I'm Birgitte Rønø, CSO and COO at Evaxion. On behalf of the entire Evaxion team, I would like to welcome you to this exciting webinar focusing on our EVX-01 program in advanced melanoma and the phase II result presented on Saturday at the ESMO Annual Congress. I'm delighted to have Professor Adnan Khattak with us today. He led the EVX-01 phase II study at the clinical site in Perth, Australia, and he will be presenting the data from the EVX-01 study. Professor Khattak is a medical oncologist at Hollywood Private Hospital in Perth and is a key investigator on many international cancer trials assessing novel cancer immunotherapies, including personalized cancer vaccines. Before we start, just a short reminder, today's presentation may contain forward-looking statements, which are statements about the future. Actual results may differ materially from them. Here is what we'll cover today.
First, I'll introduce Evaxion, the EVX-01 concept, and the results from the EVX-01 phase I study conducted prior to the phase II study. Second, Professor Khattak will introduce us to the unmet medical need in advanced melanoma, and then he will present the data from the EVX-01 study. Then, in the end, we'll open the floor for your questions. You can type them into the Teams chat at any time, and we will answer as many of your questions as possible at the end of the session. Yes. First, an introduction to EVX-01 and the key data from the EVX-01 phase I study. Evaxion was founded in 2008 with one aim, to decode the immune system with AI to address serious unmet medical needs.
We are based in Denmark, and our team of more than 40 experts cover the whole value chain from target discovery to clinical development. Today, Evaxion is a pioneering clinical validated TechBio company. This means that we work in the intersection of life sciences and advanced data technology. AI, machine learning, and computation are deeply built into how we discover and develop novel therapies. Our AI platform is called AI-Immunology, and it is an integrated set of models for rapid, high-quality target discovery, drug design, and development. We are focusing on antigen discovery and product development in cancer and infectious diseases, and we recently expanded into autoimmune diseases. We have been listed on the Nasdaq Capital Market since 2021 under the ticker EVAX. AI-Immunology allows for rapid development of product candidates, with all of our pipeline candidates designed with AI-Immunology.
The focus of today's webinar is on our EVX-01 program, EVX-01, and the phase II data we presented at ESMO. EVX-01 is a personalized cancer vaccine, and we design a unique vaccine for every single patient in our trials. It is based on up to 10 different targets, neoantigens that arise from mutations specific to the patient's tumor. These neoantigens are selected by our AI-Immunology platform, and the vaccine is a peptide liposomal formulation. Let me show you what is behind our AI-Immunology platform. AI-Immunology has a unique building block architecture. At its core are three engines. The first is disease decoding, which identifies key pathogenic drivers in a given disease. The second is immune response decoding, which shows how the immune system sees and responds to potential targets.
The third is a vaccine design engine, which we use to design the product candidates. We can apply the platform across disease areas, and currently, we work within cancer, infectious disease, and autoimmune diseases. EVX-01 is one of the cancer applications of this architecture. AI on its own does not give you a therapy, and that is why we have built a multidisciplinary R&D capabilities around the AI-Immunology platform. These different capabilities include disease biology, target discovery, and further also preclinical development, CMC, and clinical development. Now to the concept behind EVX-01. EVX-01 is a personalized cancer vaccine targeting multiple private neoantigens. Neoantigens are ideal cancer vaccine targets as they arise from cancer-specific DNA mutations exclusively found in tumors and absent from normal tissue. They trigger strong, highly tumor-specific immune responses, and they work well together with current cancer immunotherapies.
AI-Immunology models the neoantigen process inside the cancer cells. This starts with identifying these cancer-specific mutations. Then it looks at the expression and translation of these sequences. It goes on to look at presentation on MHC molecule and the T-cell responses, and further into the clonality of these neoantigens. The AI-Immunology platform is part of a larger process that runs from mining the patient's tumor fingerprints to designing a personalized treatment. For every patient enrolled in our trial, we collect a tumor biopsy and a normal blood sample, and then we sequence the DNA and the RNA. This information is fed into our AI-Immunology platform, which then identifies and ranks the neoantigen according to their predicted likelihood of inducing a tumor-specific T-cell response.
The prediction only takes 24 hours, and AI-Immunology currently predicts immunogenic neoantigens with an 89% precision, and we will come back to this target precision rate later in the presentation. The vaccine is then manufactured and administered to the patients in combination with checkpoint inhibitors. The turnaround time from biopsy to vaccine administration is about seven weeks. We tested this concept first in a phase I study, and it enrolled patients with unresectable stage III or metastatic stage four melanoma. In the phase I study, each patient received a vaccine of up to 10 patient-specific neoantigens, again, designed with AI-Immunology. The patients were dosed with EVX-01 to activate the T-cells together with a checkpoint inhibitor according to label. The phase I study tested three different EVX-01 dose levels. These are the key results from this phase I study.
