Hello, good evening, and thank you for joining us today. This is a very exciting day for our cancer patients. It's an exciting day for cancer immunologists, and it's an exciting day for Moderna. Here's our forward-looking statement. Today, I'm going to start by giving just some brief contextual statements on intismeran. I'll then invite Dr. Georgina Long, who was the lead investigator for INTerpath-001 and gave a fantastic presentation today, to give a reprise of that presentation. I'll conclude with a few concluding statements, and then we're very fortunate to have two 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're processed in antigen-presenting cells and then brought to the surface of the antigen-presenting cell and presented 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, 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. How does it do this? 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 lipid nanoparticle, and that's used to inject into the muscle of the patient. Now, we know from non-human 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 our neoantigen intismeran, can be presented on the surface. So there are three 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. Number three, because CD4 and CD8 T cells are activated, dendritic cells are activated, and cytokines are released, there's a perfect milieu 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 0.561 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 arcs of the Kaplan-Meier curve. For the first six months, on the left-hand side, the Kaplan-Meier's are overlapping. As you heard today from Dr. Long, this is in part due to the weeks required to produce the intismeran and then weeks or a month for the immune system to be activated. At month six, the curves separate, and we know they'll eventually remain separated. However, in the primary analysis, that first six months takes up about a quarter of the entire Kaplan-Meier curve. That hazard ratio 1 for the first six months takes up a quarter of that curve.
In the longer five year follow-up, that six month hazard ratio 1 is still there, but now we have follow-up up to 60 months, and therefore, that initial six months takes up but a fraction of the entire hazard ratio. This is why we pre-specified to conduct a piecewise analysis at six months, and you'll hear that from Dr. Long during her presentation.
But it's very important, I think, to recall that the primary hazard ratio was essentially identical to what you'll hear today. 0.561 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 cells that we detect in the blood, and the X-axis is four different time points.
Baseline, post the pembrolizumab lead-in, and just prior to intismeran at cycle five, so in the middle of the intismeran regimen, and then at a follow-up. This is the phase II intismeran plus pembro versus pembro. For the first portion, notice the two arms are overlapping because 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, would higher levels of novel T cell clones be associated with clinical benefit? In theory, this should be most evident in the combination arm. That's exactly what we see. So the same Y-axis is the number of unique clones, 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 two groups. Those who, quote, "had benefit," 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. You'll notice for the combination arm, patients who had no recurrence, which is the top, their novel T cell clones continued to increase during treatment, whereas the ones who had recurrence plateaued. For the pembrolizumab arm, there's an initial increase and then there's a plateau. So this is evidence that there's an association mechanistically between the number of novel T cell clones and clinical benefit. Now, these are novel T cell clones, and we don't know if they are related to the intismeran drug product.
It is a little more complex to match T cells to neoantigens, but we were able to do it in seven patients. This requires a lot more blood than is typically taken during the routine blood assessment. We consented seven patients, and we matched their T cells to the 34 neoantigens they received in their cassette. What we found is, on average, one out of every three neoantigens in the 34 cassette is immunogenic. That is, it induces a T cell that is novel in the blood that reacts specifically to that neoantigen peptide. It ranges from about one to 18. Interestingly, it includes both CD4 and CD8 T cells. We then sought to further characterize the phenotype of these T cells.
We find, this is an example, it is a CD8 T cell that recognizes neoantigen 14 from patient three, and a CD4 T cell that recognizes neoantigen 27. 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 phenotype, meaning that they are ready to go out and kill the cancer cell. Because we were able to clone out those T cells that recognize those neoantigens, we had the TCR sequences, and we could go back to whole blood, and we could follow the frequency or the prevalence of those T cells during treatment. It is the same timeframe on the bottom, screening, lead-in with pembrolizumab, in the middle of the intismeran regimen, and then at the end.
