these tumors, except for pancreatic cancer are PD-1 sensitive, PD-1 -- anti-PD-1s activate T cells and T cell scale cancer. Intismeran also activates T cells, but it does it on the front end. And in fact, we know, based on the T cell clones that Intismeran activates different T cells against different neoantigens than pembrolizumab dose. Second is the data. So you heard from Dr. Long today, the ITT, the hazard ratio of 0.58. If you remember, the famous KEYNOTE 54, which was KEYTRUDA versus placebo their hazard ratio was 0.57. So the fact that KEYTRUDA then went on to have success in many other tumors, I think, bodes very well for Intismeran. You heard about the modified intent to treat which means this is the ideal clinical trial setting limited to only the patients who received placebo or who received Intismeran. So it excludes 46 patients who never made it to receive an injection. When you look at that comparison, which is the ideal clinical trial, the hazard ratio is 0.51. And finally, you heard about the piecewise. So this is patients who are 6 months and longer, this treatment effect, this hazard ratio of 0.42 tells you what is possible for Intismeran. It's not the top line, it's not the ITT, but it tells you scientifically what treatment effect is possible with this strike. I really do believe Intismeran will work, but of course, we need to run the trials. There's one more reason why I have belief in Intismeran will work outside of melanoma. And that's the tumor mutational burden analysis. And by the way, in case you're going to ask, we don't have that data yet for the Phase III trial, but hopefully soon. In the Phase II trial, we analyzed RFS by high TMB and non-high TMB or low TMB. And interestingly, the RFS was identical in the Intismeran plus -- or the hazard ratio was identical in both the high TMB and the low TMB. If you draw an imaginary box on the right for low TMB melanoma, you see it does cross most of the that we're studying. One of the tumors, of course, I'd like to draw your attention to is pancreatic cancer, pancreatic ductal adenocarcinoma because we do have a poster tomorrow, and I just want to share data in the abstract because I don't like to leak data presented. So this is a Phase I study of 20 patients who had resection of their pancreatic tumor. And the goal was really to see feasibility can we actually create an Intismeran drug product from a pancreatic tumor sample, which is low TMB. And then we also were curious how does Intismeran interact with chemotherapy. And here's the key data from the abstract once again, full data tomorrow, 20 patients, they had low TMB, 65% had KRAS mutation. The median number of neoantigens per Intismeran concept was actually 34. So we actually did pretty well. Of the 19 of the 20 were immunogenicity evaluable and all 19 had neoantigen-specific T cell response are seen. It's very promising that we can induce T cell responses. In the subset who were evaluable, we could see polyfunctional T cell responses. And interestingly, the T cell response increased over time as we had seen. But there does seem to be an interaction with chemotherapy and the Intismeran-induced T cells go up even further after the full [indiscernible] is complete. So it is feasible and possible to do this and full poster to be presented tomorrow. Now I'd like to invite up our experts to come and join here, and we certainly open this up for questions and answers. Oh, actually, before I do, sorry. Before I do -- sorry, just let me close on this. And then actually, I want to invite up our 2 experts to give some thoughts and comments. So you saw the melanoma today. The 3 lung cancer trials, one of them should be finished randomizing soon. The non-pathologic complete response post-neoadjuvant is still enrolling as is the Stage I. RCC in was the first to complete enrolling and the data readout, the interim analysis will be event-driven. Bladder cancer is fully enrolled, and we expect to have an event-driven readout as well. And then nonmuscle invasive bladder cancer, it's still enrolling as is first-line melanoma and first-line lung cancer, and then we have solid tumors. Now I'm going to invite up our 2 experts, Professor Ascierto, who I have had the pleasure of collaborating with across 4 different companies. And then Professor Ribas, who is one of the world's experts in immunotherapy. So maybe you can...

We have got the pleasure of completing [indiscernible] different companies and we're still friends.

Yes. Actually, just as an interesting side note, investigator I ever visited -- when I joined BMS was Jeff Weber on an [indiscernible] trial. And Dr. Ribas here was the lead of the [indiscernible] trial, and the science was always better for [indiscernible]. It's a big program. They did a great job. So maybe I could ask Professor Ascierto just to give some clinical context. And then maybe you could just give some of your immunotherapy expert context as well. And then we'll open up for questions.