EVX-01 was safe and well-tolerated with only grade one and two adverse events reported. Eoght out of the 12 enrolled patients responded to treatment with an objective response rate of 67%. EVX-01 induced a specific immune response in all these 12 patients. We also looked into the individual ability of the neoantigens to induce a T-cell response, and we saw that we had reactivity against 53 of the 91 neoantigen analyzed across the patients, with a target precision rate of 58%. Manufacturing was efficient with a turnaround time of approximately seven weeks. We took three learnings from this trial into phase II. We selected the highest dose level of 200 μg per peptide as the recommended phase II dose. We added EVX-01 boosters to sustain the T-cell level, and we improved the prediction power by updating AI-Immunology. All three shaped the phase II study.
With this introduction, I am now happy to hand over to Professor Khattak to present the EVX-01 phase II data. Please go ahead.
Thank you, Birgitte. Thank you everyone for joining online. Today, specifically talking about advanced melanoma, where the role for vaccine has been proven, but the discussion, obviously thinking ahead, can be obviously rolled out to a much broader level across other tumor types as well based on some recent data. When we talk to our patients in our clinic, our current standard of care is immune checkpoint inhibitor treatment as a single agent or as double immunotherapy in the form of ipilimumab and nivolumab combination or nivolumab and relatlimab combination. As you can see, the five-year survival statistics, now we have got 10-year survival statistics as well, but roughly you can expect about 50% of your patient to be alive at five-year time point despite having a diagnosis of metastatic disease. Then the problem is, what about the rest of the 50%?
If I was to see a patient in the clinic today, I can share this data with them, but I cannot tell them whether they are going to be in this 50% of patients who are likely to live, or they are going to be in those 50% that unfortunately do not benefit from checkpoint inhibitor treatment. Now, these treatments are very generic, very broad-brushed approach. If I get 10 advanced melanoma patients, my standard of care treatment options that I will discuss with them will be pretty much the same in terms of these agents that I just listed. With the unmet needs that obviously we have got a significant proportion of patients who would not benefit from our standard checkpoint inhibitor treatment, a single agent or even double agent as well, and obviously, there is significant toxicity as well.
The field in oncology moved obviously to personalized treatment, but that was primarily the personalized targeted therapy what we saw in melanoma as BRAF targeted therapy or EGFR, ALK or other targeted therapies in lung cancer. Obviously, reading in the immune system at a personalized level has always been a challenge and remains a challenge, although we have made significant advances, particularly in the last two to three years, including the data that was presented at ESMO recently. In terms of personalized treatments now, as we mentioned, how the neoantigens work, it is just like the fingerprint of cancer cell, which is unique to an individual patient's cancer that is different than any other patient on a particular clinical trial that we are enrolling on at that particular time.
These are called neoantigens, what we used to call personalized cancer vaccine, and now we call them INT, or Individualized Neoantigen Therapy. The data that was presented at ESMO from Evaxion, from the presidential session, from Moderna data, and some trial that have completed recruitment, hopefully, we will see more and more success of these new novel therapies. I will move to the next slide. In the phase II study, last year in Berlin, we presented the two-year data, and now in Madrid, we presented the three-year data. The objective response rate, I will discuss the design of the clinical trial in the next slide, but in summary, the objective response rate was 75%, meaning three out of four patients benefited. We enrolled 16 patients in this phase II trial.
What we also looked at is that after the run-in of three months of treatment with pembrolizumab, once the Evaxion vaccine was started, we looked also at the conversion rate of the best response to pembrolizumab to see if we can further improve on that by exploiting the synergy between the checkpoint inhibitor and Evaxion vaccine, EVX-01. What we found was that in four out of six patients, about 67%, the response converted from stable disease to partial response, and in about 42% of the cases, three out of seven patients, it converted from a partial response to a complete response. That response was maintained at two -year follow-up in 11 out of 12 patients. We also saw vaccine-induced specific T-cell responses in all patients receiving at least six vaccinations in about 15 patients.
What we saw in the three-year data, six patients consented in the extension phase. I will cover that in a second. Probably move on to the next slide so that we will go through it nicely. The phase II design, pretty simple and straightforward, very clean design. It took patients who were treatment-naïve in unresectable stage III or advanced metastatic melanoma who were checkpoint inhibitor-naïve or had a good performance status and RECIST measurable disease with no active brain metastasis. The primary endpoint was obviously the conversion rate. If a patient, in terms of CR or PR from patients with stable disease and also conversion from partial response to a complete response with a secondary endpoint of objective response rate, progression-free survival, overall survival, safety and tolerability data, and also the immunogenicity data in terms of neoantigen-specific T-cell responses.
