As a reminder, this call is being recorded and a replay will be made available on the PDS Biotechnology website following the conclusion of the event. I'd now like to turn the call over to Dr. Kirk Shepard, Chief Medical Officer of PDS Biotechnology. Please go ahead Kirk.
Thank you Tara good morning and good afternoon. As just said, I'm Dr. Kirk Shepard, Chief Medical Officer for PDS Biotechnology and welcome to the webinar entitled Unmet Need in HPV 16 Positive Recurrent Metastatic Head and Neck Squamous Cell Carcinoma an opportunity for Versamune HPV. Next slide. This is our forward looking statements. Next slide and this is our disclaimer. PDS Biotech is the sponsor of this roundtable. Each KOL is speaking at the request of PDS Biotech. Under the terms of the consulting agreement, information presented is consistent with FDA regulations and guidelines. Next slide recently at the ASCO Annual Meeting, PDS was fortunate to have three poster presentations which will be a part of the presentations and discussions today.
The first ASCO poster was an update on the survival and other outcomes from our global phase II VERSATILE-002 trial treating HPV 16 positive recurrent metastatic head and neck squamous cell carcinoma patients with Versamune HPV plus pembrolizumab in a clinical trial demonstrating enduring median overall survival of 30 months, unchanged now from past presentations. The second ASCO presentation was a trial in progress poster showing the design of our currently ongoing phase III pivotal trial, VERSATILE-003 evaluating Versamune HPV plus pembrolizumab vs pembrolizumab alone in patients with HPV 16 recurrent metastatic head and neck squamous cell carcinoma with activation of the clinical sites occurring in March of this year. A third ASCO presentation was a report of data from a study performed by the Mayo Clinic using Versamune HPV as neoadjuvant treatment in locally advanced HPV 16 positive head and neck squamous cell carcinoma.
The agenda for today is shown on the slide. We are very fortunate to have two renowned leaders in Head and Neck Squamous Cell Carcinoma with us today to give presentations and to discuss questions. Our webinar will begin with a presentation by Dr. Kevin Harrington on the unmet need in HPV 16 positive head and neck squamous cell carcinoma. Dr. Katharine Price will then present the VERSATILE-002 ASCO data update and the VERSATILE-003 clinical trial that is now ongoing. Dr. Harrington then returned to present the VERSATILE-003 trial in context, particularly with other studies such as KEYNOTE- 689 and other ongoing clinical trials. We will then close with question- and- answers, at which time we will take written questions. The total time for the webinar with Q&As will be about an hour.
Next slide. Our first speaker, Kevin Harrington, MD, PhD, is Head of the Division of Radiotherapy and Imaging at the Institute of Cancer Research in the United Kingdom. In addition to expertise in Radiotherapy and Chemoradiotherapy, he is an authority on therapeutic approaches to metastatic head and neck cancer. Dr. Harrington is a Professor of Biological Cancer Therapies at the Institute of Cancer Research. He was one of the principal investigators 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 was an investigator for the VERSATILE-002 clinical trial and is on the steering committee for VERSATILE-003. He studied medicine at St Bartholomew's Hospital in London and began focusing on head and neck cancer as a PhD student at Hammersmith.
He has published more than 600 articles on cancer treatment. Dr. Harrington, please proceed.
Many thanks for that kind introduction, Kirk, and thank you for having me at this webinar. I'm very excited to have this opportunity to discuss the data relating to the unmet need in HPV 16 Positive Head and Neck Squamous Cell Carcinoma. On this slide I show you the scale of the problem that we are facing at the present time, and that which we will be facing for nearly the next century. As you can see, the incidence of HPV positive cancer as a whole in the head and neck region is currently undergoing a rapid expansion with some contraction of that rate expected over the course of the next 40 or 50 years or so. As you can see, the number of annual cases of oropharyngeal carcinoma is going to remain high even into the next century.
I draw your attention to the fact in the light blue color. The HPV 16 burden of that disease is by far the most prominent problem and represents a significant problem for clinicians facing this disease and of course the patients who suffer that disease. Now of course we are aware of the fact that there is a vaccination program against HPV-related malignancy and there is a confident prediction that there will be a reduction in the risk and the incident rate of oropharyngeal carcinoma as a consequence of that of the burden of disease that patients face. Here I show you modeled data looking at a number of potential scenarios in which vaccination rates may vary.
