Ladies and gentlemen, thank you for standing by, and we do thank you for your patience today. Welcome to the PDS Biotechnology Webcast, Current and Future Treatments for Recurrent Metastatic HPV Positive Head and Neck Cancer. If anyone should require operator assistance over the phone, please press star zero on your telephone keypad. A question and answer session will follow the formal presentation. You may ask a question at any time by typing it into the Ask a Question feature on your screen. As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Dr. Lauren Wood. Dr. Wood, please go ahead.
Thank you, Kevin. Good morning, everyone, and welcome to PDS Biotech's Current and Future Treatments for Recurrent Metastatic HPV Positive Head and Neck Cancer, and the potential application of PDS0101 KOL Web-Roundtable Webinar. Again, we apologize for the delay. With me today are Dr. Ricard Mesía from the Catalan Institute of Oncology, Dr. John Kaczmar from the Medical University of South Carolina, Dr. Katharine Price from Mayo Clinic Comprehensive Cancer Center, and Dr. Glenn Hanna from Dana-Farber Cancer Institute.
I will provide formal introductions in a moment, but before we begin, I would like to caution listeners that comments made during this webcast may include forward-looking statements within the meaning of the federal securities laws, including the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements involve material risks and uncertainties, and the company's actual results may differ materially.
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Each panelist is speaking on behalf of PDS Biotech under the terms of a consulting agreement, and all information presented is consistent with FDA guidelines.
With me today are a distinguished group of cancer researchers who it is my distinct pleasure to introduce. Again, all of these esteemed academic investigators are consultants for PDS Biotech. Dr. Ricard Mesía is Head of the Department of Medical Oncology at the Catalan Institute of Oncology, with a focus in head and neck cancer treatment. He is the chair of the Spanish Group of the Treatment of Head and Neck Cancer, the Spanish Foundation for the Treatment of Head and Neck Cancer, and a principal investigator on the landmark KEYNOTE-048 study that led to the current standard of care in the first-line treatment of recurrent metastatic head and neck cancer. Dr. John Kaczmar is a head and neck medical oncologist at the Hollings Cancer Center of the Medical University of South Carolina.
He obtained his MD at Columbia University Medical School and completed a fellowship in Hematology Oncology at Fox Chase Cancer Center in Philadelphia. Since joining the faculty of the Medical University of South Carolina in 2017, his clinical research focus has been optimizing the treatment of patients with head and neck cancer. As the lead medical oncologist in head and neck cancer, he serves as principal investigator on numerous trials and is also director of the phase I program. Dr. Katharine A. R. Price is a medical oncologist and associate professor of oncology in the Division of Medical Oncology at Mayo Clinic in Rochester, Minnesota. A graduate of Harvard University and Mayo Medical School, she completed an oncology fellowship at Memorial Sloan Kettering Cancer Center and specializes in the treatment of head and neck cancer.
Her clinical research interests include the treatment of head and neck cancer, with a focus on HPV-associated cancers and salivary gland cancers. PDS Biotech is pleased to announce that Dr. Price has agreed to serve as the lead principal investigator for the upcoming PDS0101 phase III trial, VERSATILE-003. Dr. Glenn Hanna earned his medical degree from Georgetown University and completed Hematology and Medical Oncology fellowship training at Dana-Farber Cancer Institute, becoming a faculty member of the Center for Head and Neck Oncology in 2017. Dr. Hanna's clinical translational research efforts focuses on both molecular and immunologic biomarker discovery to foster precision medicine approaches to treat head and neck cancers and improve patient outcomes, including diverse immuno-oncology approaches.
He has an additional interest in treating salivary gland cancers and in using cell-free DNA, also commonly known as circulating tumor DNA or ctDNA, to treat and monitor HPV-associated head and neck cancers. Over the next hour, we'll be discussing the future of treatment of recurrent metastatic HPV-positive head and neck cancer. Dr. Mesía will open our session with a review of the current unmet needs of this growing patient population. Dr. Kaczmar will then review the updated data from the VERSATILE-002 study of the combination of PDS Biotech's novel investigational HPV-16 targeted immunotherapy, PDS0101, delivered in combination with Keytruda, also known as pembrolizumab, in immune checkpoint inhibitor-naïve subjects. Dr. Price will follow with the overview and study design for the planned VERSATILE-003 phase III clinical trial, due to be initiated in the fourth quarter of 2023.
Finally, Dr. Hanna will conclude by reviewing the emerging use of circulating tumor DNA, ctDNA, in the treatment of head and neck cancer. At the end of the presentations, we will open the discussion for a question and answer session. As Kevin previously noted, if you have a question and would like to submit during the presentation, please feel free to type it into the open text field at the bottom of your screen and hit Submit button. For those who would like to ask a question directly, please hit star one on your keypad. Welcome to Ricard, John, Katharine, and Glenn. With that, I would now like to turn the meeting over to Dr. Mesía. Ricard?
Thank you, Lauren, for your nice presentation. I'm going to introduce the current treatment of HPV-16 positive head and neck squamous cell carcinoma and unmet needs. Factors that determine our decision for the treatment of patients with recurrent metastatic disease are based on patient characteristics, mainly performance status and comorbidity, and also tumor characteristics that include tumor burden and PD-L1 value measured by CPS. HPV status is not included up to now in this decision, so we treat equally HPV-related and HPV-not related patients. In platinum-refractory patients, we usually treat our patients with nivolumab in first line and regardless of the PD-L1 status. In those patients who recur, we plan chemotherapy plus minus cetuximab in second line.
