Welcome to this webinar sharing the two-year readout from our Evaxion phase II study in advanced melanoma. We're very, very happy with the virtual turnout for this call here. Together with Professor Adnan Khattak , I look forward to sharing results and discussing data and implications of these data with all of you, right, from this important phase II study in high-risk melanoma. If we look into the next hour or so, we will be covering an exciting agenda. Initially, I will deliver an introduction to Evaxion, an introduction to our AI-Immunology platform, and briefly cover the data from the phase I trial in advanced melanoma that really paved the way for the phase I study that Professor Khattak will present. I'll then hand over to Professor Khattak, who will take us through the phase II design, perform a detailed review of the results, and also discuss implications of this data.
We'll end with a questions and answers session, and we really encourage that all of you, if you have any questions, please post them. There will be two different ways of posting questions. One is to simply put it into the chat here, to type it directly into the chat. Alternatively, feel free to type in Q or question, and we will then ensure when we get to the Q&A session to unmute you, enabling you to post a question directly to myself or to Professor Khattak. On that, I'm happy to initiate this webinar with an introduction to Evaxion, AI-Immunology, and the phase I data as previously explained. My name is Benjamin Wolthers. I'm a physician, and I serve as the Vice President of Clinical Development here at Evaxion. It's truly a privilege for me and a great pleasure to be able to present for all of you today.
If we look first at Evaxion, we were founded in 2008 here in Copenhagen, Denmark, as a truly AI-first company. We leverage our proprietary AI-Immunology platform for vaccine discovery, for vaccine design, and for development. Based on AI-Immunology, we've developed a clinical stage oncology pipeline, out of which EVX-01, that we of course are presenting today, is by far the most advanced project, but where we had several additional projects in the pipeline. Moreover, we leverage AI-Immunology in our infectious disease pipeline, where we target bacterial, viral diseases with a high unmet medical need. If we look at AI-Immunology and the AI-Immunology platform, this is really at the core of what we do. It's the pumping heart of Evaxion. AI-Immunology decodes the human system for therapeutic target discovery. AI-Immunology integrates data from the genome, from the transcriptome, and from the proteome, really to identify optimal targets for our vaccine.
As we'll show later in this presentation, AI-Immunology has proven a very, very high success rate in selection of targets, inducing potent vaccine-specific T-cell responses, and then enabling these T-cells to interact with cancer cells and elicit tumor killing. If we look at our pipeline here, EVX-01 is our lead candidate, really demonstrates the performance of our AI-Immunology platform, and is really our proof of principle, proof of concept. EVX-01 is a personalized anti-cancer vaccine, really designed to match the heterogeneity and the high number of tumor mutations that we observe in melanoma. If you look here in this slide, this is from a similar publication in 2013 by Accenture and colleagues in Nature, where they listed on the X-axis a list of different cancers. On the Y-axis, the prevalence of somatic tumor mutations.
You see that on the left side, at least my left side of the slide here, you see the acute lymphoid leukemia, you see AML as well, with low numbers of somatic tumor mutations. On the other side of the slide, highlighted here in green, you see melanoma, really harboring a high number of somatic tumor mutations. Also, of note, you'll see that on the same side of the slide, with a high number of mutations, you see indications such as lung cancer, bladder cancer, and also importantly, head and neck cancer. We have done phase I and II to show proof of concept with EVX-01 in melanoma. There are certainly also other indications with a high unmet medical need, where we could see a therapy such as EVX-01 making a big impact for patient outcomes. Now turning to the phase I trial design.
The phase I trial was conducted out of an expert melanoma site here in Copenhagen, enrolling patients with stage 3B, stage 4 melanoma. Patients were required to have a performance score of zero, one, and at least one measurable tumor lesion per RECIST 1.1. Additionally, we did not allow any patients to have active brain metastasis when going into the study. If you look here on the slide on the bottom left corner, we have the dosing regime. When patients were eligible and initiated the study, we initiated checkpoint inhibitor therapy with a dose according to the label. We initiated the process of designing the personalized vaccine. This process is projected in the table on the right-hand side of the slide. What we do is that we obtain material, tumor biopsies, and also samples from non-cancer cells in the patients.
These two types of tissue are sequenced, DNA and RNA sequenced, and then we load the data into the AI-Immunology platform. The AI-Immunology platform then selects up to 10 optimal patient-specific targets for the vaccine. The vaccine is a peptide-based vaccine, and this is manufactured, shipped to sites where it is administered to patients. In the phase I trial, we manufactured with a needle-to-needle time of between six to eight weeks and administered EVX-01 for the first time at week eight. This was then followed by administrations at week 10, 12, 14, 16, and 18. If we turn to the results and some of the learnings from the phase I trial, we saw that very importantly, EVX-01 was safe, well tolerated, with only grade one and two adverse events. These adverse events being mainly injection site reactions, low-grade fever, and fatigue.