You can see that the status quo, the current rate of vaccination, still leads us to having a significant ongoing peak of this disease over the course of the next 30 years. If vaccination were to cease, the rate would continue to rise and clearly we hope that that will not happen. You can see a number of modelled scenarios in which there are rates of vaccination, including female only, male and female at 80% and 100% coverage. The stark message from this slide is that this is a problem that's here to stay into the next century and more pressingly over the course of the next 20 or 30 years. We can see we are still on the upslope of an increase in incidence of this disease and this is going to continue to be a healthcare problem for those of us who treat head and neck cancer.
Now, we know that HPV positive and HPV negative disease may have different prognoses in response to certain treatment types. Here I show you data not from the KEYNOTE- 048 data set itself, but instead I show you real world data recently published earlier this year from the Flatiron Health database encompassing over 2,500 patients. I'll show you first of all the slide on the left hand side indicating the fact that HPV negative disease carries a poor prognosis in relapsed metastatic status and that this is benefited by both PD-1 inhibition and PD-1 inhibition plus chemotherapy. On the right hand side of the slide there are a number of messages. The first is that the overall survival is higher for those who are HPV positive.
I show you that even at five years that survival rate falls as low as 25% and there is not a clear winner between the various treatment options that are available. The take home message I feel from these data is that anti- PD-1 therapy alone is not sufficient and represents an unmet need for patients with HPV 16 related head and neck cancer. Now the point I'm also making here is that in this data set there is not a separate analysis by HPV 16 status. I'm going to show you that in the forthcoming slides. Let's look at what these two diseases are because we are now in an era where we have to think about two different types of head and neck cancer.
The more historically conventional form of cancer, HPV negative disease driven largely by alcohol and tobacco consumption, with mutagenesis in the TP53 gene for instance, a pathology well recognized under the microscope with a well keratinized and a better differentiated appearance. Current U.S. prevalence in the relapsed metastatic state is between 40% and 60% and we predict in the 2030s this may fall as low as the 40%s, less than 40% both in the U.S. and EU. On the right hand side of the slide I show you the data for HPV positive disease.
This is defined by P16 positivity and you notice here that broken out for you are the different HPV genotypes, so a number of the high risk genotypes, but with HPV type 16 in a separate box in green on the right hand side of the slide you can see that it has many features pathologically and epidemiologically that are indistinguishable from other types of HPV related disease. It is the dominant pathology currently both in the U.S. and as predicted into the 2030s with a rate of greater than 60% is the forthcoming incident rate. This is a problem that we need to wrestle with. There are some suggestions that HPV 16 related forms of head and neck cancer may in fact carry a worse prognosis than other HPV genotypes.
I emphasize the fact that these data in a relatively small single center Canadian cohort of patients show us, interestingly, that HPV 16-related cancers have a prognosis both in terms of overall and progression free survival that in this analysis was more approximate to that of HPV negative disease than to the other forms of HPV positive cancer. This is something that we need to drill down into and examine further. These evaluations are not statistically significant, but they are strongly hypothesis generating. We know that HPV-related cancer is thought of largely as a disease affecting the oropharynx, but there is increasing recognition of the incidence of HPV associated with cancers in other head and neck sites, notably in the oral cavity.
I show you data now. These data, as long ago as 13 years ago, from a cohort of patients with oral cavity disease, 173 patients with accurate delineation of their HPV positivity and genotype-specific delineation, showing very interestingly that in terms of distant metastasis-free survival, disease-free and overall survival, those patients with HPV 16-related cancers had a worse prognosis than either the HPV 18-related or indeed the HPV-negative disease. I think it is important that we recognize the fact that HPV 16-associated head and neck cancers may be a type of disease that represents a significant unmet need and a problem potentially for our patients. On this slide, I want to make the point around HPV positivity, in this case HPV 16 E6/7 seropositivity, as a predictor of a better outcome in patients.
Now, the reason I show you this slide is to make the very important point that in those patients who are capable of mounting an immune response against HPV 16, they are likely to have a better prognosis. Of course, this leads naturally to the supposition that generating therapies capable of mediating that process may be advantageous for our patients. Interestingly, it's important to consider that this is true in terms of the hazard ratio for pharyngeal but also oral cavity and, intriguingly, laryngeal cancers. It may well be that HPV 16 related disease represents a broader target than disease simply confined to the oropharynx. On this brief review I come to my conclusion. I hope I have shown you that both HPV 16 positive and negative disease represent distinct entities in head and neck cancer.
The rising instance of HPV positive head and neck cancer is largely driven by HPV 16 related disease. This problem is not going to go away for decades. As I've shown you. Even with the advent of preventative HPV vaccination, there is evidence indeed that patients with HPV 16 positive disease may in fact experience worse outcomes. In the future, it will be important for us to identify properly patients with HPV 16 positive disease and to generate targeted treatments against them. With that, I turn the stage over to Kirk to introduce the next speaker.
