PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

Good afternoon, and welcome to the PDS Biotechnology KOL Event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the PDS website following the conclusion of the event. I'd now like to turn the call over to Kirk Shepard, Chief Medical Officer of PDS Biotechnology. Please go ahead, Kirk.

Great. Thank you, Tara. Good morning, good afternoon. I'm Dr. Kirk Shepard, Chief Medical Officer for PDS Biotechnology and moderator for today's webinar. It's my pleasure to welcome you to this webinar about the VERSATILE-003 Phase III trial and the pathology and prevalence of HPV16-positive head and neck squamous cell carcinoma. Next slide. This is PDS' forward-looking statements. Next slide. This is our disclaimer slide. PDS Biotech is the sponsor of this roundtable. Each KOL is speaking at the request of PDS Biotech under the terms of a consulting agreement and information presented is consistent with FDA regulations and guidelines. Next slide. The agenda for today's webinar is as follows. After this brief welcome and introduction, we have three presentations, and we're very fortunate to have world-renowned experts to speak to us today. Dr. Kevin Harrington from the Institute of Cancer Research, United Kingdom, will present VERSATILE-003, a Phase III trial of Versamune HPV in recurrent and/or metastatic head and neck squamous cell carcinoma. Dr. Frank Worden from the Rogel Cancer Center University of Michigan, will present the pathology and increasing prevalence of HPV16-positive head and neck squamous cell carcinoma. And Dr. Frank Bedu-Addo, CEO of PDS and Co-Founder of PDS, will present Versamune HPV mechanism to treat HPV16-positive head and neck squamous cell carcinoma. And then we will close the webinar with a panel Q&A. Next slide. Our first speaker, Kevin Harrington, M.D, Ph.D. is a Divisional Head and Professor of Biological Cancer Therapies at the Institute of Cancer Research in the United Kingdom. In addition to expertise in radiotherapy and chemotherapy, he is an [ authority ] on therapeutic approaches to treat metastatic head and neck cancer. Dr. Harrington was the principal investigator for KEYNOTE-048, the pivotal clinical trial that supported the U.S. FDA approval for the use of pembrolizumab in the first-line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma. Dr. Harrington is an investigator for the VERSATILE-002 clinical trial, studying Versamune HPV and pembrolizumab in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. He completed his post-doctor research in Molecular Medicine at the Mayo Clinic before being appointed as a consultant oncologist at the Royal Marsden National Health Service Foundation in 2001. He has published more than 600 articles on cancer treatment. Dr. Harrington, please proceed.