We saw very encouragingly that eight out of 12 patients showed an objective response to the treatment combination, so an ORR of 67%. However, we also saw that out of these eight patients, seven patients eventually relapsed. EVX-01 was found to induce an immune response in all patients, and T-cell responses were observed towards 58% of the EVX-01 peptides administered. Moreover, as I mentioned before, we had efficient manufacturing of the vaccine with a turnaround of six to eight weeks. Three key learnings came out of this phase I trial. First, we selected the high 200 μg dose as the recommended phase II dose. Second, we evaluated the tumor relapses, and we found also looking at vaccine-specific T -cells over time that we should include into phase II EVX-01 booster administrations.
Professor Khattak will come more into that, but really to administer these administrations to keep the levels of vaccine-specific T -cells sustained at a high level. Lastly, we took data here from the phase I trial and additional data and updated the AI-Immunology platform with the ambition of even further improving prediction power of the AI-Immunology platform. On that, I would like to hand over to Professor Khattak. Professor Khattak serves as Professor at Edith Cowan University, and he leads the phase I Trial Unit at Clinical Research Hollywood Private Hospital in Perth. Moreover, Professor Khattak has served as a Primary Investigator in this EVX-01 phase II trial. He recently, this was five days ago in Berlin at the European Society of Medical Oncology, Professor Khattak presented the data you'll be seeing now in an oral session.
With that, Professor Khattak, I'll hand over to you to take us through the phase II data.
Thank you, Benjamin. Can you hear me clearly?
Yes.
Okay, thank you. Thank you, everybody, for dialing in from various parts of the world. I'm dialing in from Western Australia. It's 10:40 P.M. at the moment. The audience is mixed, so I'll keep the discussion sort of generic as well, rather than going too much into oncology jargon. May I take control of the talk now, Benjamin?
Yes, please do. Please do, Adnan.
Okay, can you see my slides?
Indeed.
Okay, excellent. Melanoma is a fairly aggressive skin cancer with a fairly high mortality rate, particularly when patients get diagnosed with metastatic disease or stage 4 melanoma. From 1975 all the way to 2011, melanoma was considered to be the graveyard of clinical trials where about 25 - 30 clinical trials were negative. These included trials with chemotherapy, hormonal treatment, biochemotherapy, until 2011 when the first ipilimumab trial came along and immunotherapy was the first treatment to make a significant difference. Roughly about 10- 15 years ago, maybe somewhere around 2005, 2010, the one-year survival statistic for patients with stage 4 melanoma only used to be about 20%-25%, meaning only one out of four patients would see a 12-month mark from diagnosis of their stage 4 melanoma. Since then, significant progress has been made.
We got first-generation immunotherapy drugs, we got second-generation anti-PD-1 targeting drugs, and then we use them in combination as well. This is the Kaplan-Meier curve of different clinical trials of targeted therapy and immune therapy in stage 4 advanced melanoma. If you can see, these are the months since randomization, and along the Y-axis, we got a proportion of patients alive. If you look at the five-year survival statistic now, with the combination treatment, the brown line, roughly half your patients could be expected to live for five years or even longer. You can see that the curve starts to plateau around the three-year mark. If you're doing well at three years, now we've got latest data even dragging all the way up to 10 years with survival statistics sort of in a similar range. That's quite a significant improvement in the last decade.
The green line represents targeted therapy, which is the other class of drugs that we use to treat patients with advanced melanoma. Many patients develop secondary resistance, and if you look at the five-year survival statistic, they're roughly about 35%- 40%, so inferior compared to immunotherapy. Obviously, the outlook of patients has improved, but you can see 50% of patients benefit. What about this group of patients who unfortunately die? How can we help those patients? Obviously, the treatment that we use, for example, the combination of the first and second-generation checkpoint inhibitors, yes, they're efficacious, but they can be quite toxic as well. None of these immune checkpoint inhibitor treatments here are personalized. If I get 10 patients, I offer them the same treatment, but they're not specifically designed for an individual patient's melanoma, so I can't be confident. It works for some, it doesn't work for others.
They're more generic treatments. There is this ongoing need for coming up with better and safer treatment options that are more personalized as well, so that we can increase the efficacy to try to help rescue those 50% that unfortunately die in the first years, and also to come up with more tailored patient-specific treatments so that we can treat the right patient with the right drug. In the phase II trial of Evaxion, building up on and further consolidating the phase I data that Benjamin presented, in this trial we included patients with stage 3 unresectable or stage 4 melanoma. The bulk of the patients were stage 4 melanoma patients, and they were treatment naive and a typical ECOG 01. This means that they were fairly fit patients. They didn't have any active brain metastasis.
The primary endpoint included initially looking at response in terms of the conversion rate, which is conversion from stable disease to partial response or complete response. Partial response means that you see an objective reduction in the tumor volume by 30%. Complete response, if you see a 100% reduction in the tumor volume, and progressive disease, if you see more than 20% increase in the tumor volume. These are the different figures that we use. Anything less than a CR and less than in between progressive disease is called stable disease.