The patients would normally start the treatment as the standard of care, which was pembrolizumab at that stage. Obviously, we are using double therapy. At that stage, it was pembrolizumab when the trial protocol was written. After a 12-week run-in of pembrolizumab monotherapy, patients had scans, and we noted that, and then had six priming doses. Two weeks apart from week 12 to week 22. This is the priming phase. There was a boosting phase at week 30, 42, 54, and 78. The trial was followed up to week 102, and then 90 days follow-up. More recently, there was a protocol amendment in which two extension phase doses were given at week 115 and week 139, and then an end of the trial. 21 patients were screened. Four were screen failures.
17 were enrolled. One progressed, unfortunately, prior to starting the Evaxion vaccine. Sixteen patients were recruited in the trial, and then six patients entered into the extension phase of the study. Roughly two-thirds of patients were male, almost a 50/50 split between less than 65 and greater than 65. Both relatively younger and older patients were treated, and patients with good performance status, which you'd expect in a clinical trial. The median number of target lesion was two. PD-L1 expression, less than 5%, greater than 5% in 25% and 50% of patients respectively. About 50% of the patients have BRAF positive disease, and LDH was elevated in about 13% of patients. In terms of safety first, because it's a phase I study, first you need to demonstrate the safety of the study.
Phase I leading into phase II later on. We only saw mild grade one to two toxicity. If you look at, these are the grade one toxicity, grade one, two, three, four, five , and then attributed to the vaccine only. You can see there's nothing in grade three and four , only grade one and two toxicity seen. Same with pembro as well, what we expect with a normal profile, except one grade four immune-related diabetes that was seen from pembrolizumab effect. Again, no safety signals were seen for the combination as such. In terms of the efficacy of the treatment, objective response rate was 75% and 25% complete response rate. You can see the waterfall plot. This is a patient with progressive disease.
Apart from this one patient, everybody else had at least some degree of reduction in the tumor volume, including four patients with a complete response, the blue bar representing partial response, and the gray bar representing patient with stable disease. 92% of the patients who responded demonstrated sustained response at two years of follow-up. Going into the tumor kinetics. You see that the green lines in the spider plot representing patients with a complete response, blue line is representing patients with partial response, gray line with patient with stable disease, and then one patient who had increase in the tumor burden, as you can see in the red lines. In terms of complete response that we discussed, 25%, partial response, 50%, giving us a total of 75%. What I find more interesting from a clinician perspective is this diagram.
These are all the patients. The red circle is a time point when they had a response assessment. This is the first response assessment, which was done at week 12 after starting immunotherapy with pembrolizumab. These patients did not have any vaccine at this stage. You can see the priming doses with these little arrows concentrated together. Then we've got the four booster doses. The green represents a patient with a complete response, blue, partial response, gray, stable disease, and red with progressing disease. What is interesting is if you look at, for example, this patient who had a complete response, you would expect that, okay, yes, they had a complete response to pembrolizumab that was continued. You can't argue that the vaccine necessarily improved anything further because they already had a complete response.
But then if you look at patient number, this patient, and then this patient and this patient, you can see these patients already had pembrolizumab for three months. And then further, and then later on, you can see when the effect of the vaccine really kicks in, you can see that these patients start to convert from partial responders to complete responders, the blue turning into green. And then some of the patients with stable disease, this patient had stable disease and then converted into partial responders. And particularly when you look at this patient, stable disease, stable disease, and then converted into partial response. So one of the questions that was asked, I think at ESMO last year was as well, is that these patients were already responding to pembrolizumab, so maybe that was just consolidated.
But generally, we expect that most of the responses will be relatively clear in the first three to four months after starting pembrolizumab. And even when you look at these patients, these are quite far down the track at almost week 46 into treatment. So normally in clinical practice, would have seen that their best response would have been seen to pembrolizumab by that time. So in terms of overall improvement, as I mentioned in the summary slide earlier, so overall improvement in response from stable disease or partial response at week 12. So seven out of 13 patients had improvement in their response rate on top of pembrolizumab. Stable disease to partial response in 67% of patients, partial response to CR in about 46% of patients. Objective response, obviously 75%. Median overall survival and progression-free survival has not been reached.
And then the clinical responses for the six patients in the extension phase, they also continued to respond, and they also continued to demonstrate the activity. So as you can see there, the Evaxion AI platform identified with 89% success rate of the immunogenic vaccine neoantigens. And then 86% of them being de novo neoantigen response that was not driven by pembrolizumab. And if you look at this graph, so we've got the EVX specific T-cell responses measured by interferon gamma ELISpot assay. And you can see this is the pre-vaccine when only pembrolizumab was given, then the priming phase, and then the boosting phase, and then the extension phase. As you can see, as soon as the pembrolizumab is given, so we've not really seen a spike in the T-cell responses.
And then when the vaccine is given, you can see there's amplified neoantigen-specific, vaccine-specific T-cell responses and an effect of the boosting dose, and that's sustained in the extension phase, which is very encouraging. So when you look at the data for the details, so we saw both CD4 responses and CD8 T-cell responses, which is again, very encouraging. Now, some of these patients, the data is not available yet, so we'll find out when all the samples are analyzed, and we might see more CD8 T-cell responses in these patients that we haven't checked yet. As you can see, this patient number 12, you can see clearly CD4 and CD8 T-cell responses before vaccine, and then at week 30, you can see clearly their response is seen at immunological levels. So in conclusion, so we saw a good objective response rate of 75%.