Based on the figures of the pivotal CheckMate 141 trial, we know that in these refractory patients, median OS is only 8 months, and median PFS is only two months. In platinum-sensitive patients, we decide according to the PD-L1 value. In CPS ≥1, we choose between pembrolizumab alone or pembrolizumab associated with a combination of chemo with platinum or fluorouracil, and sometimes, in the States, fluorouracil is changed by paclitaxel. To choose between pembro alone or the combination of chemo plus pembro, we usually use a clinical criteria, such as the tumor burden, by adding chemotherapy in those patients who are very symptomatic or who are at high risk of some complications.
In second line, post-ICI, we use a different combination of chemo plus minus cetuximab, to have moved the first line, the old first line to the second line. For patients with a CPS less than 1, we maintain the old standard treatment with Extreme or TPEx, marketed in Europe, despite we don't know the exact role of cetuximab in the HPV-related patients with recurrent metastatic disease. We usually use nivolumab in the second line when the patient recur. Median OS in patients with a sensitive tumor is 12-15 months, depending on the CPS value, and median PFS it's from 3-5 months, based on the pivotal KEYNOTE-048 trial.
The reason to maintain the combination of chemo plus cetuximab in those tumors with a CPS less than one is based on the subgroup analysis. There's a post hoc subgroup analysis of the KEYNOTE-048 study with pembro alone that seems to be detrimental in overall survival. You have here in the curve of the left. The combination of chemo plus pembro that is not superior to the combination of chemo with cetuximab. That is for patients with a CPS less than one. Despite HPV-related and non-related tumors are clearly two different biological entities, both patients receive exactly the same treatment in the recurrent metastatic setting because HPV-related patients are usually included together with HPV non-related. Like in the KEYNOTE-048 study, where represented about 20% of the patients included in the all-comers patients.
Up to the introduction of immune checkpoint inhibitors, we use the schedules with cetuximab, the Extreme regimen, or TPEx regimen in Europe. The main goal here was a palliative intent of our treatment, and we try to improve overall survival by increasing the response rate, symptom control, and of course, improve quality of life. But now we can see these figures with pembrolizumab, with or without chemo, that have overall survival to 5 years of 15%-18% of the patients who get this 5-year overall survival in patients with a CPS over 1. So I think some patients could recur with ICIs associated or not to chemo. So now one of the new goals of this treatment is to increase this long-term survivals on our patients.
Analyzing the figures of what happened in second line in the two most important phase III trials in the recurrent metastatic setting, KEYNOTE-048 and CheckMate-651, only about 50%-60% of patients who started a first line with chemo receive a second-line therapy based on what they have received first. This 40% of patients who do not receive a second line include the long survivals that never recur, but also those patients who progress and deteriorate very fast after the first line, mainly in the pembro alone arm. Median overall survival to the second line can be predicted by the response to the first line. In the KEYNOTE trial that compare durvalumab and anti-PD-L1 to Extreme, patients who responded to the first line had clearly better overall survival than those who progressed independently of the study arm, durvalumab or Extreme.
Those who had an unstable disease have an intermediate overall survival. Comparing by arms, clearly those patients who responded to first-line durvalumab had better overall survival than those who responded to Extreme. From the analysis in the KEYNOTE-048 of the PFS, PFS2, PFS2 is the measure, measure the time, the time from the starting the first line of chemotherapy or pembrolizumab to the progression to the second line in patients who recur. We also know that those patients with a CPS over 1, who receive a first-line with pembro alone or in combination with chemotherapy, seems to go better than those who receive chemotherapy alone in the first line. The conclusion of these two trials is that we should select the best treatment for the first line.
To summarize the unmet needs in the first-line recurrent metastatic HPV-16 positive, I think we need to improve the rate of long-term survival. We need to reduce the toxicity of the actual treatments to improve quality of life. We should define the best sequence of treatment for specific HPV-related patients with a, a recurrent metastatic setting. The best option of treatment should be administered in the first line, because up to 50% may not receive the second line. And up to date, standard of care chemotherapy or IOS alone is not enough in most of our patients with an HPV-related disease. Thank you very much.
Thank you so much, Ricard. John, we'll let you take it from here.
Yeah, thank you. So it's my pleasure to contextualize and highlight some of the most up-to-date data on the VERSATILE-002 study of PDS0101 in combination of Keytruda for head and neck squamous cell carcinoma. So some top-line points, as Dr. Mesía said, for patients with recurrent metastatic head and neck cancer, the overall survival is still what I would consider and characterize as relatively dismal, only a little bit over a year. Importantly, though, there are some long-term responders. About 30% of patients now are on that tail, where responses can be durable, and we consider that maybe we're curing some patients.
To date, our treatment algorithms for HPV-positive and HPV-negative patients remain very similar, and there are no approved agents for one etiology, you know, smoking and alcohol versus the viral etiology of HPV. Importantly, when we're developing, you know, new standards of care, we're often layering treatments together. We have Keytruda as the foundational, you know, first-line treatment, trying to layer things with it. We often broaden and deepen toxicity by targeting pathways that are available in both cancer cells and in normal cells. So an agent that might target something that's not present in normal cells and is the driver of the cancer is alluring because potentially you're improving response with—and really mitigating additional toxicity.
So the goal of combining PDS0101 with Keytruda is to target the viral etiology of the cancer, potentially improve overall survival, allow people to live longer and hopefully live better. A little look at the continuum of what's been going on with this study. In 2022, the agent was granted fast track designation, along with the combination of Keytruda. This phase II study was an open-label, non-randomized study that enrolled 54 patients, which was its complete enrollment based on an interim efficacy analysis that it met. The patients that were included were the standard types of patients we would be looking for, patients that are adult, HPV-16.