The primary endpoint was to see if we can convert stable diseases into a complete response or a partial response, what we call CR or PR, or converting a partial response to a complete response to try to see if we can deepen the responses, what have been achieved by immunotherapy with checkpoint inhibitors like pembrolizumab, which is one of our main treatments that we use. Secondary endpoints included objective response rate, progression-free survival, overall survival, and different adverse events, and also the neoantigen-specific T -cell response. Exploratory endpoints included conversion of progressive disease. This means that patients that are not responding to checkpoint inhibitors, can we pull their disease back into either disease stability or response or a complete response.
Two types of treatments were used as per standard pembrolizumab monotherapy, what we call Keytruda, that was started at week zero and given all the way for a total period of two years, which is the current sort of standard set across a number of clinical trials or more contemporary trials that we generally treat maximum for two years. A standard dosing schedule of 400 mg IV every six weeks was used. At week 12, Evaxion's EVX-01 personalized peptide vaccine, as Benjamin told you, the mechanism of action and how it's manufactured, was started. Six consecutive doses were given in the priming phase every fortnight, 12, 14, all the way to week 22. There was a gap after the priming phase leading on to the booster phase, and four doses were given at week 30, 42, 54, and 78. Patients went into long-term follow-up.
More recently, an extension phase has been opened up as well for an additional two booster doses because of the preliminary efficacy that we've seen and the benefit that the booster doses are providing to vaccine-specific T -cell responses. These were the study populations. It's a phase II, a small phase II study, 21 patients, four screen failed, and 17 patients were enrolled, but one patient developed disease progression. Sixteen patients went on to the trial. Two-thirds of the patients were male, and all patients were Caucasian and with a good ECOG status or their performance or their functional status, with a vast majority of patients having stage 4 melanoma. PD-L1 expression and BRAF status was sort of 50% of patients had a PD-L1 score more than 5%, and 50% of the patients also had BRAF mutant disease.
Generally, we expect 40% - 50% of the patients with stage 4 melanoma to be BRAF positive. In terms of safety, from what we know now from the personalized cancer vaccine or individualized immunogen therapies, they got a very classic toxicity profile, which is fairly well tolerated and very well managed. Primarily, we're looking at no toxicities from grade two or above. As oncologists, we don't want to see, this is a CTCAE grading criteria, grade one, which is very minor toxicity, but when it starts to hit grade three and four, it leads to major morbidity and grade five, obviously, mortality. We don't want to see anything showing up in grade three, four, and five territory. If you look at it in the middle of the table, we can see the Evaxion monotherapy.
The vast majority of adverse events were grade one, and this included fatigue, injection site reaction, body aches, muscle aches, and then feeling tired and flu-like symptoms, which we expect with vaccines. There were a couple of grade two adverse events. When they were combined, I think the ones that were attributed to both were primarily grade ones and twos, and there was only one grade three and four adverse event when a patient developed pancreatitis and secondary diabetic ketoacidosis. From what we know, that side effect profile is not associated with personalized cancer vaccines. It was driven by the underlying pembrolizumab. This is very much in line with the data that we have from other personalized cancer vaccines like the mRNA vaccine. This is very reassuring. At week 12, these are the responses that we saw: complete, partial, stable disease.
The objective response is usually defined as a combination of complete response and partial response, which was roughly about 50% in patients who were treated with pembrolizumab at week 12, meaning three months into treatment. Once Evaxion was started, the best objective response rate later on when you combine 50% and 25% was 75%. Generally, with pembrolizumab monotherapy, we expect response rates roughly around 40%-45%. Seeing the best objective response rate of 75% is fairly encouraging. It means that you could potentially convert some responses into deeper responses. Obviously, it's a relatively small subset of patients, so we can't make any bold statements, but it's a very good signal. This is the waterfall plot. This is 0%. Anything lower than this line is generally good. Anything above this line is bad. The green lines represent patients with a complete response. There were four patients with a complete response.
This curve is not reaching 100%, but this patient had a substantial reduction in their target volume to less than 5 mm . The disease didn't disappear, but anything less than 5 mm in terms of the neural disease is classified as a complete responder and can be put down as 0 mm . The blue lines represent partial responders. The gray lines represent the stable disease, and there are three patients with progressive disease. This patient did have shrinkage of the tumor but developed new lesions, hence progressive disease. The responses were measured according to the standard clinical trial evaluation criteria of RECIST 1.1. I quite like this graph. It sort of tells us how the responses transformed, where they started at week zero and then week 12, and it sort of tells us how things changed by the introduction of the vaccine.
You can see these are the vaccine priming doses and the booster doses. I'd like to highlight these patients who started with a partial response first and then transformed into complete response. These two patients also transforming into complete response later on. The argument some people preferred is that obviously these patients were already responding, and you would expect, I think I'll show in the graph probably later on, that these patients were expected to have a good response anyway. Usually when patients are responding, they will be responding quite early on in the journey. Generally, in the first three to six months, you will get quite substantial or they will achieve their peak response. Here you can see that some of the complete responders are converting around about week 72, so quite delayed.