Yes, the sample size is small. We saw some preliminary evidence that we could potentially consolidate further and improve further on the responses achieved by checkpoint inhibitor treatment. Vaccine-induced T-cell responses were sustained, and then there's a durable benefit seen clinically as well as looking at the immunogenicity data, particularly from the extension phase. None of these patients who went into the extension phase have had disease progression, and the vaccine manufactured success rate of 89% is very encouraging. Thank you.
Thank you so much, Professor Adnan, for sharing your perspectives on our data. We will now open the session for questions, and please type them into the Teams chat, and I'll just give you one minute to start asking or typing the questions in the chat.
Birgitte, can you see the chat box? Because I can't see it.
I can see the chat box. You need to, in the upper ribbon, there is a chat function. If you click on that, you should be able to see the questions. I can read them if that works for you.
Okay. I'm in the chat box, so I think maybe if you can read the question and then I'll try to answer it.
If you scroll down, you'll see the questions. Do you see them?
Sorry, no. I think if maybe you start reading the question, and then I can try to answer, yeah.
Yes. So first question is from Miguel Longobardi. Hello, Birgitte and Professor Khattak. Miguel Longobardi here. It was a pleasure meeting you both recently. I have two questions for today's discussion. So for Professor Khattak, what evidence most strongly supports EVX-01's contribution to durable response or disease control after pembrolizumab discontinuation?
I think in clinical practice, obviously, it's harder to tease out exactly what drug has contributed, because obviously we do see the checkpoint inhibitor that you don't need to continue the checkpoint inhibitor treatment beyond a certain time point. The trial protocol stipulated two years of treatment, but obviously in clinical practice, we also see patients who continue to derive benefit even if we stop their treatment at six months, sometimes 12 months. The checkpoint inhibitor response can continue. Additionally, if you look at the immunogenicity data and the T-cell response data that I just showed on the slides, we can still see that there's vaccine-specific T-cell responses going, and there's also corresponding clinical responses ongoing, as none of these patients, particularly in the extension phase, have serious disease recurrence.
I think further obviously also comes from the conversion data that, yes, I think pembrolizumab did the heavy lifting to begin with, but I think after three, four months, I think generally we would expect most of the responses to plateau rather than continue to improve. Yes, we see some late responders coming through, but beyond five, six months, it is a bit less common. Most of the routine clinical practice scans that we look at, usually the first or the second scan, you'll be able to see most of the responses. I think when you look at those dotted lines, some of these scans were happening at week 48, and at that time, they were converting into their best response from partial response to a complete response, or down the track from stable disease to a partial response as well.
Yes, I think molecular level, we can't say that this is definitely not related to pembrolizumab. But I think clearly we see that when you look at it, that from a clinical practice, you know that we're not expecting too many late responses. On top of that, we see that there's a spike in the antigen T-cell response, CD4 and CD8 as well, looking at the immunogenicity data, and that's because when the effect of the vaccine really kicks in. From what we know, for example, from the Moderna KEYNOTE-942 and the INTerpath trial data, the curves start to separate from six months and beyond. That's when the priming doses have happened and the T-cell responses really kick in. So I suspect that's what we're seeing as well.
I think from clinician perspective, I think scientifically it makes more sense that probably most of the late responses of conversion is happening from or to a certain degree, definitely from the vaccine, as well.
There is a second part of the question from Miguel. Given EVX-01's 89% neoantigen immunogenicity rate and Moderna Merck's positive phase III results, which is EVX-01's strongest potential competitive advantage, and what further evidence would a pharmaceutical partner need? I can give that a go. There are of course several differences between EVX-01 and Moderna Merck's therapy. First of all, EVX-01 is a peptide-based vaccine, and we know that peptides are immediately active upon administration, whereas the mRNA molecules, they need to be translated. There are also differences in terms of the stability of these different vaccines. Peptides are normally quite stable, whereas RNA molecules are prone to be degraded by different enzymes in our environment, and they also require a cold chain supply, which can be quite, I would say, challenging.
We have a very high immunogenicity rate, so 89% of our neoantigen targets across the patients in the phase II study are giving rise to a strong and specific T-cell response. We have not seen a lot of data from Moderna Merck in terms of T-cell responses at ASCO. This year, they reported data from seven patients in their phase II trial, and the immunogenicity rate, or neoantigen hit rate, as we also call it, is significantly lower than what we have reported in this phase II trial. Approximately 30% of their targets are giving rise to a T-cell response. We believe that this is a clear testament of the precision and predictive power of our AI-Immunology platform. Further, we cannot compare the clinical data directly between the two programs.