Yes. So how many time I have. So just to set 5, 10 minutes. good. Okay. Take some notes. So first of all, good evening, everybody. My name is Paolo Ascierto. I'm a medical oncologist. I work in Naples, Italy. And the daily practice, before to speak about daily practice, the first question that probably discuss should discuss was it will be Intismeran, the new standard of care, Intismeran plus pembrolizumab because this is an important question. And if it will be for the Stage IIb and V because this is the patient's population enroll it and have Georgina showed you in the forest plot, this is effective for all the groups at the moment. So if we look at the data from anti-PD-1 [ BRAFMEK ] in Stage II, Stage Ib, [ IIc ], we have only anti-PD-1 -- the data in terms of relapse-free survival at 5 years looks similar with double trauma and anti-PD-1. So we cannot say that there is one better than another one. So if we have in terms of relapse-free survival, a treatment better than anti-PD-1, I guess that this will be the new standard of care in the high-risk patient population. Now the discussion about adjuvant and neoadjuvant that was the topic that was discussed by the discussion. So in clinical practice in real life, I see my institution per month, 60 patients, high-risk melanoma patients, Stage IIb, IV resected that could be treated with adjuvant. So among these 60 patients, I see probably 10 patients Stage 3 with clinical palpable lymph node. That is the population that can be treated with neoadjuvant or perioperative approach. So in the daily practice, that population is a population where we can treat with the neoadjuvant. I strongly support neoadjuvant as Georgina knows, but it's a limited number of patients. The big group are the patients with sentiment node positive. that we cannot treat with neoadjuvant. We need to treat with adjuvant. So it's probably surely the higher number of patients that we will treat with adjuvant. And now with this new data, surely more patients will be treated with this regimen because we have seen the data. What is really important with this data was pointed out by Dave, the consistency of the data, Phase II, Phase III, I have seen consistency of data with [indiscernible], you remember. If you look at the survival curve of CTL4, it's always the same in the different clinical trial. If you look at the survival curve of the sequence, RAF/MEK and CTL4, PD-1 is the same in seccond bit, TRMS. So consistency is the key to better understand. And I believe you will see in the future interim analysis by interim analysis, the data will improve like we have seen for the [ KEYNOTE-942 ] if I. Second, what is really exciting with this new treatment is that after 3 trial that failed and Georgina show it, the combination of PD-1 the combination PD-1 LAG-3, the combination of PDL anti-TIGIT. Why? Because in the field of adjuvant, what is important is the minimal residual disease. We don't have the tumor from an immunological point of view is totally different from the condition where you have the tumor, [indiscernible] disease and new adjuvant. So with the minimum residual disease, we don't need to add Checkpoint, checkpoint, checkpoint. We need to improve the priming and messenger [indiscernible] vaccine is able to improve the private. This is the key in the mechanism of action for the results that we have seen. I believe that I said about everything that I wanted to tell you.

So it's perfect to build up on what Paolo was just finished on, which is the reason why are these curves separated? Why do we have a hazard ratio of 0.58. And the difference is because you stimulate more immune cells against what the immune system uses to differentiate between cancer cells from normal cells. That's the key to all kinds of therapies. Can you get a therapy that attacks the cancer cells specifically spares the normal cells? By doing the process that Georgina has explained and David about sequencing the tumor knowing the sequences that are different from the cancer cells from the normal cells making an mRNA vaccine like for every patient, you then are able to stimulate to turn on more T cells that recognize the cancer. And then with pembrolizumab, they get unleashed. If we get pembrolizumab alone, which is the control group, you're only relying on the immune cells that the cancer has turned on by itself. Cancers are not -- they don't want to be turning on T cells. They want to hire them. So this is a way to use those new antigen sequences and turn on much more T cells I'm excited to have Georgina present the data today. I'm excited to see that big room and overflow rooms of all these people coming to see -- to look at a melanoma presentation. This is a landmark in cancer drug development, which is we've been -- as Georgina said, for over 100 years, people have tried to inject somebody to patients with cancer to increase the immune response against it. Now we have a rational design platform that make feasible, validated by the billions of people who received the COVID-19 vaccines and personalized to this level of precision and then positive clinical data.

Great So Georgina, can we invite you have now, sorry. And we're happy to take questions online or in person.

[Operator Instructions].

Salveen Richter, Goldman Sachs. Could you put the data in the context of the competitor regimens, including the neoadjuvant and the pros and cons that were laid out by the discussant? And maybe walk us through how INT really is positioned based on that totality to become standard of care.

Yes. Well, it is not unusual that you have multiple tools in the toolkit that are developed together. That's not we see this all the time in cancer. So the next steps are how do we integrate the 2 tools that are doing really well. The one thing about neoadjuvant is we get a very early readout at 6 weeks as to those who are not doing well with neoadjuvant treatment and checkpoint inhibitors, I refer to that group as the third space. My colleagues have heard me say that, but that's the group of people who are dying of cancer in melanoma. It's those who resistant to all the checkpoints and checkpoint combinations. So neoadjuvant gives us an early readout. There are still people in the space. So one natural question is, well, Intismeran in that group, we know from the Phase II study, for example, that the group that benefited the most based on biomarkers at baseline. So lower tumor mutation no PD-L1 expression, they actually had the greatest benefit by the addition of Intismeran. So the next few years are about us sorting that out in this field, how we're going to combine excellent treatments. We are not worried about that. We're not worried about integrating and doing this work. They work very differently. The Intismeran is completely different from the checkpoints. They're very complement -- so it's about working out what we give it to which patients. However, as Paolo beautifully explained is that not a lot of patients in that Stage IIb to Stage [indiscernible] state population in INTerpath-001 then the DNA population exactly.