Kirk, thanks very much indeed for that very kind and probably over long introduction. I have great pleasure joining you today, and I have great pleasure in having this opportunity to discuss the Versamune platform, the Phase II and the Phase III planned studies. But before we get into that, what I'd like to share with the audience is where we are at the present time. And so Kirk mentioned briefly that I was involved in the KEYNOTE-048 study. And indeed, with the other studies that now represent in the NCCN guidelines, what we see is the standard of care opportunities for patients with recurrent and/or metastatic squamous carcinoma of the head and neck. So you can see here that we have first-line options for patients, either pembrolizumab and chemotherapy in the form of a platin plus 5-FU regimen or single-agent pembrolizumab. And in patients who have received platinum previously and then go on to subsequent lines of therapy. The CheckMate 141 study gave us nivolumab as a new standard of care, and the KEYNOTE-040 study gave us pembrolizumab. But we are now in a time where we're looking really to improve upon the outcomes of these initial changes to try to improve outcomes for our patients. So I want to start, first of all, by just outlining some of the competitive landscape against which clinical trial development is taking place. I mean I'm giving you some vignettes of what I think are the most plausible candidates to become new standards in our management. So the first one of these that I'd like to highlight to you is the drug petosemtamab from Merus, as you know. This is a bispecific antibody targeting both the epidermal growth factor receptor and also the LGR5 protein on the surface of cells. Now I show you on this slide, data recently presented, in fact, at ESMO Asia of the second line use of this agent in patients with relapsed and or metastatic head and neck cancer. You can see that this is a population of 75 patients that you can see that these patients who received the single agent therapy to weekly had an overall response rate of 36%. This is an impressive level of response against historical controls. I draw your attention to the fact that there were only 15 patients, so about 20% of the population had P16 positive oropharyngeal cancer. And the response rate in that group of patients in this small cohort was only 13%. You can see from the right side of the slide, the swimmer lane plot, that there are some patients who derive significant benefit from this treatment, but many of these patients are developing progressive disease relatively early in the treatment course. Nonetheless, in the first line setting, this drug, petosemtamab, is now in a randomized study, looking to see whether or not it can approve upon pembrolizumab as a partner therapy, and we await the results of those studies. Now this study with petosemtamab is allowing patients with HPV-positive disease. And we may question the wisdom or otherwise of doing that based around the relatively small level of experience here in this phase in the second-line study. And within their initial experience in the first-line setting, really rather small numbers of patients who were treated with petosemtamab against the background of HPV-positive disease. The second agent that I want to discuss with you is the agent from Bicara. This is ficerafusp alfa. This is an agent and that targets epidermal growth factor receptor, but also has a binding capability whereby it can bind TGF-beta out of the tumor microenvironment. And again, as you know, TGF-beta is a prominent immunosuppressive mediate within the microenvironment. The data I show you here in relatively small numbers of patients from the Bicara initial experience shows us that they see responses predominantly in the HPV negative population. You can see that there's a small number of patients represented with HPV-positive disease, with only 2 of 11 of those patients demonstrating response. It is interesting to note that in the subsequent Phase III evaluation of this agent in the first-line setting, again, with the format of pembrolizumab plus ficerafusp alfa versus pembrolizumab. The HPV-negative population is the population that will be tested. There will be no patients with HPV-positive disease. The third area that I discuss with you is small molecule inhibition, in this case, with the Exelixis' agent, zanzalintinib. This is a multi-tyrosine kinase inhibitor targeting the VEGF receptor pathway with also additional activities around receptors such as MET. You can see in this initial Phase II, hopefully going into a randomized Phase III design that they are testing again pembrolizumab plus zanzalintinib versus pembrolizumab plus a matched control. This study is attractive in that it represents the combination with an orally active drug. But as with other experience with agents, including lenvatinib in the LEAP-010 protocol and with cabozantinib in a Phase II study. We have to bear in mind that this treatment motive can be associated with significant toxicity and also significant exclusion criteria, including ulceration of disease within the mucosa or on the skin surface, proximity to great vessels in the neck, which is extremely common in patients with recurrent and/or metastatic disease; or any bleeding tendency. I suggest that this study may be rather difficult to recruit to. And again, we may discuss that. And finally, I want to highlight to you the recent press release, not in the setting of relapsed metastatic disease, but in the setting of primary treatment for newly diagnosed head and neck cancer, of the preoperative, perioperative and post therapy use of pembrolizumab as a therapy in patients about to undergo surgery for locally advanced head and neck cancer. Clearly, in developing agents in the relapsed metastatic setting, one needs to be certain about what the likely changes of therapies such as this, which have met the primary endpoint, which include two primary endpoints, the event-free survival rate and the major pathological response. We need to know what the impact of this might be on subsequent treatment in relapsed metastatic disease. It's really important to note that I think many in the field see that 689 is most likely to change standard of care practice in patients for whom surgery is the main stay of treatment. And those are going to be predominantly tumors in the oral cavity or in the larynx, but mainly oral cavity cancers. This is not an HPV-driven disease, and oropharyngeal cancer is rarely treated with surgery. So now I turn to the design of the VERSATILE-002 study. This was a single-arm Phase II study evaluating PDS0101 with pembrolizumab for first and second line HPV16-positive relapsed metastatic disease. The subjects were 18 years or greater in age, good performance status. And all of those in the first-line group had a CPS greater than or equal to 1. Patients were treated with standard of care pembrolizumab for three weekly cycles up to 35 cycles, so two years of treatment. And the PDS agent was given subcutaneously every three weeks for 4 initial cycles and then again at cycle 12. The primary endpoint of this study was best overall response by RECIST. And the enrollment for this study is now complete. At the latest data cut in May of 2024, we see the overall survival data -- we also see safety, objective response rate and progression-free survival data for the first-line population. So here are the demographics and the patient disposition. You can see that there are 53 patients in this analysis in the efficacy population, predominantly male, predominantly white mixed between 0 and 1 for ECOG performance status roughly equally. Interestingly, a greater preponderance of patients with the CPS between 1 and 19 compared to those with greater than or equal to 20. And you can see the majority of patients that had previous chemotherapy and/or radiation therapy. These are the data from the waterfall plot demonstrating the responses. Along the bottom of the slide, you can see the CPS groups illustrated in the color coding. You can see that these are the cut points for patients with progressive disease and those who achieved a response. You can see that the overall response rate was about 36% with both complete but mainly partial responses. And I draw your attention to the depth of the response in many of these patients. I now go on and show you in the spider plot, the data in terms of the patients initial response. And you can see here many of these patients achieving a response relatively early in the course of treatment. And impressively, for a number of these patients are continuing evolution of the response to a very deep, either partial or indeed, in many patients achieving a complete remission. Interestingly, a number of patients also had as a best response, stable disease, potentially indicating patient benefit. And this, again, was often extremely durable. The advantage of a spider plot such as this is it gives us a clear indication that for those patients who did derive benefit from the therapy, this was very frequently of long-standing to the patient and, therefore, of great clinical significance. These are the data for the overall survival plot. And you can see that a median follow-up of 16 months, the median overall survival is -- overall survival in a month is 30 months. This is a very significant result, in my view, compared with the historical controls that we saw from the KEYNOTE-048 data. And you can see that many of these patients in the green dots are still ongoing in terms of their response. The treatment is tolerable. You can see that there is a relatively low rate of treatment-related adverse events of Grade 3 or greater. And you can see this is around about 13% in this data. And you can see here, many of these indicate the sorts of things that we would expect to see fairly typically for patients receiving pembrolizumab. There is no significant safety signal in these data to my mind. So from the conclusions of a study that is now complete with the last data cut having been reached, 10 subjects remain on study and 27 patients continue to be followed for survival. The drug is tolerable in this first-line setting of relapsed metastatic head and neck cancer. And the median overall survival of 30 months is extremely encouraging, it has a lower confidence in full of 19.7 months. And again, we can discuss how that relates to the KEYNOTE-048 data set perhaps. Clinical activity within a response rate of nearly 36% is very impressive, and the disease control rate of over three quarters is again impressive. The deep responses and the symptomatic gain that, that will give, again, our cause for great optimism. And the data is strongly supportive of a subsequent global randomized Phase III clinical trial of PDS0101 versus immune HPV plus pembrolizumab versus pembrolizumab monotherapy in the first-line setting in patients with a positive CPS. So here is the design of that VERSATILE-003 Phase III study. And you can see that this is the randomization between study agent and pembrolizumab versus pembrolizumab alone. And you can see the design of this study with a plan for 351 patients with a 2 to 2:1 randomization, extremely attractive for patients, primary endpoint of overall survival. Secondary endpoints, as you can imagine, including response rate and disease control rates. And you can see that the key eligibility criteria for this, as you'd expect, HPV16 positive disease, a positive CPS and a good performance status. As you can see, there are interim analyses planned in the survival follow-up, which give us a potential for early approval of this agent. But obviously, there is also a final analysis that will yield our further data. The key features of 003 is it builds on the success of the Phase II study, exploiting the Versamune combination with pembrolizumab. The population -- the study population is a population that is widely distributed within our clinical practice and the 2 to 2:1 randomization, I think, is extremely encouraging and going to be likely to be very popular amongst patients. We're going to build into the study, quality of life assessments and also exploratory assessments around ctDNA, immune response and health care resource, which will add further weight to the evidence in support of this approach we hope. And with the availability of two interim analyses, we have the opportunity for early approval and potentially a new therapy. The trial design, of course, is aligned with FDA recommendations, and the first site is likely to be initiated within the first quarter of next year. So with that, I hand the microphone back to the Chair.

Thank you very much, Dr. Harrington. Next speaker is Dr. Frank Worden. He is a clinical professor awarded the Nancy Wigginton Oncology Research Professor of Thyroid Cancer endowed chair at the Rogel Cancer Center at the University of Michigan. He is a clinical investigator with a multidisciplinary head and neck and lung cancer teams. Dr. Worden is a leading expert in the treatment of HPV-positive oropharyngeal cancer, and he's co-authored approximately 200 peer-reviewed articles and participated in approximately 20 clinical trials with three ongoing in head and neck squamous cell carcinoma, including the VERSATILE-002 trial. He completed a combined internal medicine and pediatric residency at Detroit Medical Center and finished medical oncology/hematology fellowship at the University of Michigan, where he joined the faculty at the Rogel Cancer Center Faculty in the year 2000. Dr. Worden?