EVX-01 phase II study was in advanced melanoma, whereas the Moderna Merck trial is in a different patient population, so in resectable melanoma. There are definite differences also in terms of safety profiles. We, as Dr. Khattak just alluded to, we only have grade one and grade two adverse events, whereas there are a little bit higher or more severe adverse events reported from Moderna Merck. Not anything that could not be managed, but they do see some grade three adverse events.
Thank you, Birgitte. I will also probably like to build up on that. These are obviously two different sort of ways of administering personalized neoantigen therapy, which Birgitte very nicely summarized peptide vaccine versus mRNA vaccine. Obviously, the patient context is different. The Moderna data is purely from high-risk resected melanoma patients, in the phase II study and also in the phase III study as well. They were primarily stage two, three , and some resected stage four patients. The tumor microenvironment is expected to be different in that context compared to late-stage disease, which is Evaxion study. I think Birgitte is absolutely spot on as well, that there is limited translational data from the KEYNOTE-942, phase II study.
We probably might get some better quality data from the INTerpath-001 clinical trial down the track, but it will take some time, because we've just seen the preliminary results. In terms of, I have been involved with both those trials and have been involved with Evaxion trials as well in terms of patient feedback. I think the personalized cancer vaccine from Moderna, I think definitely, I thought it was a bit difficult to tolerate in terms of the vaccine-specific adverse events, and the flu-like symptoms was more with the mRNA vaccine and much easier to give to the patient, the Evaxion vaccine. And Merck is also trying, obviously, the INTerpath-012 study is currently running, so pembrolizumab versus pembrolizumab plus the mRNA vaccine. It's recruiting slowly.
It's got a difficult inclusion/exclusion criteria, but that will probably provide us some more evidence as well in terms of how the vaccine data will compare with the mRNA data in the metastatic setting.
Thank you.
The next question is, I can see the question now from Thomas Flaten. So thank you. Yes, Birgitte?
Please go ahead.
Okay. If this phase III data informed the basis for regulatory approval, where in line treatment will you see Evaxion? I think as a clinician, I can see Evaxion's application in multiple. Obviously, the data is supporting advanced disease. We don't have three years sustained personalized cancer vaccine data from any other vaccine at this stage in the metastatic setting. Evaxion is winner by miles in that. In addition to that, we got sustained immunogenicity data to support its use as well, and with a high precision rate of neoantigen selection. Moderna one was 34, we got 10 here. In the data that we haven't presented here is also this further that we can refine it further by a PIONEER score, which is like a biomarker where you really pick up the top 10 neoantigens.
You enrich your population, enrich your neoantigens who are more likely to respond. Where will we use it? I think it can apply both in the early and late stage. In the late stage, obviously, we don't have data for IPI-NIVO or NIVO-RELA in combination with Evaxion because that is the preferred standard of care for most patients. But we still see a lot of single agent use in routine practice because not everybody is fit enough to face the toxicity of the IPI-NIVO combination. That's why I think in Merck study as well, pembro is the backbone. I think definitely, I think with a single agent in a metastatic setting, starting off with a checkpoint inhibitor treatment and then adding in the vaccine is the way to go.
Although we probably won't put patients with high disease burden that are rapidly growing because they might progress faster and not well enough to be able to tolerate by the time the vaccine is manufactured six, eight weeks later, their disease might be raging away quickly. Generally, we would put patients with relatively low disease burden. Then also you can start up with a checkpoint inhibitor, and those who do not respond, then you can use it to rescue them potentially, which we sort of did in this trial, not necessarily as a rescue, but try to further consolidate what we can achieve with a single agent. I don't see any reason why it can't be looked at in combination with doublet as well.
And then in terms of early stage, obviously in routine practice now what I've found is that we're seeing less and less advanced melanoma patient because we're now using the checkpoint inhibitor in stage two and stage three setting. We're using a lot of neoadjuvant treatments as well, which is complicating how we pair these different treatments. One other exciting area where we could park this is potentially in the neoadjuvant setting, but more in terms of those who do not respond to the neoadjuvant treatment, whether we can rescue that group of patients. Because if you look at the NADINA neoadjuvant trial data, you look at major pathological response rate of about 60%. This means about just under half of your patients are not deriving good clinical benefit. So using it for those patients in an adjuvant setting rather than giving it to everybody.
So that will be one field as well. Then looking at other types, like mucosal melanoma or acral melanoma, which are less susceptible to treatment with checkpoint inhibitor treatment. So that would be another area to look at potentially.
I think we skipped the first question in the chat. Not on purpose, but maybe we should just go back to that question from Michael Okunewitch. Can you see that, Adnan?
Yes. I think 10 neoantigens is fairly low compared to personalized vaccines. Why not target more? And what in particular gives you the confidence? I mean, I'll start at this, but I think it doesn't work that way, that if you have 100 neoantigens, that will lead to success, or 10 is inferior compared to 34. I think what is important is that 89% success rate in terms of generating a vaccine-specific T-cell response, that is more important. You can load 34, and that's the maximum that can be done in Moderna's case, this doesn't mean all 34 of them are immunogenic, and we do not have the data, integrated data in terms of how much the proportion are immunogenic.