What you will see in these three 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 those who are immunologists, one of the interesting features, which is known, is that there are usually multiple T cell clones that can recognize the same neoantigen peptide. At this point, I would like to invite up Dr. Long to give the presentation of INTerpath-001, and then I will return to give a few closing comments. Please come up this way so you do not fall. Okay.
Thank you.
And you press this one to advance
Okay
strangely.
Okay. Thank you. Thank you. It is a pleasure to present these data again to a smaller, more cozy audience. It is a true honor to be able to present results on something so transformational for cancer. This is a phase III randomized clinical trial of intismeran combined with pembrolizumab. We refer to intismeran as a type of INT therapy versus pembrolizumab alone for the adjuvant treatment of stage II-B up to stage IV melanoma. I do not have my glasses, but I can see this slide. I am not that blind. I do present this on behalf of my co-investigators. There were 157 global sites and all of their teams. These are my disclosures. We know that there is a clinical benefit for the adjuvant treatment of melanoma patients with anti-PD-1 monotherapy alone. That is clear.
Shown here are the two curves for stage III resected melanoma and stage II resected melanoma, stage II-B. The red curve is placebo. The blue curve is pembrolizumab alone. Yet, despite their significant clinical benefit and absolutely changing the field, we still have 44% and 33% of patients recurring or dying at five years. In the melanoma field, we see that there is a lot more work to do in terms of getting to zero deaths and to curing cancer. It is not that we have not been working at it. These are three landmark phase III clinical trials combining anti-PD-1 with three different checkpoints, CTLA-4, LAG-3, and anti-TIGIT, all negative. We have not had any improvement in the adjuvant setting over and above anti-PD-1. Sorry, go back again.
What I presented today was really asking the oncology world, how did we get here to reflect on how we got here in 2026? There really is over 100 years of work in immunology, cancer biology, and the technological innovation that has happened, particularly in the last 60 years. If you are looking at where we are today with intismeran, there are three 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's tumor. They are not found in their normal cells, and they are not found in anyone else's cancer. That begs the question, if they are so unique, could they be seen as foreign to that patient's immune system?
Then the second big 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 anti-tumor response. 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. There's demonstrated robust CD4 and CD8 tumor response or responses to these proteins. That's wrapped in a lipid nanoparticle, injected into the patient. 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 to the patient takes six to eight weeks. In terms of the mechanism of action, this is now a busy slide without the animations, but 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. It is hypothesized that with the release of more epitopes as the tumor is killed, that this enhances that cycle of immune activation. Where's the machine here? You've just seen the data for the phase II-B trial. Just to reiterate that the clinical benefit is durable out to five years. Left is relapse-free survival.
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 0.41. 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. I won't go through that in any more detail than as we've already heard. This is the design, and this is a standard adjuvant trial design in terms of eligibility. Resected cutaneous melanoma, AJCC eighth edition, stage II-B right up to stage IV. These are high-risk patients of recurrence. Each patient had to have formalin-fixed paraffin-embedded tissue that was of sufficient quality and quantity for intismeran manufacture, which required next-generation sequencing, and then no prior systemic therapy.
Patients were randomized two to one to the active arm of intismeran, 1 mg intramuscularly every three weeks for nine doses, plus standard dosing of pembrolizumab every six weeks versus placebo and standard pembrolizumab. The pembrolizumab was started first at randomization within 13 weeks of resection. The intismeran was started as soon as it was available to the site. The earliest was cycle one, Day 22, and the latest was cycle four, day one. The primary endpoint was the relapse-free survival as per the investigator. The secondary endpoints are shown here, but the key one for today is the distant metastasis-free survival. The statistical considerations are very important. 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, then to the overall survival.
The treatment differences, just to see if they are significant, was tested by the log-rank 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 endpoint, it was the Cox 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 pre-planned sensitivity analysis to look at the robustness of these results. One is called the piecewise hazard ratios. I really do think that this trial will be the first to 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.