Thank you, Dr. Harrington. Our next speaker is Dr. Katharine A. Price, Medical Oncologist who specializes in treating patients with cancers of the head and neck. After her oncology fellowship at Memorial Sloan Kettering Cancer Center, she returned to the Mayo Clinic in Rochester, Minnesota as a Head and Neck Medical Oncologist. Dr. Price is an Associate Professor of Oncology and Tumor Group Chair of the Head and Neck Medical Oncology in the Division of Medical Oncology at the Mayo Clinic. Her primary interests include new and de-intensified treatments for those who have oropharyngeal cancer related to HPV. Besides investigating new therapies for patients with squamous cell cancer of the head and neck, Dr. Price is actively involved with efforts to decrease health disparities and increase access to cancer clinical trials for minority and underserved populations. Dr. Price was an investigator for the VERSATILE-002 study and is the global principal investigator for the VERSATILE-003 trial. Dr. Price.
Thank you, Kirk, for that kind introduction. It really has been a great session. Pleasure to be involved in the VERSATILE-002 and VERSATILE-003 studies, as well as the small study that looked at the combination in a preoperative setting. I am happy to share my insights here today. Just stepping back on a wide range of this. Why are therapeutic vaccines really promising or why are they being studied for HPV-associated head and neck cancer? One of the main reasons is that the fact that it is a virally mediated cancer lends itself to a target antigen. In the case of Versamune HPV, this is looking at late proteins that are expressed by the virus. It allows us to have a uniform target for a specific patient population.
When we look at the patient population overall that is affected by HPV related head and neck cancer, there are a couple things that stand out. One is that on average, these patients tend to be younger than the patients who get smoking and alcohol related head and neck cancers and they have fewer comorbidities. This is extremely important because one, it means that most of the patients that we see are in the middle of their active life, they're raising kids, they have careers, and they have potentially years to live with their disease. These are patients who typically don't have a lot of other comorbidities. Their life and their overall survival is driven primarily by their cancer and not so much by other medical conditions like heart disease.
Dr. Harrington outlined the difference between HPV-related head and neck cancer and HPV-negative head and neck cancer and how, truly, we think about these as different, distinct diseases. One of the important distinctions is that when we look at HPV-related head and neck cancer and we think about the number of patients who will develop recurrent and metastatic disease, we are primarily seeing that those recurrences are happening in distant organs. These are patients who are developing metastases to the lung or the liver. This is different from smoking and alcohol-related cancers where we typically will see recurrences in the head and neck. What does that mean? It means that we really do need to escalate or think differently or develop new treatments that will affect the distant disease.
That's where building on the current systemic therapy like pembrolizumab is very important to try and control these important influences on overall survival for these patients. Before we go into the VERSATILE-002 data, I did just want to present a case scenario. I think it's important to remember that there are real people behind all of this data. This is a patient of mine, a 71-year-old man who in March of 2021 was noted to have an enlarged right tonsil and had a biopsy that confirmed HPV 16 positive squamous cell carcinoma. He underwent imaging at that time which showed the mass in the tonsil as well as right-sided cervical lymph nodes. He received radiation and chemotherapy through June of 2021 at an outside hospital and about 16 months later was noted to have enlarging lung nodules.
A biopsy confirmed metastatic HPV 16 positive squamous cell carcinoma with a PD-L1 score of 60%. I met him in January 2020 and he enrolled in the VERSATILE-002 clinical trial, which was a combination of first line pembrolizumab plus PDS0101. Depicted here is a representative CT scan from this patient. The images on the left, you can see there's a large blue arrow that points to a lung nodule. This was biopsy-proven head and neck squamous cell carcinoma. This is a patient that had a complete response to this combination. You can see on the screen on the right that that nodule has completely disappeared. This patient completed the full 24 months on VERSATILE-002 and currently he's now in observation.
I'm seeing him every few months and just saw him about a month ago and he remains without any evidence of active cancer. Moving on to the data that was presented by my colleague Dr. Weiss at the American Society of Clinical Oncology this past year. We reported on the Overall Survival of HPV 16 positive recurrent metastatic head and neck squamous cell carcinoma patients treated with PDS0101 and pembrolizumab. As a reminder, this was the study design. These were patients who had biopsy proven recurrent or metastatic HPV 16 positive head and neck squamous cell carcinoma. There were two arms for this study. For the remainder of this presentation and what we presented at ASCO was just on the treatment naive cohort.