I think that the 10 neoantigen, these are specifically selected by the AI platform that are most likely to be immunogenic, which is supported by the data for 89%. Birgitte might have further to add to it as well at the molecule level.
Yes. We are definitely in favor of quality over quantity. The reason for that is that we don't want to administer neoantigens that are not driving a strong immune response. Whether 10 is the ideal number, we don't know. 15 could also be the case. What we do know is that we would like to target the tumor with multiple different neoantigens. There is evidence in the literature of tumor escape, et cetera. If you hit only one target, there might be clones that are outgrowing that does not contain this single neoantigen. Multi-targeting is important. It's also important that we choose the right neoantigens and that we don't dilute or disturb the immune system. That's the approach we have been taking, and I think the 89% target precision speaks for itself.
It's definitely a testament to the precision of our AI-Immunology platform. We don't know how many is needed in terms of driving a strong clinical response, but we believe that a strong and specific immune response is the key factor here.
Yes.
There's also a second part of this question, Adnan, and I think that is more down your alley. What degree of relapse would you normally expect in the year after checkpoints stop?
Yes, I think good question. It sort of depends whether the treatment was stopped due to toxicity and what degree of best response we got from the checkpoint inhibitor. Because in clinical practice, we would normally stop treatment sometimes if the patient had toxicity or if they had a complete response, or sometimes even if they had a partial response as well. But generally, I think if you look at the data, I think there's some fresh data on that as well, presented by Caroline Robert that if patients had voluntarily stopped treatment due to either toxicity or due to complete response, and when you look at particularly patients where they had a good response and the treatment was stopped, you would expect probably somewhere around about 15%-20% potentially recur. Not all of them will respond to treatment on re-challenge.
I think it's a bit complex to answer this because it depends upon what happened, what was their response. But it is somewhere around about 15%-20% the number. I think we answered Miguel's question, and we answered Thomas' question.
Yes.
Patrick, for the future of EVX-01, is a major partner required? I think the answer to that is yes. I think ideally, we would like to have a major partner in terms of the immune checkpoint inhibitor treatment. Obviously, we collaborated with Merck on this study. But certainly, I think a major partner is required and obviously to further build on the data and explore other avenues of future use of Evaxion, not only in melanoma but potentially other tumor types as well.
Yes. The strategy of the company is definitely to out-license our product candidates, including EVX-01. There is, of course, a need for further clinical development also on EVX-01. We, as Adnan is alluding to, we are also looking at other indications where we definitely see a fit for our therapy, and that includes different indication where there is a high mutational burden and where checkpoint inhibitors is approved, but there is still a need for adding additional therapies. So we see a fit for other indications, so beyond advanced melanoma.
Okay. The next question is, what is your perspective on developing peptide DNA or RNA-based vaccines? What is it? Would you consider exploring RNA-based vaccines for different indication? It is a good question. I think absolutely the field will really take off, I think based on the research that is going into it now, trying to personalize the immune modulating treatments rather than using more generic off-the-shelf immune modulating treatments, although they are probably likely to be used in conjunction, I think, for quite some time. We have seen the RNA vaccine data from Moderna, the phase II and another phase III data, then we got the BioNTech vaccine data as well and some early biotech data as well. Certainly the field is likely to head this way.
Rather than one size fit everyone, we will have more in terms of one drug for each patient, in combination with checkpoint inhibitor treatment and certainly exploring in other tumor types as well. We have not looked at Evaxion's use in other types yet, but it is being discussed internally between the Evaxion team. In terms of the mRNA-based vaccine, certainly I have participated in trials or INTerpath-001 results were just presented. INTerpath-002 has nearly completed recruitment for adjuvant lung cancer. INTerpath-005, which is adjuvant bladder cancer with checkpoint inhibitor with Moderna's mRNA vaccine. INTerpath-007, which was in squamous cell carcinoma, got rolled back. Then we are actively participating in a stage one highest lung cancer as a preventative strategy for highest stage one lung cancer pembrolizumab with the mRNA vaccine as well.
So across lung cancer, bladder cancer, and then INTerpath-004 RCC adjuvant study that has completed recruitment. Some phase III trials have already completed recruitment and probably get the data in the next couple of years, and some are actively recruiting as we speak. The field is really exploding and we all excited as oncologists and clinicians and collaborating with our pharmaceutical industry colleagues as well as translational research colleagues as well.