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. This is 24.6 months of median follow-up at the data cut. So 1,749 patients were screened, 1,137 randomized. The biggest reason, the most common reason for screen failure was due to inadequate tissue supplied by the site. I can 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 for the combination, 380 to pembrolizumab alone. In both arms, one patient didn't receive treatment, the rest all did.
When you move to the addition of the placebo intismeran that was equal in both arms, 96% of patients received placebo or their intismeran 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 treatment. So 91% of all patients in the trial had the maximum of 34 neoantigens identified for their intismeran design. Over 99% of those randomized to the combination, when I say we, Moderna were 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 was 64 days. Baseline characteristics is what we would expect for this population and similar in both arms.
The most common stage was 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 over single agent. I've also got the two-year landmark, relapse-free survivals, with 82.2% and 70%. Now looking at the piecewise hazard ratios. As expected, in the first six months, the hazard ratio was 0.99. After six months, the hazard ratio was at 0.42, so a 58% reduction in risk of recurrence or death after six months.
The reason this was done, as I will 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. Secondly, the median time to injection of intismeran was nine weeks. This is the modified intent to treat. 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. 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, a hazard ratio of 0.62 and a P value of 0.002.
A 38% reduction in the risk of distant metastases or death with the combination. Similar sensitivity analysis hazard ratio in the first six months, 1.01. Hazard ratio after six months, 0.50, so a 50% reduction in the risk of distant metastases or death. The confidence intervals after six months do not cross one. The sensitivity in the modified intent-to-treat population, hazard ratio of 0.55, that is a 45% reduction in the risk of distant metastases or death, and the two year landmarks for distant metastases are shown there. In the pre-specified 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. It also means the estimate, so the diamond can switch like this with one patient.
You really have to be careful at looking any information with wide confidence intervals. We do not 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 that is risk-based. We saw both groups benefit from the combination. In terms of adverse events, the left are what we call all-cause adverse events. 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. I am 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 would expect. intismeran does cause local adverse events.
Importantly, when we look at grade three to five 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. The deaths, the two deaths due to treatment in the combination arm all occurred before intismeran was commenced. So they were due to pembrolizumab. The eight deaths due to all-cause adverse events, not related to treatment, only the two I just explained, five of them occurred before the intismeran started and three after and were not related to either treatment. These plots are really nice because they quickly visualize where you are seeing the adverse events. This is all-cause adverse events in more than 10%. What we have boxed there are those that are greater 10% incidents in the combination, because that is what we want to know.
Well, what is this combination doing? What was really interesting is they're very low grade. They're all grade one or two. 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. What we can say is that it does not appear that intismeran is potentiating pembrolizumab adverse events. The conclusions are 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 and death. If we look at the sensitivity analysis, the combination reduced the risk of recurrence or death by 58% after month six.
The benefit was observed in almost every pre-specified subgroup. The overall survival is immature, and so 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'd seen before in the phase 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. This is not as bold as it could be, but INTerpath-001 really does set a new benchmark for melanoma. Critically, it is a huge advance. It is a landmark for the advance in personalized cancer medicine. Thank you. I just want to also make note of all of the people, all of 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 death in 2024. 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 two large pharma companies that have had intense competition with Merck, and I can say it's been absolutely fantastic to be collaborating with Merck for once rather than competing with them. They're absolutely excellent partners. Just a couple words in conclusion. Beyond melanoma, there still remains an unmet need across many different adjuvant settings, as you can see here. We have intismeran in clinical trials in all of these tumor types. One of the common questions that is frequently asked is, will intismeran work outside of melanoma? 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 cells kill cancer. intismeran also activates T cells, but it does it on the front end. In fact, we know, based on the T cell clones, that intismeran activates different T cells against different neoantigens than pembrolizumab does. Second is the data. You heard from Dr. Long today, the ITT, the hazard ratio of 0.58. If you remember the famous KEYNOTE-054, which was KEYTRUDA versus placebo, their hazard ratio was 0.57. 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. Finally, you heard about the Piecewise. So this is patients who are six 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 drug. 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 intismeran will work outside of melanoma, and that's the tumor mutational burden analysis. By the way, in case you're going to ask, we don't have that data yet for the phase II trial, but hopefully soon. In the phase II trial, we analyzed RFS by high TMB and non-high TMB or low TMB.