These were the partial responders that continued, and these are the patients with stable disease who later developed a partial response. Particularly if you look at this patient 12, stable disease, stable disease, and by the time the vaccine effect kicked in and the booster doses had been given and there was a spike in their T -cell response, you can see they converted to partial response. That's what we were hoping to achieve, that we can deepen the response on top of the checkpoint inhibitor. The overall responses in terms of the conversion rate, seven out of 13 patients. This means that three patients transformed from partial response to complete response and four patients from stable disease to partial response, leading to a conversion rate of 54% and an overall objective response of 75%. The median follow-up was about two years.
The median progression-free survival and overall survival has not been achieved yet because the vast majority of the responders, up to 92%, continue to respond to treatment at this stage. What was more encouraging also was that identifying a neoantigen, so a neoantigen is like the fingerprint of the cancer cell. All of us have got their own fingerprint, which identifies us similarly. The neoantigens are the fingerprint of the cancer cells. Identifying a neoantigen is important. Quantitative effect is important, but also qualitative as well. Not every antigen is going to lead to a significant anti-cancer immune response. What Evaxion's AI-Immunology platform identified was that the neoantigen induced T -cell responses in 81% of the cases, which is very encouraging and further built up on the phase I data, where it was roughly about 65% from memory.
This is a very nice graphic representation of how the vaccine-specific T -cell responses happen. These are both a combination of CD8 and CD4 T -cell responses. This is where the Evaxion priming doses started and then the booster doses came along. If you look at this, this is the pre-vaccination period when pembrolizumab was given. This is with the priming phase. You can see the T -cell responses happen quite early on in the priming phase. This means that you start to see an effect because particularly when you're treating a patient, you want to have a therapeutic effect that starts early on because many patients with melanoma will present with high volume metastatic disease. You want to generate an anti-cancer immune response that translates into reduction in the tumor volume so that you can make patients' quality of life better by reducing the tumor burden.
You want a drug that kicks in early. What we also saw more interestingly was the boosting phase where the four booster doses were given, where there was further improvement in these T -cell responses and they were sustained throughout the period, highlighting the importance of the booster doses. That's why I think further a couple of booster doses are being rolled out as well. These are the spider plot. I'll start off with patients who developed disease progression. The red lines, so this patient experienced disease progression, you can see. If you look at this patient's T -cell response, when they were progressing, I think the vaccine had just been started. When the vaccine effect kicked in, there was some reduction, but obviously after that it sort of plateaued and then further disease progressed. We don't have any further follow-up sort of T -cell data from it.
This patient with stable disease, very interesting, one of my patients, you can see the disease volume jumped from 0%- 50%, so almost doubling of their tumor volume at the completion of the first three-month treatment with pembrolizumab. Things started to improve when the vaccine was given as well. You can see how the T -cell responses sort of correlate with that. When the vaccine hadn't been started, you were seeing an increase in tumor volume. The vaccine effect kicks in. You see a tumor-specific T -cell response that's going up and the volume of the tumor is going down, down, down, down. Because this patient had developed disease progression at the beginning, we can't call them a responder, but we have done a couple of PET scans for this patient now and they've shown a complete metabolic response, but obviously as per RECIST criteria.
I think we still call them a stable disease. In terms of the deepening of the response, you can see these patients were responding, but then after that plateaued. The vaccine effects have kicked in roughly around about this period, and that's when we start to see these patients coming down, transforming into complete responders. The trajectory, if you can see also here, these patients in the blue line, this is the 25% line you can draw here. At three months time point, these patients had stable disease. They hadn't crossed the 30%, and they sort of continued in the stable disease up till here, and then they start to respond after the six weeks time period. Obviously, these are a small number of patients.
We need to further study the T -cell vaccine data, and ideally have a bigger cohort of patients to draw more meaningful and more statistically robust conclusions. This patient who developed quite a late complete response, you can see how the tumor volume started to go down when the T -cell response went up, and when it really spiked, you can see the tumor kinetics hit zero, transforming into a complete responder. In conclusion, I think before we look at the efficacy data, we always want to make sure that whatever treatment we roll out is safe to use. This combination was well tolerated with a good safety profile, consistent with the phase I data. The objective response rate is very encouraging, but again, it's a small subset of patients.
What is quite encouraging is that most of the patients, 92% of the responders, demonstrated a sustained response at the 24-month time point. More interestingly, the ability of this combination to induce potent and sustained T -cell responses, and the AI-Immunology platform's ability to recognize the neoantigens that will generate anti-cancer immune responses in eight out of 10 patients. The vaccine was successfully manufactured for all of these patients. We don't want to screen fail. I'm involved with other personalized cancer vaccines like mRNA vaccines. We do have a certain vaccine failure rate, particularly the recent clinical trial that we concluded. This is very encouraging that in this small subset of patients, nobody fails screening because of an inability to make the vaccine. These findings are very encouraging. They give a very positive signal, and they support the ongoing development of Evaxion in high-risk melanoma.
Further discussions are ongoing by Evaxion's team. Thank you.