These were adult patients who had good performance status and they were required to have a CPS score of greater than or equal to one to enroll on the study. The reason for this is that requirement is also needed to give pembrolizumab as standard monotherapy for this disease. All patients received the same treatment on this study. They received pembrolizumab at standard doses every three weeks for up to two years and then they received it in combination with the vaccine PDS0101 and there were five total doses of vaccine given. The first four were given concurrently with the immunotherapy. There was a brief period of time where patients then received immunotherapy alone and in cycle 12 they received a booster of the vaccine and the remainder of the study was with pembrolizumab alone.
The primary endpoint was best overall response and secondary endpoints were overall survival, progression free survival, and safety and tolerability. The patient demographics for VERSATILE-002 were similar to what is seen for many head and neck oropharynx studies in this day and age. This is a disease that predominantly affects men over women and that is reflected in the 92% male participants. Predominantly in this study was a Caucasian population, very good performance statuses, and as was required, all patients needed to have a CPS score of one or higher. You can see the breakdown here with about two-thirds having a CPS between one and 19 and one-third greater than 20. The primary endpoint was best overall response. This is depicted here in a waterfall plot.
If you're not accustomed to looking at these graphs, this is a visual depiction of either tumor shrinkage or growth for each individual patient. Each individual patient is represented by a bar graph, and the bar graphs above the X- axis represent tumor growth, and those below the axis represent tumor shrinkage. You can see just visually that the majority of patients had some degree of tumor shrinkage. If they cross over the dotted line, which is a shrinkage of 30% or more, they're considered responders. You can see that there were a large percentage of responders, and notably 21% of patients had a complete or near complete response as represented by the bar graphs on the right. What's also important is that responses were seen both in the CPS one to 19 group as well as the greater than 20.
This combination was very well tolerated. Depicted here are the percentages of adverse events or side effects that were felt to be related to either the vaccine or to pembrolizumab. You can see that the majority were grade one and two toxicities. This means either very mild toxicities that do not require any kind of treatment, they can just be observed, or those that require simple interventions to manage. The percentage of patients that had higher side effects, grade 3, 4 or 5, was quite favorable when we think about what we see compared to standard chemotherapy regimens. Notably, there were no deaths on the study. By far and away the most common side effect was an injection site reaction. Patients were administered vaccine on their upper arm.
Many patients would have a day or so of some redness or mild discomfort or swelling that was self-limited. Some of the other common side effects included fatigue, headache, itching, diarrhea, and the others are listed here. The progression free survival in VERSATILE-002 was very encouraging. Of course, we did not have a direct head- to- head comparison in this study. Historically, this population will have a progression free survival on the order of one to three months across studies. You can see, broken down by CPS score, that the progression free survival was quite encouraging for this population. The overall survival is and remains very encouraging for these patients. Historically, head and neck cancer patients will have overall survivals on the average of around one year.
You can see that even going out to over three years, there were still approaching 40% of patients that were alive and well on this study. This is very exciting, particularly when we think about that. These are patients that we anticipate are going to be alive and are going to go on to receive other therapies. One of the things that is so encouraging about this overall survival is to keep in mind that this is the very first treatment that these patients received. All of the other options for treatment, including standard systemic chemotherapy, have not even been given yet. We would hope that starting off with this combination will lead to the ability for patients to live longer and to be candidates and be able to get additional treatment for a long time.
When we look at some of the responses based on the CPS score, you can see there is a difference which is not unexpected that the overall response rate, the disease control rate, progression free survival, and overall survival are slightly better in the CPS greater than or equal to 20. Still, when we look at all comers, we can see that survival is very strong for the whole group. We do very much see that patients in that CPS one to 19 do appear to benefit from this treatment. In terms of VERSATILE-002, the enrollment in this study is complete. We have seen excellent tolerability in this combination in our patient population. The median overall survival of 30 months is very encouraging and the clinical activity remains very strong with an overall response rate for the whole population of 35.8%.
Disease control rate, which refers to the number of patients who had both responses and stable disease, was 77.4%. Very exciting are the percentage of patients who had really deep tumor responses. As we will illustrate in the next slide, the phase III study has just started to enroll patients. My final slide here is just a schema of VERSATILE-003. This is a global, randomized, controlled phase III study of PDS0101 or Versamune HPV plus pembrolizumab versus pembrolizumab monotherapy in patients with first line HPV 16 positive recurrent metastatic head and neck squamous cell carcinoma. Similar to VERSATILE-002, these are patients with recurrent metastatic disease. They need to have a CPS score of greater than or equal to one, and this has to be the first treatment they are receiving.