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 tumors 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. I just want to share data in the abstract because I don't like to leak data before it's 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? Then we also were curious, how does intismeran interact with chemotherapy?
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 cassette was actually 34. So we actually did pretty well. Of the 20 were immunogenicity evaluable, and all 19 had neoantigen-specific T cell responses seen. So very promising that we can induce T cell responses. In the subset who were evaluable, we could see polyfunctional T cell responses. 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 FOLFIRINOX is complete. So it is feasible and possible to do this, and full poster to be presented tomorrow.
Now I would like to invite up our experts to come and join here, and we'd certainly open this up for questions and answers. Oh, actually, before I do, sorry. Just let me close on this, and then actually I want to invite up our two experts to give some thoughts and comments. You saw the melanoma today, the three lung cancer trials. One of them should be finished randomizing soon. The nonpathologic complete response post-neoadjuvant is still enrolling, as is the stage I. RCC 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. Then non-muscle invasive bladder cancer is 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 two experts, Professor Ascierto, who I have had the pleasure of collaborating with across four different companies, and then Professor Ribas, who is one of the world's experts in immunotherapy. So maybe you could-
We have had the pleasure of competing with each other
I didn't want to
four different companies, and we're still friends.
Actually, just as an interesting side note, the first investigator I ever visited when I joined BMS was Jeff Weber on an ipilimumab trial. Professor Ribas here was the lead of the tremelimumab trial, and the science was always better for tremelimumab.
Yeah.
It's a big regret.
He 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.
Yeah. So how much time I have? Just to set with five, 10 minutes.
Yeah.
That's 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. In the daily practice. Before to speak about the daily practice, the first question that probably discussed should discuss was will it 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 IV, because this is the patient's population enrolled, and as 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, BRAF/MEK in stage III. In stage II-B to C, we have only anti-PD-1. The data in terms of relapse-free survival at five years looks similar with dabrafenib 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 patients population. Now, the discussion about adjuvant and neoadjuvant, it was the topic that was discussed by the discussant. So in clinical practice, in real life, I see in my institution per month 60 patients, high-risk melanoma patients, Stage IIB, full resected, that could be treated with adjuvant. So among these 60 patients, I see probably 10 patients Stage III with clinical palpable lymph node. That is the population that can be treated with neoadjuvant or perioperative approach. So in 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 sentinel node positive that we cannot treat with neoadjuvant. We need to treat with adjuvant. It is surely the higher number of patients that we will treat with adjuvant. 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 ipilimumab, you remember. If you look at the survival curve of CTLA-4, it is always the same in the different clinical trial. If you look at the survival curve of the sequence, BRAF/MEK and CTLA-4 PD-1 is the same as [inaudible] . Consistency is the key to better understanding.
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 remember correctly. Second, what is really exciting with this new treatment is that after three trials that failed, Georgina showed the combination PD-1/CTLA-4, the combination PD-1 LAG-3, the combination PD-1 anti-TIGIT. Why? Because in the field of adjuvant, what is important is the minimal residual disease. We do not have the tumor. From an immunological point of view, it is totally different from the condition where you have the tumor, metastatic disease and neoadjuvant. With the minimal residual disease, we do not need to add checkpoint, checkpoint. We need to improve the priming, and messenger RNA vaccine is able to improve the priming. 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.