Thanks a lot, Dr. Khattak, for this comprehensive overview of the data and running through this. I think this takes us to the Q&A part of the webinar here. I'm happy to see that we have quite a number of questions here. I think I will start by, I have so far looked at three people who have their hand raised. Maybe we should start with Scott trying to, we'll ensure that you should be able now, Scott, to unmute and pose your question to Dr. Khattak and myself. You're still muted, I believe, Scott. Maybe while we figure this out, I'll go to one of the questions in the chat. This is from Wim, who asked whether EVX-01, if EVX-01 was licensed to another company, how dependent would that partner be on Evaxion 's infrastructure considering its personalized therapy? How do you see this working in practice?
Thanks a lot for this question. This is, of course, something that we're discussing with relevant partners. Without disclosing any of that, I will say that if we break down the designing of the EVX-01 vaccine, the sequencing part is very straightforward in many locations. Such can happen decentralized at the site. The predictions, AI-Immunology is, of course, a core, as I mentioned, of what we do. This is after being developed. We have a 24-hour turnaround time on this, making it quite really removing any complexity from this. I'll also say that the manufacturing of the peptide-based vaccine is using very conventional peptide vaccination manufacturing production methods. In that sense, not complex. However, how this will work when we move forward into our development of EVX-01 with a partner, that is really, of course, dependent on discussions between Evaxion and that partner. I hope that that suffices.
I don't know whether Scott has been able to unmute. If not, then let's try to go to, I have an RK listed here as having his or her hand up. Maybe RK, if you are able to now unmute and pose your question, let's give it a shot.
Good evening, Dr. Khattak. First of all, thank you very much for doing this call and talking to us this late in the night for you. A couple of quick questions. The first one being the ORR, which you report 75% in the 16-patient study. It looks better than the 40%- 45% that we had seen with the monotherapy. How would you think about this response rate, based on not just what has been approved, but other therapies that you have worked with? What does this say or what should we be expecting as we go into the late-stage studies with the same molecule?
Okay, I think very, very good question. I think our current first-line treatment options across Australia and across the globe, obviously, this is a very busy area. A lot of new clinical trials are happening. Different molecules are being added to each other, but unfortunately, they also bring a lot of toxicity as well. One of the most common regimens that we use is a combination of ipilimumab and nivolumab, where we expect response rates somewhere around 50%- 60% with the combination. It's a fairly expensive treatment, number one. Number two, it can lead to substantial toxicity where you probably saw that when I mentioned that we didn't want to see a high grade 3 or higher adverse event rate. That grade 3 adverse event rate with this combination hits about 50%- 60%.
This means that you expect that 50%- 60% of the patients are going to end up in the hospital in one way or another due to some sort of toxicity. We have a very good efficacious regimen, but it's fairly toxic and obviously quite substantial for patients who are 65+ years . We tend to shy away from using treatments like this. We certainly want to cross that 60%-70% mark and try to approach more into that territory, 75% +, but at the same time not lose in terms of safety. Tumor infiltrating lymphocytes are being rolled out as well in the first-line setting. I'm involved with those trials as well, but that's quite a cumbersome process.
At this stage in the melanoma community field, we're not entirely convinced that the cell therapy has got any striking role in the first-line setting when we have other good efficacious options available that are off the shelf and we don't have to go through a complex process of cell therapy manufacture. The personalized cancer vaccine field is very interesting. Obviously, we're seeing improvements. The personalized mRNA vaccine data that I presented at ASCO a couple of years ago was very encouraging in the stage 2, early stage melanoma setting. Now we're waiting for the results for the phase III from the early stage melanoma setting. Doing them in the metastatic setting poses a challenge because we need to start treatment, but at the same time, because these are not off-the-shelf treatments, they need to be manufactured.
We don't want to be in a situation where you start a patient on their standard treatment, plus send off the tissue to your central lab to do all the DNA RNA sequencing and come up with a personalized vaccine, and then find out six, eight weeks later that we failed to manufacture the vaccine because I've seen it in other clinical trials, vaccine failure, and I've had recent experience in the context of another trial where we waited for a good six, eight weeks for a patient to be even randomized because you can't randomize patients till you obviously have the approval or the indication from your lab that the vaccine can be manufactured. Unfortunately, for those couple of patients, we could not obviously proceed. You don't want to waste that time.
At the same time, try to deliver the vaccine as early as possible so that you can start your priming phase early so you can generate your T -cell response. The data from Evaxion is quite encouraging with the 100% manufacture success rate. Obviously, small population need to be replicated in a bigger, ideally a randomized phase II study, but this is very encouraging that the toxicity profile goes in its favor, the manufacturer, and I think the translational response in terms of patient-specific and durable responses are very encouraging.
Thank you. Can I ask a follow-up?
Yeah, maybe a quick follow-up question.
Okay. The follow-up is, you know, the four patients that did not respond, you know, was there anything unique about these four patients, either in terms of failure of the vaccine itself or in terms of meaningful T -cell response in these individuals? Thanks. Thanks for taking my questions.