In the recurrent and metastatic setting, patients will be randomized in a two to one fashion, meaning that two-thirds of patients overall will get the combination and then one-third will get pembrolizumab alone, which is a current standard of care for this patient population. The primary endpoint is overall survival. Secondary endpoints include objective response rate, disease control rate, duration of response, progression free survival, and safety and toxicity. There are a few exploratory endpoints that we're very excited about. One is the incorporation of HPV 16 circulating tumor DNA to look at the molecular responses to this combination. Quality of life will be collected in a systematic fashion. We're also looking at Progression Free Survival 2, which means the Progression Free Survival of patients after they start their second line treatment.
After the study, because we believe that there may be some ongoing benefit in terms of the immune response that could allow patients, even if they develop progression on this combination, to continue to do better. Notably, there will be the development of a companion diagnostic tool to identify specifically the HPV 16 positive patients.
At this point I have pleasure in just setting in context the VERSATILE-003 study. I'm going to focus on two main areas. The first is I'm going to discuss the recent presentation of data relating to the KEYNOTE- 689 study. I'm going to make the point that the success of this study, which will lead to practice change, there is no doubt of that, will actually have relatively little impact, if any, in patients with HPV-related cancers. In this study, presented recently at the AACR and currently in press, patients were randomized between treatment with pembrolizumab or going directly to surgery.
Now, the patient group were those with resectable locally advanced head and neck squamous cell carcinoma tumors affecting the larynx, hypopharynx, oral cavity at stage 3 and 4a. For patients with oropharyngeal cancer, for P16 negative disease, again it was at stage 3 and 4a, but for those with HPV related P16 positive oropharyngeal cancer, the stipulation was that disease needed to be at T4 N0-2, so really advanced disease in the oropharynx. For the HPV positive population, patients had a good performance status by ECOG and tissue was available for testing for PD-L1. Now, patients, 714 in total, were randomized roughly 1-1 , as you can see, between a neoadjuvant phase in which they received two cycles of pembrolizumab at standard flat dose every three weeks and then surgery, or directly going to surgery.
Subsequently, on evaluation of the surgical specimen, patients were treated with radiation or chemoradiation in a risk-adapted strategy based upon the pathology, and those who had initially been randomized to pembrolizumab continued with that treatment concomitantly and then adjuvantly for a total of 17 cycles. Just a year of treatment in total. For those who had been randomized to going straight to surgery, they completed the radiation or chemoradiation and then entered follow-up. Patients were stratified as delineated here with fairly standard stratifications. The primary endpoint of this study was event free survival per RECIST with a blinded independent central review, and there was a key secondary endpoint of major pathological response.
Now many of you may be aware that this study met both of those endpoints, both the primary and the key secondary endpoint, and as a result of that has led to a change in practice which I will discuss in a few moments. Before that I want to emphasize the reason I said at the beginning that I do not believe that this study is going to change practice in HPV related disease. You can see here from the breakdown of patient entry into the study a fairly typical population of patients entering into a study that had surgery. At the heart of it you can see that the majority of patients are current or former smokers. Alcohol use was a fairly dominant feature.
The majority of patients comprised those with oral cavity or laryngeal carcinoma and indeed you can see approximately 10% in total had oropharyngeal carcinoma, but critically about 4% of patients in total had HPV related disease. This is not a study that is really speaking to that population of patients with HPV related cancer. Nonetheless, it's important to recognize and to celebrate indeed the fact that the FDA has approved the indication for this treatment. I want to make key points here.
Pembrolizumab is now indicated for the treatment of adult patients who have resectable locally advanced head and neck squamous carcinomas with disease expressing PD-L1 with a CPS greater than or equal to one, and those patients will receive this treatment as a single agent therapy and then subsequently go on to an adjuvant treatment where they will also receive pembrolizumab either with radiation or with chemoradiation. It is important to recognize and to emphasize only 3%-4% of the patients in the study had HPV positive disease and that group of patients are not typically candidates for curative intent resection.
The second area that I want to discuss to set the scene for discussion is that in relapsed metastatic disease, so the setting for the VERSATILE-003 study, which is of course the only phase III clinical trial in the first line setting in HPV 16 positive relapsed metastatic head and neck cancer. I list here a number of currently active or recently completed phase II and III clinical trials. The LIGA study with pitasemtamab, so a bispecific antibody targeting both EGFR and LGR5, will include a population of patients with HPV positive disease, but it will largely be recruited from those with HPV negative disease. A number of the other studies, and I would like to emphasize the amivantamab research here with the OrigAMI-4 study, will also include patients in limited cohorts with HPV positive disease, but the main emphasis being on HPV negative disease.