It is perfect to build up on what Paolo just finished on, which is the reason why are these curves separated? Why do we have a hazard ratio of 0.58? The difference is because you stimulate more immune cells against what the immune system uses to differentiate between cancer cells from normal cells. That is the key to all cancer therapies. Can you get a therapy that attacks the cancer cells, specifically spares the normal cells? By doing the process that Dr. Georgina has explained, and David, about sequencing the tumor, knowing the sequences that are different from the cancer cells from the normal cells, and making an mRNA vaccine-like for every patient, you then are able to stimulate to turn on more T cells that recognize the cancer. Then with pembrolizumab, they get unleashed.
If we give pembrolizumab alone, which is the control group, you are only relying on the immune cells that the cancer had turned on by itself.
Immuno cancers, they do not want to be turning on T cells. They want to hide from them. This is a way to use those neoantigen sequences and turn on much more T cells. I am excited to have Georgina present the data today. I am excited to see that big room and overflow rooms of all these people coming to see, to look at the melanoma presentation. This is a landmark in cancer drug development, which is, 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 rationally designed platform that is made 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. Thank you. Great. Georgina, can we invite you up now? Sorry. We are happy to take questions online or in person.
There is one here in front. Yeah.
Oh.
I will just remind everyone to please introduce yourself and your affiliation.
Salveen Richter, Goldman Sachs. Thank you so much for this meeting. Could you put the data in context of the competitor regimens, including the neoadjuvant, and the pros and cons that were laid out by the discussant? Maybe walk us through how INT really is positioned, based on that totality to become standard of care.
Well, it is not unusual that you have multiple tools in the toolkit that are developed together. We see this all the time in cancer. The next steps are how do we integrate the two 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 are resistant to all the checkpoints and checkpoint combinations. Neoadjuvant gives us an early readout. There are still people in the third space.
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 burden, no PD-L1 expression, they actually had the greatest benefit by the addition of intismeran. The next few years are about us sorting that out in this field, how we're going to combine two excellent treatments. We are not worried about that, are we? We're not worried about integrating and doing this work.
No.
They work very differently.
Yeah.
The intismeran is completely different from the checkpoints. They are very complementary, so it is about working out what we give to which patient. However, as Paolo beautifully explained, not a lot of patients in that stage II-B to stage IV resectable, the population in INTerpath-001 fit the NADINA population exactly.
If I can add something, just coming back to the discussant. The right study for a formal comparison is not NADINA, it is the SWOG. Because in the SWOG, we have the pembrolizumab, we have the perioperative. Okay? Probably if I was the discussant and to discuss this aspect, I would have used the SWOG trial more than NADINA.
Thank you.
Thanks so much. 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 see that for KEYTRUDA, but just confidence level there. Then maybe for Dr. Long, one question we've gotten is just investigator versus central review. I know in a lot of studies you do 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 gotten. Thank you.
Okay. About the overall survival, we'll see. As Georgina showed, there is a hierarchical concept in the study design. RFS, distant metastasis-free survival, and we'll see overall survival. In general, we consider the distant 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 metastases. There's no rescue intismeran at time of progression.
Yeah.
Just as a small point. Do you want to talk about was there on functional blinding? Actually, you
Oh, yeah.
Paolo are probably the two largest enrollers.
We just had a discussion about this, because we are finding that independent blinded review can be very problematic, particularly with immunotherapies. Immunotherapies is a big It's a big umbrella of many treatments, but checkpoints 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. Recently there have been trials which would've been positive had the radiologist been trained appropriately to interpret, "Oh, everything's shrinking, but the lymph nodes are growing. Oh, that's progression." No, these are immune-stimulated lymph nodes that don't actually have cancer. I even proposed yesterday or the day before, can we just get rid of blinded independent review? That's just that point. 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 everything's going to come out in the wash anyway. We were blinded, so we didn't know what patients were receiving. I think that speaks most highly. 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 growing. They just need to pick up a recurrence, and that technically is much easier than monitoring multiple metastases in the setting of immuno-oncology. I don't know if that was your question, but it doesn't worry us, put it that way, in terms of the strength of these results one iota.