Yeah, I think obviously they're different. Obviously, it becomes hard to drill down to an individual patient's data because I don't have access to each individual patient's data as an investigator. Eventually, we're looking to those details. Yes, I think as I saw the patient where they had disease progression, we couldn't have the T -cell responses sustained in some of them. I'm not sure if Benjamin, you want to comment on that as well. The others that progressed, what was their individual T -cell response because I don't have all those curves. Maybe I think the backup slides, you had something on that maybe?
Yeah, so indeed I can say that we are, of course, drilling down. The data presented today is with a data cutoff of end June, right? We've been cleaning data, getting everything ready for ESMA in this presentation. Over the coming weeks to months, we will for sure be evaluating together with Professor Khattak and also our other key opinion leaders that have served as PIs in this study, whether we can decipher any trajectories in responders and non-responders. To Dr. Khattak's point, we had 12 out of 16 being responders, right? They are small numbers, and we see T -cell responses in all patients, all 16 patients. I will go to the next person I have here on my list. That is Thomas Flaten. Thomas, if you are able to unmute, please do so and pose your question to Professor Khattak and myself.
I think his mic is. Yeah.
We may just wait until we get the connection there. I have Kevin on my list as well here, who has raised his hand wanting to ask a question. If there's any of you who have a question but are not able to unmute or whatever for technical reasons, feel free, of course, to type in the question in the chat. We will take those after this question from Kevin. Kevin, are you able to unmute and please pose your question? Maybe not. If that's the case, please type in your questions in the chat. We will take them in this way. I'll go.
Benjamin, do you think maybe everybody has been muted by the organizer? Is that the reason? I think Thomas pointed that out.
We are able here in the background to unmute.
Can you hear me now? Sorry. I think I broke the code. Thank you for this. It's a wonderful discussion. I just want to maybe one follow-up and then a question. I appreciate your responses, RK, in the context of, you know, what else is out there in terms of other potential new therapies. At ESMO, the primary focus in other tumor types was really sort of the ADC space. Do you have any comments with regard to, you know, ADCs and melanomas? Is there a path in your view or maybe just that? I maybe have a more substantive follow-up.
Yeah, so I think yes, ADCs are very topical. Obviously, there are different bispecific antibodies. There are T -cell engagers that are being used in melanoma. These are not necessarily patient-specific. There's no proven role of ADCs at this stage, but a number of clinical trials, phase I and II, are looking at melanoma subsets, particularly in PD-1 refractory patients. Some of them are purely sort of chemotherapy, or put it that way, a fancy version of chemotherapy drugs, top ADCs, where you use a topoisomerase inhibitor. What we're seeing more promising now is the anti-PD-1 and anti-VEGF bispecific antibody, like, for example, ivonescimab, which had some really good results in the lung territory recently. Those types of molecules certainly also hold a promising future in this field moving forward.
I think this will be in a not patient-specific, patient-tumor-specific territory where we would expect that some patients will respond and then a certain patient population would not respond. It will be then wiser than what we already achieved with other checkpoint inhibitors so far. In terms of clinical trials, I think I've just become aware of this ESMO meeting that some sponsors are looking into this territory in the early phase melanoma setting and the perioperative setting. For example, patients, not everybody responds in the neoadjuvant setting to the checkpoint inhibitors to see can we rescue the patients who are non-responders after the neoadjuvant treatment. Can you add in an antibody drug conjugate? This area is going to be explored and quite interesting to monitor moving forward.
Thank you for that. My question specific to the Evaxion data, which is very interesting, is just, do you think we've learned anything in this most recent data set with regard to kind of dose and schedule? I mean, on adverse events, clearly it looks like if there was a rationale for going with a more intensive regimen either on dose or an alternative dosing frequency, it seems we have that flexibility. When you look at the patient responses and specifically maybe some of the T -cell data in the patients that you've seen, are there improvements that might be captured through schedule change and improvement?
Do you mean in terms of changing the dosing schedule or starting vaccine early potentially?
In terms of, for example, a more intensive boosting window or maybe having the option to go to more frequent dosing in the first year and then to a kind of a different sort of taper in year two and beyond.
Yeah, I think a number of possibilities can be explored. I think probably somebody posted a written question that could we start the vaccine earlier? Yes, I think that we waited for three months. This doesn't mean that we didn't have the vaccine ready for three months, but it makes a smaller study like this very cleaner so that you can tease out the difference between what vaccine is contributing compared to what pembrolizumab has done. If we were to do everything together and somebody gets a response, it becomes hard to tease out how much the PD-1 contributed, how much the vaccine contributed. Ideally, you obviously have a phase II study of the vaccine combined with pembro versus pembro alone to tease out this question, what is the vaccine adding?
Like what we did in the KEYNOTE-942 trial, which was in the early stage melanoma setting where a personalized vaccine was given in combination with pembro versus pembro alone to sort of answer a similar question. In terms of the frequency, could we change that? Certainly, yes, we can. Obviously, every dose that you give has got a dollar amount associated with it, unfortunately. How much that would contribute? I mean, we've got a good schedule. If you look at, for example, Moderna's mRNA vaccine, all the clinical trials, the INTerpath trial that they're doing in melanoma, RCC, lung trials, perioperative trials, they're giving a total of nine doses. There's no booster doses involved. Evaxion is the first trial that I'm involved with where a boosting dosing schedule was rolled out and has gone proven efficacy.