CPS was all equal to or greater than 1, so these were CPS-positive patients, which mirrors the approval for Keytruda in the first line. And the study treatment was standard of care Keytruda, given every 3 weeks for up to 2 years, and the PDS0101 was given cycles 1 through 4, and then a booster dose at cycle 12. Endpoints were what one would expect to see in a phase II study with best overall response as the primary endpoint, and then very important secondary endpoints: progression-free survival, overall survival, and of course, safety and tolerability, which is increasingly important in the care of these patients, who oftentimes have a high symptom burden. Quickly looking at the demographics, we'll see that in the intention-to-treat and the modified intention-to-treat population are very similar.
The patient population is what one would expect in a cancer that has the highest incidence rate in white males. Performance status was relatively split between 0/1. And importantly, the CPS, not surprisingly, we see no one who is CPS negative, and the majority of patients were CPS 1-19 intermediate. I think it's important to note that number. It relatively mirrors KEYNOTE-048 and potentially a little bit more skewed to the intermediate rather than the high. If you saw a study with the vast majority of patients high, you might be biasing to seeing a better response. So I think this is a pretty real-world group of patients, I would contextualize it as.
Then importantly, did people receive a reasonable dose of the study treatment? You can see the median dose of PDS0101 was 4, and the median dose of Keytruda was 7, which is a pretty good exposure to the agents under study. I think this is the wow slide. When we're really looking at the overall survival at some landmarks, and we've increasingly been looking at this with immune therapy. So seeing 80% of patients on the study, 80% of these 54 patients were alive at one year, and even which is impressive.
Even more impressively, almost all those patients were still alive at 2 years, which is, as we'll see, far better than what we're seeing in the current standard of care, on this slide right here. We can see with the KEYNOTE-048 data, about half to a little bit over half of the CPS-positive patients are alive at 12 months, paralleling I think about 30% higher on the VERSATILE-002 study. More impressively, more than double improving the long-term 2-year overall survival patients. It's always important to note on cross-trial comparison, you can't be sure the patients are the same, but still, this is very tantalizing data.
And really suggests that we may be broadening the base of patients that can have a long-term response and truly enjoy a long-term quality of life with what previously was something that generally people would not be living a year with. And then looking at the responses, I think, you know, everyone looking at a study will oftentimes be drawn to the overall response rate. What's the response rate? And this is 27%, which is superior, looking to be superior, to immune therapy as a monotherapy, which is more in the teens to about 20%. But not, it's not double, it's not triple. And maybe you say, "Gee, that's disappointing." But the thing that's really impressive is the number of patients who had tumor reduction.
So 60% of patients had tumor shrinkage, 81% of patients had control. And I, for one, have had patients. A partial response for stable disease is a little bit in the eye of the beholder, so you have a 30% reduction is needed for a partial response. I, for one, had a patient who was about a twenty-pegged at a 25% response, who seemed to have excellent control. And his ctDNA, which we'll get into later, had turned negative. So he went from being able to detect cancer in his blood to being persistently negative.
So in my discussions with the patient, I was considering potentially someone who's potentially had a complete response, because we all the time will see patients who receive immune approaches, who might have scar tissue that we really can't adjudicate whether it's alive or dead, but we see it on imaging, so we have to report it. So I think the key here is that many patients are having their tumor shrink, and then that is leading to a progression-free survival that is far better than historical controls. We're at 8 months for an immune- basically an immune-only approach, compared to 3 months with Keytruda alone. And with our most aggressive treatments, either the Extreme chemo regimen or Keytruda plus chemotherapy, we're only at 5 months.
So, looking like a better progression-free survival, potentially compared to any of those modalities. Whenever we're adding, as I alluded to, whenever we're adding a new treatment, we have to be concerned about potentially broadening toxicity or deepening toxicity. The nice thing here is we're seeing only 13% of patients had grade 3 treatment-related adverse events. If you look on the left, the adverse events, along with the PDS0101 injection, are really what one would expect from any kind of vaccine approach. You know, a flu vaccine would probably have very similar adverse events if it was reported. We can see other AEs of note that we think of with standard of care immune therapy, at least to my eye, kind of parallel our usual experience.
So it doesn't appear that we're seeing a new safety signal or a synergy with increasing the side effect burden for patients. And that's really highlighted here. Comparing to the data in KEYNOTE-048, we see that the chemotherapy plus Keytruda arm had a very impressive grade 3-5 rate of 72%, which is similar to the Extreme regimen. And VERSATILE-002, the grade 3 adverse events paralleled and was very similar to Keytruda monotherapy, really, really strongly suggesting that there's not a new safety signal, and the added toxicity is really equivalent to the short-term effects of a vaccine approach.
So really, really to highlight, we're seeing in this phase II study, a great increase in the 24-month overall survival, significantly more than double the historical control and historical standard of care. Similarly, at one year, it's markedly improved. We're not appearing to broaden or deepen toxicity, so potentially this could represent a new standard of care and really goes to show why a phase III study has to be performed to hopefully bear out these results.
Great. Thank you so much, John. Really appreciate those insights. Katharine, I'll turn it over to you so that you can provide our listeners with an overview of our plans for the phase III VERSATILE-003 study.