I want to add to what Georgina is saying. The local radiologists have more information and more ability to query things if it's a questionable finding. Sometimes they have more parts of the body, more higher resolution than the central radiologist. Also, in some of our centers, our radiologists read the local radiologists' and the central radiologist's at night. I would query how they report it differently.
Thank you.
Hi, this is Dina from UBS on behalf of Mikey. I guess just two 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? 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 the KEYTRUDA? Just wanted to kind of get your thoughts about that.
Yeah.
Thank you.
Okay. The first question is about biomarker. 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. 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?
Again, the neoadjuvant patient is just the 20% of the patients, okay? Having said that, now with this data, of course, there will be clinical study in order to explore all the several things, even in the neoadjuvant and of course in the adjuvant, which will be the patient that should receive adjuvant. Pathological complete response? No. But all the other, probably yes. Now if the standard of care is this combination, this will be the best option for the 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. Oh, so 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. Every subgroup we've looked at seems to be benefiting. So that's that answer to that first question.
Again, we are increasing the priming. The priming is something different from the effector phase.
Okay.
Before we go to the next live question, I am going to take a question from online. To the physicians, what is the best way to rationalize why the hazard ratio was much more impressive for RFS versus DMFS at this interim?
That is usually standard. If you look at most trials, you will always see that trend. Phase III landmark trials, you see relapse-free survival is often a greater hazard ratio at the very first interim analysis than metastasis-free survival. What we saw in the phase II was actually a little unusual. It is standard that that is what we see. We are not surprised by this data. It is exactly as we expected. We were actually super impressed by this data is what I should say.
Yeah.
Would you support that?
Oh, yes, I agree with you. We need time because we need the event, that moment. I am sure that in the next follow-up we will see an improvement.
Yeah. Just to add, this trial, of course, included stage II patients who have a slower
Yeah
time to distant metastases. The additional point is if you look at the modified intent to treat, which is patients who got placebo or INT injection, so people who actually received something, there the hazard ratio was 0.55. I think those are the two things to keep in mind. Next question.
Thank you very much. Louisa Hector from Berenberg. Wonderful to see this data, so thank you. I have a question on the tissue sampling, the 17% of the samples that were too small. I think, Dr. Long, you implied that you were learning through the trial how to do that better. So how much could that be reduced? Anything you can add on that?
Yeah, I cannot tell you how much that will be reduced, but it will be reduced.
Yes.
My own experience, and I would love to hear the other investigators, was the first few patients we screened, some got on, but some we did not supply enough tissue, so we had to go back to the blocks and give more tissue. What I did is I got the team together and our pathologists, and we had a protocol that worked for our site because of the way our site works and our pathology, and then we did not have screen failures after that. We were able to pick patients so that we had enough tissue up front.
Okay.
Because it is not fun for a patient to
Yeah
to consent, and then we send the tissue, it is not enough, and then they have to wait longer.
Yeah.
We really wanted to get that right up front. This is not new to oncology. You probably remember 15 years ago when EGFR inhibitors in lung cancer-
Yeah
tissue was the issue. It is not an issue anymore because we have got infrastructure and resolved those issues.
Yeah.
Then it may be too early to comment, I do not know how much data you have, but in the patients who are recurring, is there anything about their T cell clones or any pattern you can see from that?
Do not know. Do not know yet.
Explains it, no. Okay. Thank you.
But they are blinded still. They are blinded, the patients, so won't know.
But we did look at recurrence in the phase II, and I thought we presented that. I can't remember. But anyway, yeah, we did, didn't we? Yeah. So there is some data out there from the phase II.
Hi, Ellie Merle from Barclays. Thanks for taking my question. Just on a similar vein, you mentioned that there were some neoantigens that are more promising in inducing T cell responses. Any learning so far from the data on which ones might be? Then you have also shown that the patients with more novel T cell clones have greater clinical benefit. Any thoughts or early hypotheses on which patients might be more likely to have more novel T cell clones versus others? I guess the reason for these questions is how you interpret this data in terms of what it could mean for success in other tumor types.