Thank you for that introduction. So I'm going to capitalize upon what Dr. Harrington is talking about in terms of treatment and why it's important that we are targeting the virus in this particular cancer, so the HPV-positive tumors. So looking at HPV-positive versus negative tumors, these -- the ideology and molecular characteristics are different. So in the HPV-positive tumors, they are controlled or governed by these oncoproteins known as E6 and E7, actually that degrade certain tumor suppress regimes, and I'll show you that in another slide. Whereas HPV-negative tumors are really related to oncogenic mutations that are mainly due to exposure from an excessive use of tobacco and alcohol. So when we look under the microscope, we can see a difference between the HPV-positive versus HPV-negative tumors. So these HPV-positive tumors are of non-keratinizing. So they're almost kind of very mushroom like and they grow very quickly. And oftentimes, when patients present clinically, they have a very large cystic mass that can come and go in their neck. The HPV-negative tumors on their hand are keratinizing. So we think about like an onion sheet that's surrounding the tumor, this keratin layer. And those make these more difficult to treat with chemotherapy and radiation therapy due to that kind of blocking effect. And they have frequently due to smoking these mutations in and again, the p53, which is, again, tumor suppressor gene. So this is important because this tells us how HPV works. So HPV creates these, as I said, oncoproteins, E6 and E7. So it's a small circular virus that E6 then blocks out this tumor suppressor gene, p53 and the same thing with E7 blocking out retinoblastoma protein, which is a tumor suppressor gene. So what I'd like to think about this is basically that you block these 2 brake pedal. So then you have a bicycle tire that's spinning and out -- without the ability actually to have its brakes to stop. So then these cells start propagating and growing and growing and you get this with the, call, cell proliferation as the tumor continues to divide. What's important in the red box here is that when you block retinoblastoma protein, you get this elevation of what they call p16 or protein p16. We use that as a marker, actually, to show that these patients actually have HPV-related cancers. So that can be helpful in us to identify the tumor and actually, in certain cases, when using DNA from the HPV to follow responses to treatment. So in terms of clinical behavior and prognosis, so this population of HPV-related cancers is younger. So these people are not -- people have advanced age because they haven't had tobacco and smoking exposures for a long period of time. So we're seeing these people show up in their mid- to early 50s. There are 20,000 cases that are diagnosed [indiscernible] men more than women, actually with the white population more than other ethnic groups. And a lot of people are aware of cervical cancer and perhaps anal cancer related to HPV, but they're not really aware of the association of HPV and oropharyngeal carcinomas because there's only 0.07% of the population. In general, these people do have better prognosis when the disease is treated with surgery or chemotherapy and radiation therapy because they have an enhanced sensitivity to radiation and chemotherapy, and there's more of a robust response with the immune system. So there's a higher level of these tumor infiltrating lymphocytes that allow degradation of these tumors. But what's important what I tell every patient who comes in is that, yes, in general, the prognosis is better. However, however, this does not guarantee that even with a low-stage tumor that you will actually be cured from your cancer. So yes, smaller amount of disease is better. But we do know that stage matters, so larger tumors and other biologic factors that we'll talk about do have an influence on this cancer. So essentially, any patient who comes in with any stage is not guaranteed to have a 100% overall survival. HPV patients that are negative are older and in general have more resistance to the standard treatments. So this actually talks about early-stage disease in this locally advanced disease where we can do surgeries and chemotherapy and radiation therapy. And then shifting over to the right is this recurrent or metastatic population that we just spoke about. And here, this is about [indiscernible]. So we're no longer able to cure the patients. And like Dr. Harrington talked about, we are looking to improve survival, improve progression-free survival to allow people to live longer with a better quality of life and hopefully with for example, having a better tolerability to treat. So what we see here is this shift in -- by 2030 and having HPV16 as the most common type of HPV that's prevalent. And that's because this type of HPV can evade the immune system. It has great oncogenic potential due to the E6 and E7. There's also different variants that can exist. So there's like an Asian-American variant of HPV16. So they can adapt very well to certain environments and certain patient populations. So the reason there's a shift here is because we know that there's like a 2% or 3% increase since about the 60s and 70s due to changes in sexual practices or sexual activity that's been published, for example. But we're also seeing this downward trend because of the vaccinations that are becoming more available. But nonetheless, this population of metastatic patients related to this more aggressive HPV variant is not going away. But we do know smoking rates due decline and people were aware of that in society that the HPV-negative patients are starting to take a downward trends. What's important here is that because of good screening with cervical cancer, now HPV oropharyngeal cancers are becoming the number one HPV-related cancer. And again, this is due to different demographics related to the HPV vaccination. So again, there's no screening. You can't do a Pap smear in the -- the top of the tongue because the virus lives in the crypts of the tonsils and the cancer works its way up versus cervical cancer, which is on the surface, you can detect precancerous cells there, even though the same thing is happening with HPV-related oropharynx cancer. So vaccines. Unfortunately, only about 54% of women and 49% of men are actually getting all the recommended doses. And this is despite efforts of education and what happens here, we cannot gain the herd immunity if a number of people are not vaccinated. So this is important. And now with certain government changes and this kind of stuff, probably there are more concerns that people may not want to be vaccinated, time will only tell. But what happens here is education, despite our best efforts, is still lagging with these vaccines. Parental hesitancy, HPV replacements can happen, which means that if we vaccine enough of these people, we have different types of HPV that can cause cancer. They're not covered in these vaccines. So we may see this ecological shift or this new niche in the more aggressive HPV types. So again, this means that this is not going away. And remember, the Gardasil or HPV [indiscernible] are preventative. So people who have cancer, it's not going to help them. They have to be given early before actual sexual activity or exposure to HPV in order to be effective. So I like this slide because this is how I present this to patients that come into the clinic. So on the left is your cancer, these lines. They're growing the line and you have weed be gone, you can pour it on that. And that essentially is the chemotherapy and radiation therapy that actually are taking down those actively residing cells. However, there are cancer stem cells. So there are cells that we have that are not actively dividing yet. And what happens is these become resistant in a certain population of patients due to invasion of the immune system, certain mutations that can happen. And so what happens is, if these stem cells are not killed off by our chemotherapy and radiation therapy, the virus can persist and the cancers actually can come back. So what's important here, too, is the HPV infection. Remember, the E6 and E7 oncoproteins. So the E7 oncoprotein can have silencing of this -- the immune sensor genes. And then the E6 protein can actually down rate -- down regulate immune gene expression. The tumor microenvironment is important. These are tumors that have substantial lymphoid presence. So that can influence with the lymph system, many of the metastasis we see in the lungs, sometimes in the brain and other areas of the body. And molecular alterations can play an important role in HPV-naive cancers, but they could also play a role in HPV-driven cancers. So we have new data about certain mutations that actually are identified in the subset of these HPV patients that can actually lead to recurrence. And then this association with this certain beta signaling can maintain the presence of this episomal HPV. So that's a circular form of HPV that sits there and it's basically making or generating these proteins that we talked about that sit on these tumor suppressor genes and allow the cancers to grow. Interesting people who show up with larger tumors actually have a higher risk of having their center come back and retroperitoneal nodes. So we know now from data if people have nodes that are in the -- or back part of the neck. Those people have a higher propensity to have metastatic disease. So integration is important. So as I talked about, that circular forum called episomal that sits there, we now have new data from different centers. And this data was from my friend, Maura Gillison, from MD Anderson, where they actually showed integration. What's so interesting about this is that the HPV DNA in certain cases can actually hijack the tonsillar or base of tongue DNA. So it takes out the DNA from the tonsil and it replaces it. And then it encodes for these certain proteins. And these proteins then go on to lead to this in permeability of the chemotherapy and the radiation therapy of working. The issue behind here is due to biology, you cannot pick where your integration is going to occur and you cannot choose what kind of proteins is going to encode for. So for example, when these patients have disease that comes back, I've seen them present almost in a small lung cancer kind of fashion, which means they have brain mets, they have lots of disease involving their lungs spread through the limb system. And that's because it's coding for certain proteins that are believe to what they call differentiation or very aggressive tumors. So this is why it's important for us to focus on targeting these E6 and E7 oncoproteins with these vaccine therapies and immunotherapy because this is the only way we're going to be able to treat this population of patients successfully. So in summary, the virus can become integrated into genome as we just talked about. This is a different population in different tumor physiology. Recurrent disease have multiple sites, like I said, if they're encoding for the right progressive proteins leading to dedifferentiation, you can see very aggressive cancers. HPV16 infection can lead to persistent expression of these oncoproteins. And in general, we tell people that, yes, people are exposed to HPV and your immune systems are able to handle it to eliminate it. But in this population of patients who has these cancers, the immune system is dysregulated and therefore, these oncoproteins become the most important source of being driven by the virus, again, leading to the growth of cancer. So targeting HPV16 virally infected tumor is potentially affected. This is really, I believe, the most important strategy that needs to happen for this population of patients versus trying to alter the immune system in other ways with some of these other treatments that Dr. Harrington spoke about. And the one thing I will say in comment about the study that he presented the data from VERSATILE is compared to other vaccine studies, our -- this study with VERSATILE was the one to show that it worked in all populations of CPS or where those immune cells actually work. So in general, some of the other studies you had to have large numbers of PD-L1 where these immune therapies work. In this population of patients that we treated on this study, actually, you could have lower expression and still see good results. So this then leads into the next section about generating T cells to target the E6 and E7 with first immune. So I will finish there.