If I can add something, just coming back to the discuss and the right study for a formal comparison is not the ADNA, it's the SWOG because in the G, we have the pembrolizumab, we have the perioperative, okay? Probably if I was discussed and to discuss this aspect, I would have been used the SWOG trial, more than NADENA.

Terence Flynn, Morgan Stanley. I guess a couple of questions. One is just for the physicians. Maybe the likelihood that these data translate to an OS benefit. I think we're still waiting to for KEYTRUDA, but just confidence level there? And then maybe for Dr. Long, one question we've gotten is just investigator versus central review. So I know in a lot [indiscernible], you typically central review, but here it was investigator review? And how to think about that in the context of functional unblinding, that's another question we've got.

Okay. So about the overall survival, we'll see, as Georgina showed, there is a theoretical concept in the study, study design, RFS, Dent metastasis-free survival, and we'll see overall survival. In general, we consider the dent metastasis-free survival, a very interesting endpoint because it's close to the overall survival. We have seen that it's positive. And if we consider the Phase II improved year-by-year and probably, I believe and I feel the overall survival will be positive as well. It's my personal feeling, of course.

Can I add just one other point on that, and then we can go to Dr. Long. One of the things also to keep in mind is for all of the anti-PD-1 adjuvant trials, there was a rescue anti-PD-1 at time of catastases. There's no rescue Intismeran at time of progression, just as a small point. Do you want to talk about the -- was there a functional blinding you actually you all probably [indiscernible].

We just had a discussion about this because we are finding that independent blinded review can be very problematic, particularly with therapies and immunotherapies is a big -- it's a big umbrella of many treatments, but checkpoint is one type. Now we have individualized neoantigen therapy, of which Intismeran is one. In that the radiologists that do the blinded central review have to be very well trained and have to understand these drugs. And so recently, there have been trials which would have been positive had the radiologist being trained appropriately to interpret, "Oh, everything shrinking but the lymph nodes are growing or that's progression. No, these are immune stimulated lymph nodes that don't actually have cancer. So I even proposed yesterday or the day before, can we just get rid of blinded independent view. So that's just that point. So in this, it does not bother me at all. I don't know if it's a concern that you're expressing, I think the relapse-free survival. It was done in 157 global sites. So you're going to -- everything is going to come out in the wash anyway. We were blinded. So we didn't know what patients were receiving. And I think that speaks most highly. And the other thing is this is an adjuvant trial. So it's not like you need the radiologist to watch and see how things are shrinking and grow. They just need to pick up a recurrence. And that technically is much easier than monitoring multiple metastases in the setting of immuno-oncology. So I don't know if that was your question, but it doesn't worry us that way in terms of the strength of these results, [indiscernible].

I want to add to what Georgina is saying, the local radiologists have more ability to query it's a questionable finding. And sometimes they have more parts of the body, more higher resolution than the central radiologists. Also in some of our centers, our radiologists read are the local radiologists and the central radiologists at night. And I would query how they report or differently.

This is [ Dina ] from UBS on for behalf of Mike Yee. I guess just 2 quick questions. You reminded us kindly that in the Phase II, we saw a really great benefit in the PD-1-negative population [ BRAF ] and also in the low tumor mutation burden. How do you think about that benefit translating into the Phase III? I'm sure we'll see that subgroup data if you do have it or have any color on that. But how do you see the right population to treat first and foremost, based on those biomarkers. And then on the back of the conversation for neoadjuvant, is there maybe a scenario in the real-world practice where if there are patients that do get neoadjuvant checkpoint could they go on to adjuvant therapy and do get INT and KEYTRUDA? Yes. And so I just wanted to kind of get your thoughts about that.

Sorry. The first question is about biomarker. So at the moment, we don't have biomarker. No PD-1, no TMB. In the field of adjuvant, the only biomarker that was explored, but in the target therapy was interferon gamma signature that Georgina reported years ago, but it's not for the clinical practice. It's still something in the science. So at the moment, we cannot predict patients who can get adjuvant and benefit from another patient. The second was -- the second question?

Can Intismeran eventually be administered after neoadjuvant therapy?

So again, the neoadjuvant patient is just 20% of the patients, okay? Having said that, now with this data, of course, there will be a clinical study in order to explore all the several things even in the new adjuvant and of course, in the adjuvant, which will be the patients that should receive adjuvant. Pathological complete response, No, but all the other probably, yes, and now if the standard of care is this combination, this will be the best option for patient.

I was just going to add to your very first question. And I think what you were asking is since we were seeing a greater benefit, is that going to -- no, we see a benefit in all groups. The point I was making with that is it would be easy for some people to say, "Oh, it's higher tumor mutation burden, easy to identify neoantigens, also that's who's going to benefit". My point there was not necessarily, they do benefit. We know that. The data shows that. But hey, we've got patients with lower tumor mutation burden in the pancreatic and we've got patients with no PD-L1 that are benefiting. So that was the point. It's not to pick out a population. At this point, as Paolo said, there is no population. It's -- every subgroup we've looked at seems to be benefiting. So that's that answer.

And again, we're increasing the priming. So the priming is something different from the effector phase.