At the bottom of the list, the Fortify HN study with ficerafusp alfa , a drug that targets TGF beta by trapping that agent, is exclusively for an HPV negative population. For a number of the other studies, you will see that they involve drugs that include antibody drug conjugates, so not chemotherapy-free options, or multityrosine kinase inhibitor agents such as Zanzalintinib, which come with a significant toxicity burden. You see, I've also mentioned a number of studies that have already press released as being negative, and the work with tisotumab vedotin has closed, and it is unlikely that that drug will proceed further in the development for relapsed metastatic disease. The take home message from this slide is that VERSATILE-003 represents a very important and almost unique offering and is in phase III for patients with first line HPV 16 positive relapsed metastatic disease.
With this, Kirk, I turn back to you, and I hope you're now going to lead us in the Q& A session.
Thank you very much, Dr. Harrington, and also Dr. Price, for your previous presentation. Now let's look at some of the questions that have come in, and please, moment here to get to them. The first question, this is from Mayank Mamtani from B. Riley Securities. Could you touch on the mechanistic rationale for Versamune and pembro combination performing in low CPS score in first line recurrent metastatic subjects, especially since pembro performs poorly in this cohort? What's your expected mix of CPS low versus high in the ongoing phase III trial?
I think I can start with that. I think it's challenging when we look at CPS score, which is widely used because it's what we have, and there's definitely a correlation between responses and CPS score, but we know that it's not a perfect biomarker. In practice, we see people who have good responses to immunotherapy, really across the spectrum, with the exception of CPS zero, where it's more unlikely. The way I think about the combination or when I think about immunotherapy alone, when we look at patients where pembrolizumab as a monotherapy works, it's very likely that they already started to have some engagement of their immune system. Adding the pembrolizumab is really just like putting lighter fluid on a fire.
When we think about the combination, what Versamune HPV is going to do is to really stimulate that fire, get that immune system engaged, or increase the likelihood of that immune system engagement so that the pembrolizumab can have an additive effect. I do think that as a clinician, when we think about pembrolizumab monotherapy, you know, it's unfortunately a minority of patients who benefit from that. Trying to increase the likelihood that the immune system is going to respond by something like a therapeutic vaccine, then using the pembrolizumab as an adjunct.
Kirk, maybe I could just add a few words. I agree with everything that Dr. Price has said, of course. I think the other important thing to recognize is that the PD-L1 score is an indication actually that this is a tumor microenvironment that was once experiencing interferon gamma, and that gamma probably came from an initial immune response. Unfortunately, that will have triggered expression of PD-L1 within the tumor microenvironment that can snuff out that immune response. The strength of the Versamune HPV approach is that it offers the prospect of generating new activated T- cells, and it offers the prospect therefore of reinvigorating what might already be a rather stagnant immune microenvironment.
Now, if those activated immune cells go to that microenvironment, where the tumor is capable potentially of putting up the barriers of PD-L1, adding in the pembrolizumab makes perfect sense in terms of taking that barrier down and unleashing those T- cells. I think it is a very strong rationale to combine these two treatments. We could predict that the PD-L1 will be some form of a predictor, but it will not necessarily dictate. I do not think it is a given that the one to 19 population will not be able to benefit from this treatment. I think it is highly likely that we will see good responses due to new T- cell reactivities that we will generate.
Great, thank you. Next question from Joe Pantginis, H.C. Wainwright. Anything in the competitive landscape to consider when enrolling patients in VERSATILE-003?
Maybe, if I may have first go at that, I'm sure we'll have slightly different views of this from different sides of the Atlantic, Katharine, but we consider all options when looking at patient options for treatment. Of course we run a portfolio of studies where we have both first and second and third line offerings. Of course in the first line setting, for me the most advantageous thing to consider if possible is a chemotherapy free option. Dr. Price made the really important point actually that you reserve those treatments, you keep them up your sleeve, you keep them there for the patient.
For me, if there is a chemotherapy free option that is all the stronger and if that can employ an antigen that we know is expressed in the tumor because it's a HPV 16 related oropharyngeal cancer, so much greater strength for that strategy with a chemo free option. That is something that I will always take into account and when possible I will offer those sorts of trials to patients, especially when the tumor burden is relatively modest, when the disease is not causing a strong burden of symptoms.
Now when we see those sorts of scenarios where patients have a high volume of disease or have lots of symptoms, relating that you may need something that is a little bit more than just an IO plus something else like a vaccine strategy, but generally speaking, I will always prioritize a non-chemotherapy containing regimen where it is possible for a patient to derive benefit and HPV positive related cancers. Those particularly I think are a group of patients who really stand the chance of deriving long term durable benefit. Dare we even begin to dream about this curing of their disease?