Thank you, Dr. Worden. Our next speaker, Dr. Bedu-Addo, has served as Director, President and CEO of PDS Biotechnology since its inception in 2005. He's one of the Co-Founders of PDS Biotech. He is a veteran biotech executive, experienced successfully starting growing biotech organizations. He has been responsible for the development implementation of both operational and drug development strategies. Frank?

Thank you very much. Thanks, Kirk. Before I start, I would like to thank both doctors, Dr. Harrington and Worden, for their valuable insights. Now as Dr. Worden shared, the emerging science demonstrates that HPV-positive head and neck cancer is quite different from HPV-negative disease with different molecular in histopathological characteristics as well as very different underlying causes. Now recent publications also report that HPV16 specifically is highly effective in shutting down the immune system's ability to fight cancer. As Dr. Worden presented, the rules of the E6 and E7 proteins of HPV in promoting cancer make them suitable targets for immunotherapy. We believe that the targeted approach with our Versamune platform presents strong potential to effectively treat HPV-related head and neck cancer. So how does our targeted HPV16 immunotherapy work to result in the deep clinical responses and promising survival that was presented by Dr. Harrington. So as you can see here, Versamune is based on a single proprietary synthetic lipid called R-DOTAP. It's the first of its kind to demonstrate potent and highly specific activation of the immune system. Now in Versamune HPV, R-DOTAP forms spherical nanoparticles called liposomes, which are mixed with our proprietary HPV16 E6 and E7 short proteins in my cell form. Now it's important to note that we do not encapsulate the E6 and E7 proteins in the nanoparticle. The only reason why we make R-DOTAP into these spherical liposomes is to activate important immunological processes. First of all, the particles mimic a virus and therefore facilitate highly efficient uptake by the dendritic cells of the immune system. Now secondly, the bilayer wall of the R-DOTAP liposomes, as you can see, is similar to that of our human cell walls, but positively charged as opposed to ourselves that are negatively charged. So similar bilayer walls but opposing charges. Therefore, when these particles are taken up by dendrite cells, Versamune is able to destabilize the cell and enables the E6 and E7 proteins to be internalized by the dendritic cells and sent into the right compartments of the cell where they can then be properly processed or broken down into small peptides that can then be presented to the killer T cells. So this ability to enter into the right compartments to break down and process those proteins becomes very important. So let's take a look at how this actually works to promote a T cell attack on the cancer. Next slide, please. So over here, what we see is, here, we have the start on the left-hand side. So this mixture of Versamune in the HPV micellar particles is given as a subcutaneous injection underneath the patient's skin. What the R-DOTAP lipid [indiscernible] is it activates those dendritic cells, which then exhibit what we call danger signals causing more dendritic cells to infiltrate the injection site. So what we'll notice is a significant number of patients having what we call injection site reactions. This is a good sign because it is the first step of activating that immunological cascade that's going to lead to the T cell response. So -- and we have these positively charged nanoparticles, therefore, providing a depot allowance sustained period of time for these dendritic cells to pick up these nanoparticles as well as our immunotherapy and get activated. When these dendritic cells get activated, they then migrate into the lymph node, which again is extremely important that we get almost exclusive presentation of the immunotherapy in the patient's lymph nodes. What then happens is those danger signals are again emitted in the lymph node sending signals to T cells to infiltrate into the lymph node. This we've shown and this has been published in the Journal -- our Journal of Immunology publication that this occurs for over 10 days after a single injection. This is what we call the recruitment phase. To have an effective army, recruitment of the soldiers is absolutely critical. So this is actually a very important space for an effective immunotherapy to be effective in recruiting those T cells to migrate into the patient's lymph node. Now once these T cells get into the patient's lymph node, the other very important factor here is, as I mentioned, breaking down the protein into those small peptides that can be presented to the killer T cells. The only way to prime and activate a killer T cell to recognize the cancer or the peptide is to present an 8 to 11 amino acid peptide. So Versamune's ability to destabilize the cell, allow the protein to enter into those right compartments that allow for effective processing and breakdown of that protein is extremely important in being able to present via what we call MHC Class I to the CD8 killer T cells. We're also able to present the larger proteins or larger peptides to the CD4 helper cells -- T cells. And so with this process, this is what we call the training phase. So now we recruit it efficiently and now by being able to present these process peptides to the T cells, we can now prime and train both CD8 killer T cells as well as CD4 helper T cells. What we've also published is that these are sequested in the lymph node. And what R-DOTAP then allows the dendritic cells to do in the lymph node is to induce other proteins or immunological proteins called cytokines and chemokines. These then activate those killer T cells to form what we call multifunctional T cells that are the most powerful type of T cell. So now we can recruit, we can train and we can arm. These arm T cells then exit the lymph node, seek out, invade the body and attack any cells in the body expressing those E6 and E7 peptides. What the KEYTRUDA also does simultaneously is to reactivate preexisting T cells, which have been deactivated. And so we get these T cells activated by Versamune HPV as well as those preexisting T cells now activated by KEYTRUDA. Another very important characteristic of the Versamune HPV based upon its residence in the lymph nodes is to induce what we call memory T cells. Dr. Harrington presented the durability of the Versamune HPV therapy, the long-lasting effect. This is very important, and we believe strong results from the induction of these memory T cells that allow -- that long term that allow the immune system to continue to remember the intended target, the E6 and E7 proteins and allow the immunotherapy to attack that cancer long term. So for those of you who've actually followed our results since ASCO of 2023 until today, one of the key things you may notice is the deepening of the responses as the data has matured. So for example, when we look at the patients who had complete or near complete responses, 90% to 100% tumor shrinkage, we see in 2023 of May, we had 3% of -- 6% of patients that's now over 20% of the patients having these really deep tumor responses a year later. If we look at the complete responders, again, more than tripling from 3% a year ago to over 9% today. We also see the objective responses going from 26% to 36% today. And again, very stable median overall survival. So what we see here is the ability to induce the sustained attack on the enemy, which is the cancer in this case, leading to these long-term durable antitumor effects. Next slide, please. So here, I'll just briefly touch upon this, and this is what I mentioned, this has been published in the Journal of Immunology, but shows in these preclinical studies, the induction of memory T cell response. So if you look at T0, the cancer cells injected into these animals and we saw pretty aggressive tumor growth. On day 12, half of these animals were treated with Versamune HPV, and every single one of them had a complete regression of the tumors. In those animals that were not treated, we see very aggressive and continued tumor growth. On day 50, the group of animals who had received the Versamune HPV on day 12 as well as another group of animals were then challenged with the HPV tumor cells again. In the animals who had never received Versamune HPV every single one of them had very aggressive tumor growth. In those who had received Versamune HPV on day 12, every single one of them was fully protected against reestablishment of the tumor. This is a very good demonstration of induction of the memory T cell response. Next slide, please. So how does this translate into human results? This is actually a really important study that was performed by experts at the MD Anderson Cancer Center in patients who had locally