I am going to answer that question, and then I am going to invite Toni to maybe give a scientific answer. Both of those are areas of active investigation. What makes a good neoantigen? Now that we have clinical efficacy outcome, we can go back. We actually have neoantigen prediction for both the control arm and for the experimental arm. Your question was about which patients get novel T cells, so one is about neoantigens and one is a patient-level question. Is that the. Yeah, that is another great question. Toni, you have been doing this for a couple of decades. What are your thoughts?
Yeah. I have trouble trying to answer the question directly because we do not have the way to measure, count how many T cells to neoantigen HLA-presented peptides. These are the most polygenic areas of our genome between the T cell receptor. It is like an antibody that recombines. Then the HLA class one, which there is one more common, HLA A2.1, but there is 24,000 HLA class one alleles in the human population so far. The TCRs are up to 10 to the 15, the potential sequences. A long explanation to say that the measurements that we have are associations with what the real thing is happening, and that I do not think in any realistic time point we will be able to answer your question directly, which is the key question on any neoantigen therapy.
Provided I said this, the efforts that have been made are very substantial at Moderna and Merck to be able to study from the phase II trial and see that the vaccine, that the personalized therapy and the antigen therapy can turn on T cell receptor clonotypes that were not there. You would assume that some of them will be to the mRNA because that protein made from the mRNA will be the most immunogenic part. Could we then decide what is the best algorithm to get those T cells that work the best? I think that is a question that in large clinical trials may not be realistic now.
Hi, this is Greg Torres, representing Tyler Van Buren from TD Cowen. Congrats on this outcome, and thanks for taking my question. Given the apparent INT-specific T cell responses you have shown, how seriously should we think about the potential for INT monotherapy, and could removing pembro ultimately expand the addressable population more than adding INT onto pembro, particularly in stage II patients? Thanks.
I'm going to take that one. I invite Toni and the others. There's been a belief out there that for a novel immunotherapy, you have to add on to an anti-PD-1 to work, and a lot of that has come from the fact that a lot of novel immunotherapies have not had any significant monotherapy activity, therefore, that's that belief. I don't really think that's the case. I personally believe that intismeran should have monotherapy activity, and as you know, we are studying it in stage I lung cancer. Part of the reason is that first slide I showed, which is evolutionary speaking, the immune system evolved to detect and eliminate viruses, but it can also detect and eliminate cancer. It doesn't require an anti-PD-1 to do that. We don't walk around with anti-PD-1 antibodies.
If we can stimulate those T cells, they should be able to do what T cells normally do. So this is hypothetical speaking. We do have some intismeran monotherapy data showing that we can induce T cells. But Toni, what are your thoughts? We're in a speculation phase now because we don't have the data, but what are your thoughts? Intismeran monotherapy.
The field has realized that if you have more T cells for cancer, those patients do better. That is, again, by very crude measurements. But we know from studies in colon cancer from 20 years ago that the colon cancers that have more T cells, that was like being a stage lower in the AJCC staging. So more T cells is better independent if you block any checkpoint.
Prognostically.
Prognostically.
Yeah.
That tells us that if you stimulate them with INT, as you're saying, you're probably going to do better. In an earlier stage, you're right that you start worrying about the pembro side effects and the hypothyroidism.
Side effects
that can be long-term, and adrenal insufficiency, or do you have the rare patient that has really, really bad side effects? You don't want to risk that. It's great that you're testing on stage I lung cancer. I think it's a great study.
Yeah, I was going to say the same thing. I think hypothetically, given the mode of action where it's acting, the algorithm, what we've seen so far, it should have some activity in earlier stages and in single agent. Yeah. The issue is in something like melanoma stage I, which is very common, stage I melanoma, is only about 5% will recur. So we need to team things like that up with tests that tell us who's going to recur and then give them these sorts of treatments to stimulate their T cells. But theoretically, it should work.