Wonderful. Thank you, Lauren, and good morning to everyone. It is certainly a pleasure to be here this morning and to be serving as the global PI for our upcoming phase III study. VERSATILE-003, as mentioned previously, is designed to be a confirmatory trial for VERSATILE-002, which we just heard about. The official study title is listed here: a phase III open-label randomized study of PDS0101 plus pembrolizumab versus pembrolizumab alone in first-line treatment of immune checkpoint inhibitor-naïve subjects with recurrent or metastatic HPV-16-positive head and neck squamous cell carcinoma. The VERSATILE-003 phase III study design is shown on this slide. This is a global study with approximately 90-100 sites planned across the globe. The targeted indication will be for the treatment of recurrent or metastatic HPV-16-positive head and neck squamous cell carcinoma, with a primary endpoint of overall survival.
I just draw your attention to the randomization plan at the bottom of the slide. You can see that twice as many patients will be enrolled in the interventional arm, which is the combination of PDS0101 plus pembrolizumab, versus the control arm of pembrolizumab alone, as established in KEYNOTE-048. This is a randomized study, so neither investigator nor patient get to decide which treatment arm they go in. This is determined by a computer algorithm.
You can also note that there is no crossover allowed in this study, meaning that subjects who have received the pembrolizumab alone in the control arm will not have an opportunity to receive the investigational treatment so as to allow a clean comparison of overall survival. The primary objective is overall survival between the investigational and the control arm, and we have a number of secondary objectives. We have efficacy objectives, including progression-free survival, objective response rate, and duration of response, and these will all be assessed between the arms by blinded, independent central review. Importantly, we are also collecting robust quality-of-life measures, which is an increasingly important objective for cancer therapeutic trials, as we know that many of our treatments can affect quality of life.
We have a number of validated measures that are listed here that will assess both global quality of life as well as head and neck-specific quality of life, and we will be looking at the time to deterioration in these scores. We have robust safety analysis for the phase III study, which include both clinical and laboratory assessments, and a number of very interesting exploratory objectives, and I will highlight a few of these, specifically. Disease control rate is a combination of the percentage of subjects who have a complete response, a partial response, and stable disease. This is a way of assessing not just the objective response rate, which we just heard is not always reflective of what happens to patients, but really to get a sense of how many patients are having some benefit from treatment.
This also captures, in a formal way, a stable disease, incorporating that into the assessment, and we know that just stabilizing disease can be very meaningful for patients, particularly if they have a lower volume of cancer and are not symptomatic from it. So this will be formally assessed as an exploratory objective. We will also be looking at progression-free survival, too. We heard a bit about what that is from Dr. Mesía. So this is the second progression after randomization, with the first progression point being the progression on the study itself. We will continue to follow all of our subjects to see when they progress after their second-line treatment, if they go on to receive second-line treatment. And the idea behind this is that subjects who receive immunotherapy upfront may potentially have modulation in how they respond to subsequent anticancer therapies.
We will also look specifically at immune responses for the efficacy measures that have been formalized by the iRECIST criteria. We will be collecting, prospectively, ctDNA HPV DNA. I will defer that discussion to my colleague, Dr. Hanna. We will have robust immune correlates and look at changes in HPV-16-specific immune responses. And very interestingly, we will be looking at healthcare utilization with some of our sites that will be enrolled. We know that financial toxicity is extreme for a lot of our patients who get cancer treatment, and so this study will actually be prospectively looking at healthcare utilization and trying to get at that question of financial burden and toxicity. Here is the study treatment schedule.
The intervention arm will receive a combination of PDS0101, given as 1 milliliter subcutaneous injections every three weeks, along with standard dosing of pembrolizumab, 200 mg intravenously every three weeks. This study treatment schedule is identical to that in VERSATILE-002, with the first 4 cycles receiving the combination of PDS0101 and pembrolizumab. Patients then go on to receive pembrolizumab monotherapy for cycles 5 through 11. There is a booster of the combination given at cycle 12, and then the remainder of the study is pembrolizumab alone until progression. The control arm is pembrolizumab alone the entire time, conducted in the pembrolizumab monotherapy arm of KEYNOTE-048. Key inclusion criteria include adult patients with pathologically confirmed squamous cell carcinoma of the head and neck. Subjects will have unresectable, recurrent, or metastatic recurrent disease, with at least one lesion that is considered measurable.
Subjects are required to have HPV-16 positivity, as this is the target of our investigational agent, and this will be conducted by central testing. Subjects also are required to have PD-L1 expression, resulting in a CPS score of greater than or equal to 1, and this will be done by local testing through standard assays. Subjects cannot receive any prior immunotherapy and need to have a good performance status. In terms of key exclusion criteria, prior HPV-specific immunotherapy or immunotherapy in general by standard agents is not allowed. Patients who have received the preventative HPV vaccine as children or adults will be allowed to enroll, as that is not considered a therapeutic vaccine. Standard washouts will be present, meaning patients who have received chemotherapy or other anticancer therapy within 30 days will be excluded.
Major surgery within 38 days will be excluded, and radiotherapy will require washout periods, depending on the extent of radiation. Subjects cannot have received a live vaccine within 30 days, including measles, mumps, rubella, rabies, or the intranasal flu vaccine, and we will exclude patients with active central nervous system metastases, but patients who have had treatment of brain metastases that are neurologically and radiologically stable will be allowed. Here is the timeline to registrational trial initiation. You can see that this work has started for a couple of years already, and we are currently in the third quarter of 2023, having received feedback from the FDA to allow initiation of VERSATILE-003. We have started initiating site activation and related clinical and operational activities, with a goal of enrolling our first patient by the end of the year.
I will turn things over to Dr. Hanna.