advanced cervical cancer. These patients have tumors of 5 centimeters or larger. So these are the patients who are deemed as being at high risk. And what these investigators did here was to measure -- quantify the CD8 T cells that induce granzyme B. So these are the active CD8 T cells that actually infiltrate the patient's tumors. And so rather than what's done typically evaluating CD8 T cells in the circulating blood, they focused on the relevant killer T cells, right? It's important -- that's one of the key limitations of several immunotherapies. Induction of an immune response is not nearly enough. What's critical is the induction of the T cells that can actually target and actually infiltrate the patient's tumors and cause cell death. And what you see over here going -- with the green bars going from time 0 to 24 weeks is a sustained and steady buildup of the CD8 killer T cells in the patient's tumors. And this all supports the durable responses that Dr. Harrington presented with our VERSATILE-002 study. Another very important biomarker that was evaluated here is the circulating tumor DNA. So as we know today, the primary tumor is not usually what kills the patient. What's most deadly is the secondary or the micrometastatic tumors. ctDNA is a really good way of understanding the micrometastatic cancer that may remain in the patient, right? And what MD Anderson showed here was that as we saw the CD8 T cell buildup in the patient's tumors, circulating tumor DNA went down to 0. Again, this strongly supports the survival benefit that was demonstrated and shown by Dr. Harrington. What was presented by MD Anderson was that with this Versamune HPV treatment in these patients at 5 weeks, there was a 92% decline in circulating tumor DNA versus the patients who just got chemoradiotherapy who had about a 53% decline in circulating tumor DNA. Then we had a very strong indicator of the mechanism of action of Versamune HPV. Now how does this translate to actual clinical benefit for these patients. Let's take a look at the next slide. In the next slide is data that was presented by MD Anderson about a couple of months ago at the ASTRO conference. And here, what we're looking at is the IMMUNOCERV study and also have in the second column, the published data from the KEYNOTE-A18 study. Now what's important here is that we have both Versamune HPV and pembrolizumab or KEYTRUDA being combined with the same agent, chemoradiotherapy, in the exact same patient population. So this gives us a good insight into the potential of Versamune HPV, which acts by a different mechanism T cell activation compared to the published results for the most successful immunotherapeutic agent today, right? And what we see here in the first row, when we look at the 36-month median overall survival rate, with pembrolizumab, we see approximately an 83% 36-month survival rate. With Versamune HPV in the patients who got all 5 doses of Versamune HPV, we see a 100% 36-month survival rate. If we look at the patients who had 2 or more out of the 5 doses, we see approximately an 84% survival rate. If we look at the 36-month PFS rate again, what we see with the KEYTRUDA publication or KEYTRUDA combination is over 60% PFS rate, that is 6 months. If we look at the Versamune HPV, again, in the patients who had all 5 doses of Versamune HPV, 100% 36-month PFS rate and the patients who had two or more doses, about 75%, 36-month PFS rate. 88% of the patients had complete responses. Again, so this is very important in giving us insight -- clear insight into the potential of the Versamune HPV mechanism in addressing HPV-positive cancer. Let's take a look at another study -- another supporting study done by the National Cancer Institute, or the NCI, in the next slide. And here, the study is quite important because this study builds in a negative control, right? So this is more or less almost like a controlled study. And so what was done in the study, this is our triple-combination study. But here, the National Cancer Institute recruited patients who were HPV16-negative. So you may recall, Versamune HPV targets the HPV16 E6 and E7 proteins. And so a patient who is HPV16-negative should not receive benefit from Versamune HPV. So the hypothesis here is Versamune HPV is actually promoting the strong CD8 antitumor T cell responses, we should see significantly improved benefit in the HPV-positive patients. And that is exactly what we see over here with the objective response rates 75% versus 17%, which is typical of the checkpoint inhibitors. When we look at the progression-free survival in the HPV16-positive population, again, 19 months median overall survival versus 2.3 months in the HPV16-negative population, which is again typical of what you see with checkpoint inhibitors, right? So again, these data across all these 3 Phase II trials combined, it give us the confidence regarding the potential efficacy of Versamune HPV and progressing this into the Phase III clinical trial that was discussed by Dr. Harrington today. Next slide, please. So here, the key takeaways here are we have shown robust induction of tumor accumulating CD8 killer T cells, which is critical for an effective T-cell immunotherapy. We've also demonstrated with critical biomarker ctDNA, significant decline elimination and rapid elimination of these speculating tumor DNA with Versamune HPV. We've also shown strong memory T cell responses in our Phase I human clinical trial of Versamune HPV as a monotherapy. After the third injection -- 90 days after the third injection, we documented induction of memory CD8 T cell responses in these patients. And that was with Versamune HPV as a monotherapy. As I mentioned, we've also seen consistent and supporting results in each of the 3 Phase II human clinical trials currently ongoing in cervical cancer, in HPV16-positive head and neck cancer and in the basket trial looking at all types of HPV16 positive head and neck cancers. So with all that we have discussed today, let's look at the bigger picture. HPV16 today constitutes over 50% of oropharyngeal cancers in the United States and Europe. It is projected in the next few years to become the most prevalent type of head and neck cancer. The data shown by Dr. Harrington for some competing drugs in the space having weaker responses in HPV-positive disease highlights the growing unmet need in treating the growing population of HPV-positive recurrent metastatic head and neck cancer. To date, Versamune HPV has shown the most promise among all drugs addressing HPV-positive head and neck cancer with the most mature and durable response and survival data. As I mentioned, we have also seen the consistent results with indication leading survival across each of our 3 Phase II trials. So how do we get from here to a potential FDA approval? Our Phase III design is critical. We have designed our trial for survival outcomes are strongly recommended by the FDA. So to date, in recurrent metastatic head and neck cancer, if we look at the KEYNOTE-048's trial of KEYTRUDA, KEYTRUDA plus chemotherapy and the EGFR inhibitor plus chemotherapy, despite increases in objective response rate and PFS seen with the EGFR inhibitor plus chemotherapy, lower survival resulted versus KEYTRUDA. Similarly, in the LEAP-010 trial, KEYTRUDA plus lenvatinib showed significantly improved objective response rates in PFS versus KEYTRUDA, but ultimately lower overall survival. So in our study, the statistical analysis of the survival outcomes is based on a statistically significant number of death events occurring in the control arm versus the treatment or combination arm. Therefore, this should prevent extended waiting periods due to potential enhanced patient survival. Now it's important to meet the set endpoints of the trial, which we believe have been conservatively designed by our regulatory and statistical experts. The design assumes that the control arm will have the best overall survival reported for KEYTRUDA to date of 18 months. We also assume that reasonably that the combination arm will have two months less survival than seen in VERSATILE-002 of 28 months. So we, therefore, assume reasonably that the first interim data readout, which we anticipate will occur about 6 months after completion of recruitment that we may be able to present the survival data and potentially together with our circulating tumor DNA results obtained an accelerated approval for the therapy. And this is something that Dr. Harrington touched upon. And we also give ourselves a second bite of apple in case the data of the first interim data readout is not mature enough with the second interim data readout a year later. We very much appreciate the support and the guidance of all our key opinion leaders and clinical experts, and we look forward to starting this trial next quarter. Thank you very much. And Kirk, I'll hand over to you for the Q&A session.