Further extension boosting has been rolled out very much in alignment to your feedback because we didn't plan the additional booster doses till we stumbled on this, that when we saw that we're seeing a therapeutic effect and we're seeing a vaccine-specific anti-cancer T -cell response as well than another. We're learning as we're going along. Yes, things can be certainly modified and tweaked, and this is how we will learn. Obviously, at the same time, I think from a financial perspective as well, I think we just have to make sure we get a good rationale. For adding a particular treatment, for example, we saw that there was boosting benefit seen and the boosting effect seen, hence further additional two booster doses were added. We'll probably get an idea in terms of the booster doses.
Do we need to spread it out more or do we need to do it more frequently to begin with? These things can be certainly explored down the track here.
Thanks a lot.
Thank you for taking my questions.
Yeah, thanks a lot. I see Thomas, right? I apologize for you not being able to speak here. Your question is out here, but I'll try to read it through. I think the first one, Dr. Khattak, is for you, right? Can you comment on any potential read-through from this EVX-01 data into previously treated melanoma patients, particularly in light of the enthusiasm for the Moderna Merck program?
Is this question in the chat?
Yes, this is in the chat.
Any ideas or speculations to begin with a vaccine earlier? Is this the question number from.
This is from Thomas Flaten where it says, "All those speculative, can you comment on any potential read-through from this study into previously treated melanoma patients?" Any read-through from this study into relapsed refractory melanoma patients?
Yes, I think one, obviously, so one option is obviously that there will be a group of patients who would respond beautifully to pembrolizumab monotherapy. Not everybody needs doublet treatment. It's just that our understanding is that the biomarker is not at a level that we're able to tease out and identify. What I find very frustrating when I'm speaking to the patient is that we make a big deal that, oh, we got these drugs that people are living 50% survival rate at 10 years for stage four melanoma. Amazing. I can't tell that individual patient, are you going to be in the 10%, 50% who are going to live for 10 years and not for. Certainly our understanding hasn't improved to that level. I think rescuing patients who have not responded is certainly a good area of exploring further benefit from these vaccines.
The other option that I could also think of was that, for example, neoadjuvant treatment or perioperative treatment is very topical and has changed practice. That's with the rollout of adjuvant and neoadjuvant treatments. We're seeing much less stage four in our routine clinics now. One area particularly that is of interest to me and other clinicians is that patients who do not respond to preoperative checkpoint inhibitor treatment, what do we do with them? The non-responders, do we escalate their care to combination ipilimumab and nivolumab? Or if they already received the NADINA trial protocol of ipilimumab and nivolumab and they don't respond, where do we go from there? What do we do with those patients? That's another area where the personalized vaccine could be explored because we'll have access to good quality tissue in the post-operative setting. Yes, that can be certainly explored as well.
Thank you, Dr. Khattak. Thomas, you have one further question addressed to me. It reads, "Are the boosters the same as the priming doses? And has any thought been given to evolving the boosters to adjust for immunogenicity of the new antigens chosen for the priming doses?" Taking the first question first, it is the same dose, right? When we manufacture EVX-01 based on, as mentioned or described in detail earlier, that really gives us one patient-specific vaccine. It's the same vaccine targeting the same neoantigens that we use throughout therapy. We also use the same dosage throughout therapy. Has any thought been given to evolving the boosters? What we see, and it's not shown here, as I said, we're digging into the data and we'll elucidate more, is that over time, we see more and more of the neoantigens in the vaccine eliciting vaccine-specific T -cell responses.
In that sense, I don't know if you're alluding to redoing a biopsy to test whether new antigens are the same. However, that is not currently, with the response rates and also the duration of responses presented by Dr. Khattak, something we, for now at least, see is needed to provide an impact on trajectories for these patients. Thanks a lot for the question. I think then, I don't know, I have Kevin still maybe with his hand up here. Kevin, I don't know if you're able to unmute unless then I'll go upscore a little bit up here and see there's a question from Thomas, from Thomas Mantum, saying, "How does EVX-01 compare to the IO Biotech plus nivolumab therapy that was also shared here at the recent ESMO? Are regulatory challenges more pronounced for personal vaccine relative to off-the-shelf vaccine? Are there differences in the situation of outcome?
Is there room for optimizing EVX-01 during development? And was there any signs of this during the phase II study?" I'll try to maybe chip away at them, Thomas, and then comment if you're missing something, right? Compared to the cancer vaccine developed by IO Biotech, we're very, very different. They have an off-the-shelf vaccine, an iodo-based, really targeting regulatory T -cell compartment and off-the-shelf. In no way personalized to match personal private neoantigens in these patients. In that sense, all being a vaccine technology, the concept is very different between IO Biotech's approach and the one we're using at Evaxion. I'll say regarding regulatory challenges, these regulatory interactions is, of course, something we're having on an ongoing basis. When we initiated the phase II study here, we submitted and discussed with regulators across Australia, Europe, and the U.S.