Thanks so much, Katharine, and to Lauren and the other speakers, for all of this exciting work. I just wanted to spend some time clarifying the importance of the HPV ctDNA biomarker component of the trial by giving you all a flavor of where the work has led to at this point. So we'll summarize a pretty lengthy body of work in just a couple of minutes. But just keep in mind, so the idea here is that digital droplet PCR technology has come a long way and has made it feasible to monitor HPV DNA within the blood and plasma. We can detect high-risk subtypes, namely 16, for the purposes of the VERSATILE study, but also other subtypes like 18, 31, 33, 35, et cetera.
So that has obviously made this an appealing, viral-specific biomarker to monitor, in complement to other traditional measures of response and outcome. So this work began largely with the most widely available commercial assay that is available from a proprietary standpoint at this point, which is the NavDx or Naveris assay. This is a tumor tissue-modified viral HPV DNA probe towards the five high-risk subtype sequences. And this data just summarizes here what we know from baseline patients. So these are patients who are pretreated with curable disease. And what we've learned is that patients with higher lymph node disease burden often have a greater degree of shed and greater disease detectability in terms of HPV DNA testing.
Further, you can actually use HPV DNA, and again, this, this is summarized, the TTMV-HPV DNA NavDx assay work that was done by Bhisham early on at UNC and colleagues in the south. Basically showing that if you have HPV DNA that is detectable initially, and you follow that over time, for patients who become undetectable, that usually correlates with good outcomes, as one would expect. And patients who have greater than 95% viral clearance from baseline by week four or five, which is late into treatment, generally demonstrated low risk of recurrence, particularly if they maintained a negative or undetectable level. Further, we've also learned that baseline levels can give you some information about prognostication.
This is evolving, an evolving space, but importantly, the biology here is that HPV is an episomal virus initially, which means it sits outside the nucleus, but when it gets integrated into the genome, or into the genome of the cell, we call that integration, and it's non-episomal DNA at that point. We know that those patients are more likely to shed lower numbers, regardless of stage or presentation, and we think that's related to adverse outcomes. So sometimes lower numbers at baseline could potentially identify patients who are higher risk. When we put this all together, patients with higher copy number to begin with, initially, the cutoff was set at 200 copies per ml, but this is an evolving target, and we're learning more as data is coming in.
Those patients who clear by 95% by week 4 or 5 of treatment, at least in the initial, reported data, seem to do better. Patients who don't clear or have low baseline values have higher relapse, relapse rates, and that translates into lower recurrent, recurrence-free survival. And so, even though this was a small observation, or a small number of events, initially, this is an important signal that may identify this as a biomarker for sort of a higher-risk population. So many of you are comfortable in the definitive setting or the curative setting with the idea that with the patients with low-risk disease who are never smokers, we're often focused on deintensifying therapy to minimize toxicity and maintain good outcomes. And we know in higher-risk HPV-negative patients, we focus on higher-intensity chemoradiation. But what about patients in the middle?
So these are people with larger tumors who may have smoked in the past, who also have HPV disease. One area that we're interested in evaluating is: can we use the HPV DNA biomarker in real time to further risk-stratify patients? Here's an example of how we are doing that on a clinical trial. This is the REACT study that's currently enrolling, about 70% enrolled here at Dana-Farber. And I'll just point you towards the middle orange box, which takes higher-risk T4 smoking patients. Again, these patients would not traditionally be deintensified on prior trials because they're considered high risk, but we use the DNA cutoffs of higher copy number and clearance to allow modest deintensification for these patients. So we're really trying to understand in this trial for the first time, can you use the HPV DNA to further risk-stratify patients over time?
And hopefully, as I'm walking you through this story, you can see how this is going to apply nicely to the VERSATILE-003 study, in which we'll be able to pair HPV DNA metrics with response and outcomes and clearance with survival. Here's just an example of a patient on our trial, just showing you that this individual had an HPV DNA score of about 232, which was above our threshold for low copy number integration. They did not clear at week 4, excuse me, by 95%. You can see they had about 14% or 15% residual DNA based on their baseline value. They did ultimately clear, but because they didn't clear by 95%, this patient received standard dose chemoradiation on the trial.
Had they cleared by 95%, we would have deescalated to 60 Gy and less chemotherapy. Here's just an example of another way in which we're using this real time. Again, thinking of how you could apply this to the VERSATILE-003 population in the advanced setting. This is a de novo metastatic patient of mine with lung metastases at presentation, who got chemo immunotherapy, and we trended his HPV DNA from a score of 21,000 down to 2 after a single cycle of treatment. So this gives you confidence, both in the clinical response the patient's having, but getting him down to undetectable should be our goal. I will mention there is ongoing data that we're working on for a population of recurrent metastatic patients to show this in a larger series.
And we're working on that report now, which will be nice to translate with the comparative analysis that will go hand in hand with the VERSATILE program. Finally, just a little bit about kinetics in the surgical setting to be comprehensive. We know that the half-life of HPV DNA is quite short, hours in fact. This is from Katharine's group and others, just showing you that after surgery, patients often rapidly decline to undetectable when the tumor is removed in the initial treatment setting, and that if patients don't clear after surgery, we know that's not a good sign, and they often have worse outcomes. Finally, much of the work in this space, as many of you may know, has been done in the recurrence monitoring setting. So these are patients who've completed their definitive treatment.