I agree with what Dr. Harrington said. There always will be a small percentage of patients that just require more aggressive treatment up front. In general we're trying to look at both activity and also tolerability. The VERSATILE-003 study, and we know from the VERSATILE-002 that patients just tolerated this combination so well. You know, they weren't having toxicities that then took them out from being able to get second, third, fourth line treatment. There's a lot of interesting drugs out there. Most of them are, you know, showing promise predominantly in the HPV negative space. I think important to note, you know, some of the antibody drug conjugates, for example, these are not easy drugs to take. They might be promising, but they're not drugs that patients can be on for an extended period of time.
The way I look at it, you know, and when I approach a patient who has recurrent metastatic disease, I, you know, I want to have a list of treatment options because right now none of these are curative options. We know that we have to sequence them appropriately. I always try to approach treatment. What is the order that's going to get the most mileage out of every treatment and give us the most number of options down the line? The VERSATILE-003 combination is an excellent one from that standpoint.
Excellent. The next question is from James Molloy, AGP, and he's asking where would you see Versamune in the treatment algorithm should it ultimately be approved? You've answered that a little bit already, but maybe go on to the effects of the companion diagnostic. Now being able to identify a patient population with HPV 16 positivity, maybe what do you see the future like with both the approval of drug and then a companion diagnostic.
So.
Katharine, you go please.
I think that companion diagnostic is going to be really helpful as a clinician because, you know, many of the HPV assays out there, they do not necessarily tell you the subtype right off the bat, you know, so you do not always know. I think it will be very important to have that companion diagnostic to be able to flag. Okay. These are patients that, you know, can benefit from this combination. I think looking hopefully at approval would be primarily in the first line setting with an immunotherapy agent again, so that then subsequent treatments that may be more toxic can be kind of held in the back pocket.
Kevin, anything to add?
Yeah, I think it adds huge strength when a companion diagnostic is a wonderful thing to have. It adds some level of complexity to treatment selection. Assuming that we got a positive setting, we got an approval of the agent, that suggests that you've really got a valuable treatment option for the patient. Knowing that the patient has an HPV 16, specifically positive tumor and therefore is likely to derive benefit and potentially the sort of durability and also the depth of the responses that you saw. We saw 21% of patients having really very substantial reductions in volume of disease that is well worth having.
I think that most clinicians will take the view and patients, I think, will be comfortable with that notion, that actually getting the information that allows you to make the rational selection with a good predictive possibility that the patient's going to derive durable benefit, I think that is absolutely essential to correct patient treatment sequencing. I agree with Dr. Price. It's got to the point now in head and neck oncology, where it's about trying to maximize the gains of all of the treatments that you deploy and the order in which you use them in order to keep the patient as well as possible for as long as possible.
For some of those patients to begin to think that beyond five years, actually they may not die of this disease, and you actually may be able to think about curing a small number of patients.
Excellent. Thank you. As you alluded to, Dr. Harrington, it's been reported in the medical journal Lancet, there's an increase in incidence now confirmed driven exclusively by HPV 16. And some publications have suggested it will go as high as 30% a year. As you talked about, do you have any insight, either of you, to why this growing health concern is not well understood by many people outside of the medical community, as well as maybe some within the medical community?
Yeah, you addressed that to me, Kirk, and I'm happy to give some thoughts on this in the first instance, because it's a conundrum, isn't it? This is a rapidly growing incidence disease. I hesitate to use the word epidemic because that's often overblown. Nonetheless, for those of us who treat this disease, it's been a complete change in our practice over the last decade to how we see the patients presenting first with newly diagnosed and then with relapsed metastatic disease and why this doesn't gain more traction and why the discussion around vaccination has not led to greater public health efforts to emphasize the benefits against not just cervix cancer and genitourinary disease, but also against oropharyngeal carcinomas, frankly, is a bit of a mystery to me.
Nonetheless, I think we have to continue to try to push those efforts, of course, in the absence of a demonstrable reduction through vaccination yet, and as I showed you in those epidemiological data, the fact we can confidently expect, unfortunately, for the next 10-20 years we're going to still see an upstroke or even a plateau phase at high incidence. It's incumbent upon us to give our efforts to try to develop the most effective therapies that we can. No answer, I'm afraid, to why society and why governments don't take greater efforts in terms of, or at least recognition of, this. There's no doubt that the medical community understands the scale of the problem and is engaged in trying to develop the treatments that will make a difference.
Katharine, I know you've been especially focused on the population of preventative vaccines for HPV. And there you see the mix of what's going on. You're trying to get people to accept the vaccination, but at the same time you have this, as I said, I hesitate to call it back a epidemic also, Kevin, but it's a huge increase in HPV 16 positive. Any insights there that you can see why people have been resistant to accepting this?