Great. Thank you, Frank. We'll now take questions from those participating today. Tara, why don't we start first with some written questions I see upcoming and then we'll go to the live line. Is that okay?

Yes, that sounds good.

Great. Question here. Our HPV-negative and HPV-positive cancer is trending into separate treatment schema and trials. Will there be a fork in the road in the treatment approaches to these separate disease perhaps separate trials? Dr. Harrington and Dr. Worden like to hear both of your opinion on this.

Yes. I think that's an excellent question, Kirk. I think where we've come from thus far, we've tended to lump patients together and we've stratified based around the presence or the absence of HPV variously based around p16 positivity or in certain circumstances are more detailed and more molecularly correct way of defining HPV positivity. And the data have often then been presented and broken down by HPV status. I think we're beginning to see clear evidence that certainly around therapies such as the epidermal growth factor receptor targeted treatments. And I touched upon ficerafusp alfa and the petosemtamab agent, we're beginning to see that those patients really don't -- the HPV-positive patients don't respond in the same way as the HPV-negative patients. So I think that there will be segments of clinical trial activity in which there will be a clear rationale for defining different trial opportunities for patients and excluding perhaps HPV-positive patients from certain treatment approaches. So I think it is highly likely that, that will be the case. Clearly, if we demonstrate that HPV vaccine based approaches are beneficial and the data that's been presented today are highly suggestive then we have a very good chance of doing that in the near future. Then clearly, those therapies are not indicated at all for HPV-negative patients. And so that will, by its very nature, lead to a fork in the road. Now occasionally, of course, in second- and third-line settings, those patients may come back together and be considered as a similar disease group and perhaps other treatment opportunities or other further down the line therapies. But I really do envisage that we're going to see a change in the way we approach, especially in the first-line setting. And I think that vaccination against HPV is going to be a driver of that process.

Great. Thank you. Dr. Worden?

Yes, I agree with everything that Kevin has said. I mean I was thinking along the same lines. Oftentimes in some of these studies too, we didn't have HPV data available. So some of the information was done in retrospect and the numbers necessarily weren't equivalent to those with HPV-negative disease. But I do agree as time moves on in the clinical trials that he touched upon here, it does appear that bispecifics, other therapies, antibody directed therapy aren't as beneficial in this HPV-positive population. And again, that kind of goes back to the whole idea of targeting these oncoproteins because this is virally driven and not tumors that are created because of smoking and drinking that leads to mutations in these cancers. So we're really talking about two different populations -- patients and mechanisms by which the cancer is created as well as spreads.

Great. Thank you, Dr. Worden. A couple of questions here. Maybe I can take quickly because there's some questions grouped around. Do you plan to start the VERSATILE-003 in the beginning of 2025? And yes, we're well on our way to starting first site initiation in January or February of next year. Also a question about who is the principal investigator? And that's Dr. Katharine Price from the Mayo Clinic is the principal investigator of the study. And also, do you have the green light from the FDA as far as your study alignment? Yes, we remain very close to the FDA with a couple of meetings as far as the study plan, and they are in agreement. Thank you for those questions. Maybe one question here is just personally for both of you. We've been informed of the increasing incidence of HPV-positive head and neck squamous cell carcinoma versus the negative. Are you seeing this also in your practices and your colleagues' practices as far as this increased percentage of HPV-positive patients? And both Dr. Worden and Dr. Harrington, if you reply, please?

Frank, do you want to bat first on this one, but I...

Sure. Yes. And I -- the data I presented here talks about the HPV-positive oropharyngeal cancer patients surpassing that of cervical cancer because of the lack of screening and also the data about vaccination. I work with a woman here who is very involved with vaccinations for HPV and it is lacking. It truly is lacking. And I think some of the data with those percentages may even be a little bit overestimated. So in our practice here at Michigan, I would say that the patients who come in with locally advanced disease for treatment with chemotherapy and radiation, in my practice, it's probably on the order of 60% to 70% are HPV-positive tumors as compared to those HPV-negative tumors. And I do think that has to do with societal education about smoking in this country actually going down and people be more aware of that. So the answer is yes. The majority of people who show up with these locally advanced diseases are HPV-positive and then -- of those, a good 20%, 25% actually will come back or present with recurrent or metastatic disease. So...