We know lots of patients with HPV disease will do well, but being able to monitor them with an HPV DNA blood test has been very powerful. Essentially, the summary point here is that generally, HPV DNA is detectable in the blood or newly detectable before and predates clinical evidence of recurrence and biopsy-proven recurrence. Many of us have those stories of our own patients. Detectable DNA generally means that the cancer will eventually show itself and that you need to find out where it is if the patient was previously negative. Here's just a summary of over 1,000 patients, retrospectively across many institutions, showing that a positive HPV DNA following a negative value in surveillance has a positive predictive value exceeding 95%. And so, and again, with longer follow-up, that number may increase further.
Finally, in terms of what is the value of a negative HPV DNA test during surveillance, this was a complementary paper to that positive predictive value data, showing that I think the key is really the survival curves. Patients who are long-term negative generally have excellent outcomes and likely do not have recurrence, whereas if you become detectable, it's a matter of finding the cancer, and you can see the, in the red curves, the survival is much worse. So this, these metrics on the left are very comparable to what you'd see with PET imaging or CT, so the assay is in many ways just as good in terms of accuracy metrics. Of course, we'd like prospective data, as everyone agrees that that's sort of the foundation of evidence-based medicine. This is a completed prospective trial using the assay as part of surveillance.
Again, this is the NavDx TTMV-HPV DNA assay, and this trial was run by myself and Dr. Eleni Rettig, a surgeon at Dana-Farber, looking at time to detection of recurrence among patients who become newly detectable and have relapse in the HPV curative setting. We are hoping to share this data soon, but this will provide some prospective evidence. So in summary, I think, should we be incorporating this into routine care? Many of us are. There is an ongoing discussion about whether this should be in our national guidelines. I would say that, give it a few years. The momentum is building and the data is strong. Should it guide the choice of whether to pursue additional surveillance imaging? This is a great question.
You know, arguably, if you have a negative first set of scans and the DNA test is negative, many would argue that you can follow the DNA test and perhaps de-intensify your surveillance strategy. It would be nice to explore that in a prospective setting. I think for the purposes of the VERSATILE program, the third point is the most important: Can we use this to inform de- or intensification strategies for higher-risk patients? Or in this case, can we monitor patients with recurrent metastatic disease on a therapeutic vaccine program with HPV DNA to understand response and survival metrics? And then one really compelling question is, could this ever be used as a screening tool?
So are there high-risk patients, like men with certain number of risk partner or sexual partners in a certain age range who've never been vaccinated, where screening for HPV DNA testing may lead to identification of cancers and improvement in outcomes? That's gonna take a career's worth of time to answer, but is something that many of us are interested in.
Great. Thank you so very much, Glenn. I appreciate it greatly. In addition to the ICI-naïve patients, it was important for PDS to assess the role of PDS0101 in extending survival in the absence of a comparator control arm in VERSATILE-002. So I'm going to take the next few minutes just to speak to subjects who have failed immune checkpoint inhibitor treatment. These are ICI-refractory subjects that have more advanced disease or more difficult to treat and really present a higher treatment bar than ICI-naïve subjects and are receiving second-line treatment for this disease. Hence, in evaluating these ICI-refractory patients, many of whom have already failed Keytruda, it really provided us with an opportunity to evaluate the contribution of PDS0101 to the survival outcomes documented with the PDS0101 Keytruda combination in VERSATILE-002.
Importantly, it was never our intention to pursue commercialization of a dual treatment combination in this population, really to be able to get more insight in terms of clinical outcomes with this combination in this population. Published overall survival rates in HPV-positive ICI-refractory cancer has been reported to be approximately 3-4 months. So the observed survival outcomes to date really can help us understand PDS's role in the promising survival rates that we're seeing in VERSATILE-002, and also helping us to inform overall survival as an endpoint in the VERSATILE-003 study that Dr. Price reviewed, as well as an overall survival endpoint for a potential triple combination study of PDS0101, PDS0301, which is the immunocytokine NHS-IL12, and an approved immune checkpoint inhibitor in this population of ICI-refractory patients.
This slide summarizes the demographics of the ICI-refractory cohort, all of whom received prior treatment with checkpoint inhibitors. 76% of them had received prior Keytruda therapy. No tumor PD-L1 expression was required for this cohort, although it is worth noting that approximately 29% of the subjects had a combined positive score less than 1. For this cohort, Keytruda monotherapy is not approved or indicated. Importantly, again, it's about how much of a treatment patients are able to receive. 48% of subjects received 4 doses of PDS0101, and a third of these subjects received 5 or more doses of Keytruda. In agreement with our data monitoring committee, we will not progress stage two of this cohort in VERSATILE-002 since no objective responses were observed. This lack of objective response suggests that tumor regression may not be necessary to enhance overall survival.
As we previously noted, we didn't have any plans to further develop this dual combination for ICI-refractory patients and are pleased with the overall survival results to date and the important knowledge gained in this population. So let's specifically get to the discussion of the overall survival rates. So on the left-hand side of the slide, I'm just reiterating what Dr. Kaczmar has already presented to you in as far as the 12-month overall survival rates. In the ICI-naive population, we're seeing 80% of patients alive at 12 months, compared to associated with published historical results of 30%-50% with approved checkpoint inhibitors. For patients who then progress on checkpoint inhibitor therapy, we now have those patients who are in our ICI-refractory cohort, and we have a 12-month overall survival rate currently at present of 56% in this ICI-refractory population.