Yeah, I mean it is a bit of a conundrum, you know, in the outreach that we've done, sort of both out in the community as well as with healthcare providers. You know, I think there is pretty good understanding or people think about HPV related cervical cancer and they think about girls and they think about women, but there's, you know, they really, it just has not been on the radar that it's our boys and men that are affected by the head and neck cancer epidemic. I think epidemic is fair. I mean if we look in the United States, you know, the incidence continues to rise and it's been the 8th most common cancer in men in the United States for many, many years now. I don't know why there is such a barrier, but that barrier is really there.
I think just as a whole, as a society, as healthcare providers, we need to, one, just normalize the HPV vaccination as a preventive measure. I did just want to highlight when we think about therapies that are easy to administer and do not have a lot of toxicity and just think about it from a standpoint of health disparities. You know, in the United States, and I suspect this is true in Europe as well, one of the things that we see with the HPV-related head and neck cancer epidemic is that those numbers continue to really climb in rural areas and the vaccination rate, particularly for boys, is dismally low in rural areas. Those two things track together.
You know, we're starting to see in the United States, in more urban areas, some leveling off of the incidence of HPV-related head and neck cancer. We're seeing this growing disparity where our rural populations are more and more affected. If you think about this combination, which is well tolerated, easy to give, that is something that could be deployed in less well served areas compared to a complicated trial or a drug that results in a lot of toxicity. I do not have an answer for the psyche. I'm continuously sort of amazed by the lack of knowledge and the lack of vaccination uptake. We're doing the best we can and I think just as societies we need to do a better job at advocating for vaccination and normalizing that.
Great. Just a question about mechanism of attacking it. Couple studies ongoing to have EGFR mechanism. I mean, what is your thoughts about the MOA of the EGFR in the HPV positive population?
Maybe I'll have a first stab at that. We've got a fairly robust literature now backing up the fact that HPV related and HPV driven cancer is not recognizably an EGFR driven disease. Those data, I think, go all the way from the relative mutual exclusivity of expression of HPV positivity in EGFR levels, although those do not necessarily predict response to an EGFR targeted therapy. I think, you know, in the second third line setting, the recent presentation of the INTERLINK-1 data in which cetuximab with monalizumab or cetuximab monotherapy was used in an HPV related and an HPV unrelated separate population. What we really saw in that study was actually cetuximab has very poor activity in patients with HPV related disease.
We take that and we look at those data through the lens of the pitasemtamab study, which is enrolling patients with HPV related cancers. Now, pitasemtamab, as I've discussed, EGFR times LGR5, I think the literature around LGR5, which is putatively a stem cell marker feeding into the Wnt signaling pathway, potentially involved in mechanisms including epithelial mesenchymal transition. I don't know that there is a very clear line of sight to why that drug might necessarily turn around that relative lack of activity of EGFR targeted treatments in HPV related disease. We will of course see the results of the Liga 1 study and indeed the Liga 2 study that includes patients with HPV related disease and we'll get an answer for that.
It is interesting to note that I guess probably the front runner competitor to pitasemtamab, fiserafuspalfa, which is an EGFR times, well, with a TGF beta trapping moiety, they are not even going there. They are not even looking to recruit patients with HPV positive disease. I think that company has taken a view. I am not convinced as yet that there is a clear line of sight to using EGFR targeted therapies in HPV related disease. Time will tell. Again, I do not know what Dr. Price's view of this is, but I think it is not the strongest rationale.
I agree. I think clinically if we just look at it from just pure clinician perspective, we know that the cetuximab studies and HPV related cancers in combination with radiation in the definitive setting did worse than chemotherapy and radiation. I never use EGFR agents as single agents for HPV patients. You know, in the recurrent metastatic setting, I mean, you know, and the newer agents I look at primarily as HPV negative as well. You know, I think there are some patients that are very sensitive to cetuximab, which is, you know, a standard of care EGFR antibody. In my experience those are always oral cavity patients, you know, HPV negative patients. It's never been for HPV positive.
Great, thank you. It's hard to believe an hour has gone by. Thank you very much for your excellent discussions. This concludes our webinar for today. We at PDS Biotech are really excited about our current data and future studies in helping our patients. We are very pleased that we've initiated the VERSATILE-003 registrational trial this quarter. Especially, we'd like to thank today our two experts, Dr. Price and Dr. Harrington, for their excellent presentations and discussions, and also want to thank you for your participation in the webinar today. We look forward in the future to giving you updates on our progress. Again, thank you and have a great day.