Maybe I can add to that. So we of course all of us very excited about all the new data that will come out in the coming years. In terms of the modalities, so peptides versus DNA, RNA-based vaccines, I think we can conclude that the field does not know currently which is the preferred modality. We have been exploring peptides and DNA-based vaccines, both in the personalized space and now advancing into off-the-shelf therapies based on a DNA vector. But there are no direct comparisons between these different modalities. We have done a little bit preclinically, but whether that would translate into clinical settings, we of course, do not know. From an immunological point of view, peptide-based vaccines are most likely prone to drive a strong CD4 response, whereas DNA and RNA have a more skewed towards CD8 T-cell responses.
We believe that we definitely need both CD4 and CD8 T-cell responses in order to drive a strong response in the patients. The field has not settled completely on whether a DNA, RNA or a peptide-based formulations are the most favorable ones.
Thank you. Next question is, how does the evolving standard of care in melanoma change the opportunity for Evaxion? Does availability and combination to induce stronger responses make Evaxion more attractive, or durability of response now that the three-year data is durable? Doing trials in melanoma is very effective, but at the same time very challenging as well because the field is moving so fast. A typical trial protocol usually is written up to maybe at least one to two years before a trial is really rolled out. The pilot protocol is agreed on, then by the time you take it through the regulatory authorities, startups happen, recruitment happens, and the standard of care changes. It is always very difficult to obviously stay up to speed with the clinical trial landscape that is changing rapidly.
Yes, certainly, I think our data is just temporary with Evaxion, but I do not see the reason why the same cannot be done in combination with combination treatments like nivolumab or ipilimumab/nivolumab. Particularly, I think because not everybody would respond to these drugs either. The first slide that I showed you, 50% survival rate was with combination IPI-NIVO, so this means 50% will have benefit. Certainly it can be used in combination with those patients as well because, and also on top of the checkpoint inhibitors, I do not believe that Evaxion, I cannot assume for sure because it has not been done in a trial, but I would not expect that the peptide vaccine would add significantly in terms of the toxicity on top of what IPI-NIVO or NIVO-RELA do. Certainly it can be explored in that context.
Next question is, could this be used in newly diagnosed melanoma patients with lymph node metastasis? So a stage III disease, high risk, like the INTerpath-001 trial where mRNA vaccine was positive. Certainly, this can be looked at in the early-stage setting as well. Then you can argue that obviously if one vaccine has already demonstrated an improvement, doing the same thing from a clinician perspective, yes, can be done. Obviously, there are differences between peptide vaccines in terms of the logistics, the stability, the cold chain stability, some advantages of one or the other, and the timing. Also, as I mentioned in the earlier question, in the neoadjuvant space, which is also being increasingly popular, almost for 50% of the patients that we see with stage II disease or lymph node metastasis, they have got macroscopic disease.
And then obviously 40%, somewhere between 40%-50% of them do not respond or do not get a major response. So it can be used in that context as well. Some neoadjuvant trials are being planned and rolled out. It will be nice if somebody can look into that aspect as well. If you were designing a phase III clinical study, what would be your recommended control arm, pembro plus ipi, for example? I think also I need to obviously think about it with a more clear head. But yes, I think one of the major challenges is the question now asked. For example, I did this Evaxion study, the same question is asked, why not IPI-NIVO? But obviously, by the time we were doing it, IPI-NIVO is still not available in many countries in the world.
Even in Europe, I think at least German colleagues tell me they have just got access to it within the last sort of, I think, 12 months or so. So I think that is one thing, and availability is a different thing. Then IPI-NIVO generally would be considered, or nivo alone would be considered now the active comparator in the contemporary trials. But we have got many trials that have participated and still and involved. For example, we are doing a TIL therapy trial. That is also pembro versus pembro plus TIL. One of the major criticisms is that why pembro? But obviously when the trial was designed, that was the standard of care.
We also have to bear in mind obviously that there has been no clear superiority of IPI-NIVO versus nivo, for example, checkpoint inhibitor treatment in the CheckMate 069 trial, because the trial was not statistically designed to prove superiority or did not have the statistical power to prove the superiority of doublet versus single agent. We think that maybe doublet got an edge, but it was not statistically proven so. Then the last question on behalf of RK from H.C. here. Well, very different. So I think Evaxion's data is obviously a small study in the metastatic setting, so it is a different context. The data from Moderna and Merck is in a different context, in early stage with a different tumor microenvironment. The pros and cons of the vaccine delivery between peptides and mRNA, which I think Birgitte answered already.
So I think eventually we will go with whatever the data supports. Obviously, if there was an Evaxion trial in a metastatic setting, then obviously if that was to demonstrate that pembro plus or whatever is the competitor arm plus Evaxion is better than the standard of care, then obviously that clinician will follow that. So we go by data rather than necessarily specifically looking at individual nitty-gritty of the differences in the logistics. But I think logistic of maybe the peptide vaccine might have some advantages potentially, and the patient tolerability was a bit better anecdotally. But obviously, I have not treated many patients with Evaxion because the overall number of patients there is small, whereas I have treated hundreds of patients, well, not hundreds, but 100+ patients with the mRNA vaccine.