Great. Thank you.

And I would likewise agree. And this is a practice in Center of London, and these comments reflect data that are drawn across the United Kingdom. We are seeing significant numbers of patients with HPV-positive disease presenting to our practices now. And again, the figure I was going to quote was 60% to 70% because that's exactly what the latest audit that we did demonstrated so much so actually that we actually are finding laryngeal carcinoma is locally advanced larynges and locally advanced hypopharyngeal carcinomas are really quite uncommon tumors now. And actually, our residents don't really see a great deal of them. They see a good deal of oropharyngeal carcinoma presenting, but they don't see the other types so often. And again, I think I would really highlight what Frank pointed out very nicely in his presentation is, although the orthodox view seems to be that this has such a very good prognosis that you almost you could be mistaken for thinking you don't have to worry about it. A significant number of these patients develop recurrent metastatic disease, often with aggressive patterns of behavior. And there is an absolute need for effective therapies in this patient population, which is only going to increase until vaccines take hold. And unfortunately, I have to echo what Frank has said about. We know the vaccine works. The trouble is we can't force people to have it, and many, many people are not taking up the vaccine around the world. And I don't think it's going to be the success that it could be until public health policy is able to change that.

Thank you. Perhaps we should move to the phone lines now, please?

Our first question comes from Joe Pantginis at H.C. Wainwright.

Everybody can you hear me?

Yes.

Yes.

Great. So thank you for all the details today. So I wanted to ask first about 003 and the interim analyses. Frank, obviously, you gave a little bit of a broad stroke on the benchmarking, but I was curious for Dr. Harrington and Worden, what would excites you at the interims of 003 that could lead to early stopping, especially considering the quick responses that were seen in 002?

So Dr. Harrington and Dr. Worden, yes.

Yes, maybe I'd start. So in terms of the data that we would be looking to see in terms of response rates, I think response rates in the order of 40% or greater are really beginning to become the new benchmark as to what we expect to see in patients treated potentially with benefit for treatments that are going to improve outcomes. And in terms of the median overall survival data, I think the data from the LEAP-010 study [indiscernible] months, that is now the new benchmark that we need to improve upon. And I think that we need to see that those data are in the order of 25 months and above. And so the data that we saw in the VERSATILE-002 study with a median overall survival of 30 months is highly encouraging in that regard. So I think we'd be looking for those sorts of values. And clearly, I would hope that those would also be associated with improvements in progression-free survival and reductions in relapse rates.

Yes, I would agree with that. And also the improvements in duration of response. I haven't hit on something that I'd like to come back to, which comes back to the side effect profile. So high treated patients on the VERSATILE [indiscernible] I claim I have the [ green line guy ] at the bottom has a complete response. And it still is a durable response. So -- but I was struck by the treatment of these patients that the tolerability of the treatments were so good. And that needs to be noted because people come off treatments when they're toxic, and coming off treatment can also limit their ability to, a, attain further response and potentially to offset the improvements in progression free and perhaps overall survival. So that, I think, is important and also goes along with how we're approaching this by targeting the E6 and E7. So I would totally agree that this is a population of patients we want to see improvement like Dr. Harrington said in terms of these responses and overall survival. Obviously, we need to continue to move the needle. So right now, what we are seeing is exciting, and we anticipate to actually see that even, I think, potentially better.

And then maybe to build on that answer just a little bit, Frank, because you're absolutely spot on there, I think. You note that anyone who's seen the LEAP-010 data will have been impressed by the response rate almost doubled in the lenvatinib plus pembrolizumab combination, the progression-free survival, unprecedented improvements. But the problem was the toxicity of the combination meant that patients couldn't sustain the treatment and the trouble therefore, was that the patients were stopping not just the lenvatinib but potentially also the pembrolizumab. I think the really impressive thing about this therapy is that you see an injection site reaction for sure. But again, I think, as Frank made the point and Frank Bedu-Addo made the point that that's actually a good thing because it indicates actually that the body has seen the drug and is responding to the drug. So this is a very tolerable combination and I think is potentially efficacious as well. So I think that we have that opportunity that patients won't be coming off treatment because of talks.

And then I just have -- my last question is -- and this is really a long-term concept with regard to cancer immunotherapy and cancer vaccine. So when you consider patient monitoring, I guess, the question would be how well versed do you think physicians overall, not only for 003, but general IO and cancer vaccine studies are versed with regard to pseudoprogression and keeping patients on therapy for the duration versus proverbially freaking out because of the pseudoprogression?

I think people are getting better is the answer. It can be frustrating that when I meet patients coming for second opinions and they've been on an IO agent, they've been on a relatively short period of time, and they've been taken off the treatment because of an apparent progression. And in fact, their disease is not doing very much after that. I see that less and less. And I think there's an education piece to be done here. I think we're moving beyond the unfamiliarity with IO that led to that being quite a common occurrence previously. So I think that we're getting better, but it doesn't mean that it can't happen.

Yes. Excuse me, I totally agree with that, yes.

So our next question comes from Mayank Mamtani at B. Riley.

I appreciate the comprehensive overview from doctors, Worden, and Harrington. In terms of the discussion of therapeutic being effective and HPV-negative, but -- patients, but not to the same extent in HPV-positive patients. I was just curious to maybe hear a little bit more color on the need for the PD-1 combination to be there because relative to what we've seen in monotherapy activity, although in late line settings, the activity for the EGFR targeted therapies seem pretty low. So it does look like they also do need that PD-1 combination element, but I was just trying to understand how something is not that effective in HPV-positive, but seem to have a pretty good response rate in HPV-positive -- HPV-negative, excuse me. Could you maybe touch a little bit -- give us a little bit more color on that on our understanding in the field, maybe Dr. Worden or Dr. Harrington?