It's important to note, as Dr. Mesía reported, that for those patients who don't receive any salvage chemotherapy in this second-line treatment setting, the expected twelve-month and published overall survival rates are only 17%. So again, this is a very encouraging preliminary signal in this refractory patient population that has metastatic disease. Importantly, despite being more advanced and having more refractory disease, only 4% of the subjects had Grade 3 treatment-related adverse events, with no Grade 4 or Grade 5 events associated with the PDS0101 Keytruda combination. As Dr. Kaczmar noted, the adverse event profile is exactly what you might expect in individuals receiving an injection with a predominance of local injection site reactions, and then the most common systemic adverse event being fatigue, which is not unexpected in delivery with immunotherapy.
These really survival and safety results to date support the initiation of our proposed VERSATILE-003 trial in the first-line treatment of ICI-naive, recurrent metastatic, head and neck cancer. I just wanna note that we anticipate activating sites by the end of the fourth quarter of this year, which is December of 2023, with dosing of our first patient in the first quarter of 2024. In this population, we have documented in ICI-naive subjects a 24-month overall survival rate of 74%. Again, as highlighted by Dr. Kaczmar, we see improved overall survival rates at 12 months, but importantly, they really appear to be quite sustained at 24 months, compared to published results of 29%.
We have supportive survival and safety data in the ICI-refractory population, which is very difficult to treat, again, supporting this treatment combination and investigation in a controlled study. We know that the combination appears to be really relatively equally well tolerated in both ICI-naive and ICI-refractory populations. The VERSATILE-002 data that we have to date supports the important initiation of VERSATILE-003 and confirmation of these clinical outcomes in a randomized controlled clinical trial with pembrolizumab monotherapy as the active control comparator. Now I will get to our panel discussion. We've had some questions that have come in. Despite starting a little bit late, we are gonna ensure that we have an adequate time to have discussion and take advantage of the expertise of the individuals who are present with us.
One of the things that I just wanna highlight is that the FDA's Project FrontRunner initiative is designed to advance the development of new oncology therapies to earlier clinical settings. So, I'd like our investigators to just briefly comment on the VERSATILE-002 survival and safety profile to date, accompanied by the potential use of ctDNA to expand the use of PDS0101 alone or in combination earlier in disease treatment. So, Glenn, I'll start with you, and then, John and Katharine, you can also weigh in as well as Ricard. Thank you.
Yeah, I mean, I think it's an exciting time. I guess my thought here, just stepping back and thinking a little bit broader, is that, you know, these therapeutic vaccination or immune targeting strategies towards HPV certainly have to start in the metastatic setting. That's our tendency in oncology, but it is really enticing to think about how we can move these forward. I think there are a number of considerations. One area I'm personally most interested in is the adjuvant setting. So for patients who have higher risk HPV disease that I mentioned to you earlier, you know, could we think about giving them chemoradiation as a standard, and then separately, in the adjuvant setting, giving them something like a therapeutic vaccine? That has a lot of appeal. You know, we've learned that that can work in other settings like melanoma.
In addition, the likelihood of a vaccine strategy to stimulate the immune system and mitigate low-volume metastatic or micrometastatic disease could be very interesting, particularly in the patient scenario where they have HPV DNA that is detectable, but your scans and your clinical exam are negative. That patient may be very ripe for early intervention of an adjuvant vaccine, like the PDS0101 platform, in order to clear disease. And then finally, I think the neoadjuvant or early adoption space, whereby you take a patient who's favorable risk, you give them a therapeutic vaccine boost, to trigger their immune system in a specific way towards the HPV virus, could really sort of decrease the need for intensive radiation. It could mitigate the need for toxic surgeries or even removal of neck lymph nodes and hopefully improve survival.
So I think there is definitely a strong interest in thinking about adjuvant and neoadjuvant or pre-surgical or pre-radiation approaches.
Well, we actually do have a neoadjuvant study that's in progress, being done at the Mayo Clinic, where individuals receive PDS0101 alone or without pembrolizumab, prior to definitive therapy. Dr. Price is involved in that. Katharine, could you maybe comment on the interest and the conduct of the study that's going on at Mayo?
Sure. So we are very excited about this study because to date, we, you know, really haven't had any prospective data of PDS0101 kind of before people get treatment. So, this study is answering that really important question. And I think we know from just immunotherapies in general that, you know, not just head and neck cancer, but other, solid tumors, that moving immunotherapy earlier in this disease course seems to have a greater magnitude of benefit, so it makes a lot of sense. And, you know, patients are really excited about this type of treatment. I just also wanted to comment, you know, just to kind of give a flavor for, you know, real-life treatment of patients.
If we think about using PDS0101 in the first-line recurrent metastatic setting, so these are patients who have been through, most of them, curative intent treatment that's multimodality and very intensive. So they may have had intensive radiation and chemotherapy or surgery followed by radiation, and radiation and chemotherapy. So, you know, it is really important to try to find treatments that aren't going to add a lot of cumulative toxicity too early because patients basically carry forward all of the toxicity that they've had over the course of their lifetime of cancer treatment, and that's why it gets hard to give people treatments, you know, after first line, potentially. So, you know, there's a lot of excitement. Patients come looking for alternatives to chemotherapy. So this isn't, you know, just an interesting science question. It really is meeting an important need of our patients.
The use of ctDNA, I think, is just going to add a level of understanding to help us because we really struggle with imaging responses to immunotherapy. We've all had patients that are clearly benefiting clinically, and they're not quite meeting the criteria for a 30% decrease in tumor volume. You know, so it's going to add a very elegant and really important piece of information to try to understand who is benefiting from these treatments.