It can be quite challenging to give to some of the patients because they get quite a marked flu-like illness. Clearly, some of the younger patients in their 40s and 50s who we expected a stronger immune response, de novo, they have a much stronger reaction to the extent that I had to give even low-dose prednisolone or even opioids to deal with the myalgias for some patients. I think the more we use these vaccines, we will get more knowledge about what they can do and how best to mitigate with their toxicity as well. Then within what you can discuss publicly, do the approaches differ meaningfully in tissue requirements, ability to manufacture a vaccine, injection-related symptoms?
I think we sort of discussed that in terms of the injection site reaction, but definitely, I think anecdotally, I felt that it was easier to treat the Evaxion patients. I have treated many more obviously with mRNA vaccines, so probably the sample size is different, so we cannot draw any meaningful conclusions regarding that. In terms of the tissue requirements, they are different in the sense that we had much easier tissue available for the INTerpath trial because it was done in the post-operative phase where you have an axillary dissection done and a big sample provided, whereas the Evaxion was fresh biopsies in a metastatic setting, so it was a pure biopsy rather than surgical sample. I think the inherent design of the Merck trial was such that obviously they got an advantage because they got a better and bigger tissue, because tissue is the issue.
We did not have any vaccine failures, at least from our site. Birgitte might know whether we had any vaccine failures overall or not.
No, we did not.
Which is again, very encouraging because if you look at the Moderna data as well, they had a 99% success rate, so the vaccine failures are low. I mean, we had two or three patients from our site in the INTerpath trial who were vaccine failures, not because the tissue was not enough. It is just that I think they just could not, I think, extract DNA to be able to make the vaccine. Then from a translational perspective, what differences would you expect between long peptide plus liposomal adjuvant? Birgitte, do you want to take this one on, number three? So the translation one.
Yes, definitely. I think we covered some of this already, as I mentioned before, so the peptide-based vaccines, they are more prone to drive a strong CD4 response compared to the RNA and DNA-based vaccines. That is simply due to the way that the immune system takes up these different molecules. As I mentioned, we believe that there is a need for having both CD4s and CD8 T-cells. It has long been considered as CD8s are the one that drives the cytotoxicity towards actually killing the tumor cells, whereas the CD4 has historically been considered as helpers or supporters of this process. Recent evidence definitely demonstrates that CD4 T-cells do also have the capacity or the ability to drive a direct tumor-killing effect.
I think there is, again, the field is it doesn't exactly know which balance between the CD4s and the CD8s are the most favorable one. But from a pure immunological point of view, I think we can say that at least having both types of T-cells can drive a strong anti-tumor effect. Then I think there was a question around, have you seen evidence of a clinically relevant difference rather than simply different laboratory readouts? I think that's difficult because we have not done comparison.
Yeah. Also, I think the CD4/CD8 response said, again, we haven't done comparison. Also, I think we don't have enough granular data from the mRNA vaccine, Moderna vaccine, and obviously, the vaccine study in the metastatic setting so you can do some correlation with response. Whereas the INTerpath data, the KEYNOTE-94 data, that's in an early stage setting, so you can't determine the response because obviously that's in a post-operative setting, and you only find out if somebody relapses. You can't look at the success of the treatment, you only look at the failure of the treatment. So it's a bit difficult to tease out in that regard. But I think in the coming years, we'll probably drill down deeper into the CD4, CD8 responses, and see if there's any correlation with or preferential correlation with the response of one or the other.
I think I also mentioned that, yes, there's CD4 responses that we're seeing in every single patient, but there was a significant number of CD8 T-cell responses that we were also seeing in these patients, and the few that were missing, there's still some samples that need to be analyzed yet.
I think there was one part of R.K.'s question two that we didn't entirely cover. So he's also asking about injection-related symptoms or missed doses or patient willingness to continue. Do you have any comments to this?
Yeah. So in vaccine trials, everybody got the vaccine, and they tolerated it very well, and nobody questioned that I cannot continue. In the INTerpath trial and the KEYNOTE-94 trial, some patients did have a quite a strong flu-like illness and myalgias, and fever-like syndrome. So that usually happens, starts from up to six hours after the vaccine to 36 - 48 hours sometime. And if it happens every three weeks with the vaccine, nine doses that were given. So it was challenging for some patients, but patients that are motivated as well, they want to obviously they see that maybe we are seeing a stronger immune modulation going on, and that is why we are getting these symptoms. But there were some elderly patient who were quite concerned about continuing it because it was affecting them.
And from speaking to other colleagues from other centers as well, some of them did withdraw.
Thank you for that. I think we have managed to cover all the questions, and I would just like to conclude the session by thanking you, Adnan. It has been a pleasure. And I know you just arrived home in Perth in due time, so thank you very much for presenting our encouraging data and also giving your perspectives.
Thank you.
I would also like to thank all the participants for joining this webinar. Thank you all.
Thank you.