Again, I'd be happy to dive in if that's okay, Frank, In the first instance. So I think it's a bit of a paradox. So at least it's a mystery in that we have not fully understood what are the biomarkers that determine response to epidermal growth factor receptor inhibition. And one of the great puzzles is that EGFR levels don't seem to map to the ability to respond. But what is emerging, I think, increasingly clearly is that HPV-positive disease really does not seem to be driven biologically by EGFR signaling. And therefore, therapies that target EGFR signaling are far less likely. It's not impossible, but far less likely to mediate a real therapeutic gain against HPV-positive disease. You can find studies in the literature that show that HPV positivity in EGFR expression are mutually exclusive. That's not always the case, but there are certainly those data. And so we have to recognize the fact that EGFR targeted therapies of the version that I've discussed today, which have effectively, one is a bispecific antibody. The other is a bifunctional antibody that has a TGF-beta trapping [indiscernible]. The interaction with the LGR5 is not very clearly worked out, in my view, by the Merus, a company, they're getting to it, I think. But we don't really know what the drivers of that are. We know that it feeds into stem cell approach -- stem cell behavior of the tumor cells that is involved in wind pathway signaling and that it may have effects against potential immune activation. We know that for the ficerafusp drug by taking TGF-beta out of the tumor microenvironment, we can reverse an immunosuppressive landscape within the tumor. So having accepted both of those facts, we have to come to the conclusion, of course, that one of the natural partners to combine with that to come to your question would be to do so with an immune checkpoint blocker such as an anti-PD-1 drug. They are not directly mechanistically related to one another, but the hypothesis remains if you can kill cancer cells while conditioning a more inflammatory immune reactive tumor microenvironment, you may generate better levels of activity. And certainly, the relatively small numbers of patients in the early Phase I/II experiences we've seen with both petosemtamab and ficerafusp would support that hypothesis. So I think it's likely that in the format that the trials are designed, the PD-1 plus another drug such as one of those agents is likely to be active, but I really don't believe it's going to be an HPV-positive disease. I think if we see a positive trial in either of those or both of those trials, it's going to be a signal, it's going to be in the HPV-negative population. So maybe Frank has something to add to that. I'm not sure.

Yes, yes. Actually, we had data from Michigan a long time ago showing that the correlation tobacco exposure and the elevation or levels of EGFR. And interestingly, the studies combining immunotherapy and cetuximab, such as pembrolizumab or nivolumab, had better outcomes than people who were HPV-negative. And so the idea here is that you can upregulate the PD-L1 with EGFR inhibition with cetuximab and perhaps get better response with those patients when you treat them with immunotherapy. So an immunotherapy is there to just bolster what we are like in this vaccine study to bolster the immune system. And the same thing with the other combinations is to enhance the effectiveness of the immune system whilst targeting EGFR another receptor.

All right. Thank you, both. Yes, Mayank.

Yes. Sorry, I guess a related question, like given the 003 enrollment criteria focused on HPV-positive. So if you have presented an option across different ongoing studies, I don't know exactly what the time lines for Merus and Bicara or any other studies are ongoing. So I was just curious as you think about the options out there, how would you think about that right patient that's going to go in the 003 study? And how do you kind of prioritize that? And then I have one follow-up question for the company.

Well, I'll just [ try saying it ] at my center. Yes, we have multiple studies open because that's the nature of an academic center. However, the consensus here is that if it's an HPV-positive -- tumors that's driven by HPV oropharynx cancer that's metastatic, vaccine trial would take preference over another study. Now there could be criteria that patients don't qualify for one study, and so hence, that's why the available studies exist. But I know from my personal experience in using these vaccine studies in this population, they do better than in other studies that I have used. So I know my particular preference, and I believe probably the majority of investigators on this trial would invest in a vaccination study before considering another treatment option for -- that may include HPV-positive and HPV-negative patients.

Yes, I agree with you 100%, Frank. So we will -- we do exactly the same. We're an academic center. We run more than one study so that we have options for our patients. If a patient comes to me and they are p16 positive and then we subsequently confirmed that their HPV16 positive with a specific assay, then that patient is going to be offered -- as the first option, they're going to be offered a vaccine approach. And this study to me is the best option for those sorts of patients. Now if, for instance, they -- you're just screening test and actually, you don't detect genomically the presence of the viral DNA. And that happens occasionally. It happens in about 5% of people, then we would have other options available for them. But HPV-positive disease is going to be treated in a vaccine study because that's where they're going to derive the greatest benefit. If we flip the story around and we look perhaps at the clamoring now for personalized vaccines, and I know this isn't a personalized vaccine, but actually, it's a tumor selective tumor-specific antigen that is present and can deliver durable and profound deep responses. So I'm going to go with a vaccine approach for my patients every time if it's available.

Absolutely.

That's great. That's super helpful. And then for Kirk or Frank, you've shown some very good translational CD8 T cell data in head and neck. I was wondering if similar T cell profiling on memory response data could also be replicated in, say, a cervical cancer and other tumor cohort? And would you also be looking to study some of these analyses in the Phase III, just so that the entire story of durability and [indiscernible] kind of comes together?

Certainly. And this is probably the last question. I realize now we've run way over time. Frank, do you want to start with that?

Sure. I'll quickly answer that question. So Mayank, good question. Yes, so as both doctors Harrington and Worden discussed, E6 and E7 HPV16 are the targets. These would be expressed in any HPV16-positive cancer, whether it's cervical cancer, anal cancer or vaginal, vulva or head and neck cancer, right? And so what we have done, we've demonstrated T cell response were presented at ESMO, I think, late in 2023 for head and neck cancer. As I discussed today, very similar CD8 T cell responses presented in cervical cancer studies. And the National Cancer Institute presented at ASCO in 2023, the T cell responses for all types of HPV cancers in their study, which was a basket trial consisting of all types of HPV-related cancer. So in all these studies, they have been very consistent in demonstrating the induction of the CD8 T cell responses. We anticipate continuing this in our Phase III study. As I mentioned, circulating tumor DNA is going to be one of the exploratory tools we use in the study. And so collecting a lot of that biomarker immune correlates, that could potentially correlate with the clinical benefit and survival and also provide strength to support the clinical results that we will be seeing. But again, so far, these results have been very consistent across all 3 trials, and we'll continue to monitor those as we go into some of these larger trials, too.

Great. Thank you, Frank. and with that...

Kirk, one last comment.

Yes, sure.

Yes, sure. So as Kevin capitalized on this a little bit, and I just wanted to say one last thing about that press release with the immunotherapy study prior to surgery. A lot needs to be explored, obviously, with these vaccines. And I know personally, I'm excited about this as Kevin is, and I think most on this call that if we see a signal and we see that the vaccine in combination with immunotherapy is providing benefit, there may be a role or place to study this upfront in patients before they get chemotherapy radiation or perhaps before they get surgeries for their cancers. So I just want to leave you with my anticipation is that this is going to do well in that there would be space to look at this in a different area, which may have a huge impact for improving survival of those patients who present not with metastatic disease but with locally advanced disease.

Well, Dr. Worden, very great last statement because that study is actually currently ongoing at the Mayo Clinic, exactly what you just described. We are doing that study currently at the Mayo Clinic. They are leading that study. And hopefully, we'll get the preliminary result sometime in the middle of next year.

Great. Well, thank you. And we do have to end, and I really apologize for running over so long, but I appreciate the energy of the questions and the in-depth discussion. So we thank you all for your participation today. We also especially thank our esteemed expert speakers for their informative and insightful presentations. And I hope, after participating in this webinar that you're as enthusiastic as we are about advancing this important immunotherapy to help the increasing number of patients with HPV-positive head and neck squamous cell carcinoma. Thank you, and have a good rest of your day.