A few other questions coming from those who are listening online, and apologies if these are basic questions, but to the physicians, are you concerned about the KM curves crossing at 33 months for DMFS?
Oh, God, let me take that.
No. Can I take that?
That is one question. Of course, Georgina, please do speak to it, and then I have a few others.
No.
It means-
No concern.
It's nothing. You'll see there were several Kaplan-Meier curves today in other trials where you see that. It is a phenomenon of the follow-up and the fact that when you get out to 33 months, when you've got a median follow-up of 24 months, you don't have any patients at risk. So the curves are not to be looked at. A rule of thumb for those who are not in oncology, if you've got less than 10% of patients at the number at risk, you cannot judge the shape of the curves. It will change at next analysis, guaranteed. That does not worry us. We see this all the time at these sorts of follow-up early on. It's nothing to be concerned about.
But maybe, let me know. Could we put the slide back?
Curve up. Slide back? Yeah.
Because I think
Slide 37.
This is one experiment that took many years.
Oh, sorry, 36.
I think it's important to get the figure right.
There you go.
Otherwise, you have it in your handouts. The curves don't separate the first six months, as Georgina well explained, then they start separating. If you look at the bottom of the Kaplan-Meier, it has two rows of numbers.
That's the number of risk I was talking about.
Yeah.
Let me put Keep going, Toni. Keep going.
Yeah. Here are the patients at risk. Then the tick marks are the censored patients. Can we go to the primary analysis? Go to the one that says-
RFS
Backwards more.
Oh.
Backwards more.
The RFS.
Here.
Oh.
You see No.
Bring it to, yes.
We go to
Previous one.
They are the same curves.
They do not separate for six months. They start separating. There are 600 patients at risk in one group, 200 on the other, and then you get to 24 months, you see all these tick marks, and then at the end, there are 10 patients, follow them, one or the other. That is when it is not reliable. We are here trying to interpret this and interpret the future or anticipate what will happen in the future. Somebody asked about overall survival. All these curves are separating until there are not enough patients at risk. You would assume they will continue separated.
Yeah.
That is just logical.
A lot of enthusiasm on this. Actually, we have this exact example from the primary analysis on slide 10 of the phase II. Remember, the curves come together in the primary analysis because there are too few patients. In the longer follow-up, that disappears. Exactly what they said.
All of those tick marks are patients who are alive and well, who have not had an event. They are just alive and well, and they have got to 24 months. They have all got to come through the curve, so to speak. It is completely unstable from, as I said, 10% of the starting number, so 75, seven. Basically, once you get below 75 patients, ignore it. It is going to change. It is going to do this, and it does not tell you anything about the science or the patients. It is not reliable.
Great.
Can we ram that home any other way?
Yes. Sorry. Thank you. Thank you for the education. One last question on RFS as a primary endpoint versus OS in the adjuvant setting. Is OS required for approval here?
This is a question that it is usual when we talk about adjuvant. It is clear now after long discussion that relapse-free survival is an important endpoint that we should consider when we discuss with patients. Christian Blank is almost Italian, and during the meeting, we have a funny fight about neoadjuvant and adjuvant. The question is, of course, about relapse-free survival and overall survival. The point is, if we assume, a regulatory agency assume, the relapse-free survival is a good endpoint, and for me and colleagues, a good endpoint, stop. Overall survival is important, we know from a scientific point of view. But when we discuss with the patients, the patients want to be relapse-free.
Great. Thank you very much. I would like to thank our three experts. It has been a busy day, and thank you for taking the time. Thank you all for attending today. Thank you.
Thank you.
Toni, thank you so much. I really appreciate you coming here.
Absolutely.
Thank you so much.
Thank you.
Thank you so much.
No worries.
Oh my God, you are the best.