Without going into too many details, I can say that regulators were very overall positive in regards to allowing us to conduct these studies. Thus, we have not seen major hurdles there. Also, this is an approach where, as mentioned before, we produce the vaccine, we're able to test the vaccines as we should before administering this to patients. Maybe this is so very much in differentiating this from some other cell therapies needing fast infusion. Are there any duration in outcomes? As highlighted here by Professor Khattak, we see 12 patients responding to therapy. One of these patients died from an unrelated intracranial hemorrhage one and a half years into therapy. Otherwise, all of the responders remain in response. As Professor Khattak said, this is really encouraging, right? Because it's a hint of that's what we're doing here, right? Does the patient live longer? Do they live better?
We're seeing these signs of them living longer here with this therapy. In that sense, we see no differentiation in these patients. Room for optimizing EVX-01. I think Dr. Khattak went into that before in regards to dosing, et c. I will, however, say that from discussions here at ESMO with key opinion leaders, etc. , the results are promising and the effect of the boosting vaccinations compared to what we see in the phase I without boosters is really a tremendous, right? The level of sustained T -cell responses there. Good. I hope that that suffices. There's a question from Juhy asking, "Discussions are underway with regulators." On the last page, it means that there will be a possibility to make contracts with your partner companies.
Of course, we are in discussions with both relevant partners who find this data interesting and want to move this forward into further clinical testing. In regards to the regulatory discussions, as a clinical developer, you know that it's always best to be in close contact with regulators across the world. We are doing the same, right? Planning for further interactions to discuss this data and possible next steps with the relevant regulatory authorities. Maybe that's a question for you and Dr. Khattak. Were there any differences in responses based on BRAF or PD-L1 status?
I don't think we evaluated the data specifically based on BRAF status because obviously 50% of the patients have BRAF mutant disease. If you're looking at seven or eight patients, we can't draw any meaningful conclusions from that. We don't necessarily use PD-L1 status as a routine biomarker in managing patients with advanced melanoma. I think the next question is that based on slide 20, almost all responses were observed before initiating EVX. I think it's more looking at the trajectory where they started. Yes, I think there were some responses that were happening, and that's obviously the response rate was 50%. I think it's more in terms of the deepening of the response with time. Those who hit the partial response in the first 12 weeks, if you were to follow their tumor kinetics for a bit longer time, they were not all going to transform into complete response.
You can see some of the spiral plots, this initial response, and then the curve is flattened out for some period of time before it converts into a complete response. Similarly, those who started as a partial responder, then later on, sorry, those who started off as stable disease at a two-year time point, sorry, 12-week time point, they transform later on. I think one of that, the little BD diagram with the different beads which I showed. Usually, you would expect in clinical practice that we see patients sometimes have a delayed response, but they usually achieve their peak response within the first sort of three to four months in the vast majority of cases. As I showed, I think in that curve, one of the patients who had stable disease and transformed into a partial responder is quite like after week 72.
A couple of patients who were partial responders to begin with, if you look, follow those dots in those slides. They remained as partial responders up to week 60, and then the other one up to week 72. That's like one and a half years into your treatment. We generally don't expect partial responders to suddenly turn to becoming complete responders so far down the track. Again, yes, certainly this can be by chance, and hence the need always we look at statistical significance and to put the matter to rest, how much the vaccine is adding. Yes, you do a randomized trial to see how much is contributing. You will have your PFS, Progression Free Survival data, your survival data, your response rate. You get all those sort of things figured out.
Obviously, in a smaller population, we're just looking at more signal generation rather than robust evidence as such.
Thanks a lot. I think we're almost at time. However, there's a question from Jens Steenwang here that asks any ideas or speculation to begin with the vaccine earlier, any idea to treat only vaccine and not pembro? I'll say that indeed, right, I think Professor Khattak, you did a good job explaining why we started at week 12, right, for phase I. We initiated therapy at week eight, right? Indeed, this can also be moved earlier, also depending on trial design and further evaluations of the efficacy of EVX-01. Last comment may be to treat with pembrolizumab only. I think this also comes back to one of the aspects raised by Dr. Khattak from earlier, right, that of course the combination therapy will also depend on prior lines, which line of therapy you go into, what makes sense for what patients.
Those discussions are of course discussions we're having with, we'll be having with Professor Khattak, with partners, and of key importance also with regulatory authorities. As maybe I think we are at time, and I see maybe there's a few additional questions from Andrew. What's the question? Yeah, thank you. I see a few additional questions. I will reach out to you personally to answer these questions in text. We're two minutes over time, and on that, I will say thanks a lot, all of you, for attending this webinar. In particular, thanks to you, Adnan Khattak .
My pleasure. Thank you, everybody.
Staying up late, right, and trying to speak not with so much loudness so that you wake up your girls, right? We'll be in touch, of course. All the webinar slides here and the recording will be available on the website, right? If you have any further questions, please reach out to the Evaxion team. On that, have a great evening, day, or morning, wherever you are, right? Take care. Bye, all of you.
Bye-bye.