Great. Thank you so much. We had an inquiry, a question, regarding data that was released and presented yesterday at ASTRO, that examined ctDNA declines in subjects receiving PDS0101, along with standard of care chemoradiation therapy, for cervical cancer in the phase II IMMUNOSERV trial performed by Dr. Ann Klopp and her colleagues at MD Anderson. And what was reported was there was a decline of over 97% in subjects who had received PDS0101 in combination with standard of care chemoradiation. In contrast, and not a direct head-to-head trial comparison, this is just utilization of samples, individuals who only had standard of care chemoradiation therapy at week 5, 53% of them were still positive.
The specific question was: "Oh, well, could ctDNA be a biomarker that could be used for accelerated approval?" I don't think that we're at that stage. Maybe Glenn, you can just briefly comment on that. I do know that in the case of a different chronic infection, not associated with malignancy directly, HPV, HIV infection. Once we had the ability to directly detect HIV-1 RNA in copies per ml, and then in prospective studies, monitor treatment outcomes and see that declines in HIV-1 RNA were associated with improved survival outcomes, that really transformed treatment. I don't think we are at that stage. I think we're still in the very early stages of assessing this biomarker.
Glenn, I'm interested in just your ideas in terms of what it might take for ctDNA to be a biomarker for accelerated approval.
Yeah, I totally agree, Lauren, that it's- we're not quite there, but I do think the, the momentum is gaining at this point. I think there are a number of prospective trials going on at, at several institutions, including some of our own, for the, the investigators here, that are using the assay prospectively. Certainly, the trial I mentioned, REACT, is under an IND, so the FDA has reviewed that as a critical biomarker for patients to make a treatment decision. So that's an important first step.
So I would say if trials like this one, VERSATILE-003, and other large, HPV-focused studies in head and neck cancer start using the assay and show important complementary, outcome data that correlates with HPV DNA decline and clearance, I do think in the future, we could see some, potential accelerated approvals for HPV DNA as an important, integral biomarker. But I think that's probably a couple of years out on the horizon. I do think VERSATILE-003 can be a, you know, sort of a, pillar in, gaining some momentum for, that potential with the FDA.
Great. Thank you so much. There's another question that came in, regarding any outcome and efficacy differences that were seen in the ICI-naïve subject population when we looked at individuals who had CPS scores 1-19 versus greater than or equal to 20, and it was not included in the data presented by Dr. Kaczmar, but I can tell you that we performed that analysis, and we did not see any difference at all in terms of the 12-month overall survival rates, among those two subpopulations, that are in the ICI-naïve cohort.
It appears that individuals who have a lower CPS score of 1-19, who historically do not respond as well as those who have greater than or equal to 20 with Keytruda monotherapy, appear to be responding equally well in terms of the survival outcomes we've been able to document to date when the combination of PDS0101 and Keytruda is delivered together. There's another question regarding any theories as to why the PFS and overall survival data might be diverging from objective response rates in the patients who have received treatment.
One of the things that I would just like to highlight for our listeners is that we have documented in our preclinical studies that delivery of PDS0101 is associated with CD8 T cells tracking to tumor, associated with alteration in the tumor microenvironment, invasion and infiltration of the T cells, tracking to HPV positive tumors, that actually reverses the immunosuppressive ratio of T regulatory cells and CD8 T cells, so that we're able to overcome that immunosuppressive environment by the infiltration of T cells. Importantly, that's been objectively documented in a phase II study. Again, the phase II study being done by Dr. Klopp at MD Anderson reported last year at SITC that there was documented tracking of CD8 HPV-16 specific T cells to the cervical tumors, and importantly, that it was associated with declines in ctDNA.
At the upcoming ESMO meeting, we're also going to be able to highlight the fact that in VERSATILE-002, we are seeing induction of multifunctional HPV-16 specific CD8 T cells. And hopefully, from the neoadjuvant study being done at Mayo, we'll not only be able to assess these HPV-specific responses in ctDNA, but in those patients who undergo surgical resection, we'll be able to assess pathologic response. So I believe that that's kind of the mechanisms behind why we may be seeing these divergences in terms of other objective responses and the clinical outcomes.
Pardon me, Dr. Wood. Just want to let you know there are some questions over the phone as well, so when you're ready to take those questions, please let me know, okay? Sorry to interrupt you, doctor.
Okay. Well, let's go ahead and do that because we're at 9:14, and I wanted to be able to try and sample questions from that are coming in, that are typed in. So, let's go ahead and hear from our first listener who wants to pose a question.
Thank you. First question is coming from Joe Pantginis from H.C. Wainwright. Your line is now live.
Hi, everybody. Good morning, and thank you for taking the question and great details today. So, you know what, Lauren? You just addressed a key part of my question with regard to the mechanism of action, and hopefully, looking forward to some more translational data, linking, say, the lack of response in the ICI-refractory population to say, you know, pseudoprogression and what have you. So I want to link your mechanism question to sort of the real world and clinical settings. So the call mentioned today, you know, other potential issues with responses, you know, scar tissue being one of the examples. You know, struggle with imaging was one of the things that has been mentioned.
So I'm just curious now, as we look at VERSATILE-003, and then to hopefully the real-world setting, if approved, you know, how prepared is, you know, the clinical—I'm sorry, the site investigators as well as the broader doctor population to deal with these kinds of issues, or issues in quotation, you know, to not necessarily take patients off too quick if they see some relative, say, progression or lack of response, even though survival is the primary endpoint?
Thanks for that question, Joe. So I wanna highlight that, on VERSATILE-003, ctDNA will be an exploratory biomarker. It has tremendous potential, and we will be examining ctDNA, but it's not going to be available to be able to influence decisions for patients enrolled on the trial in real time, because we really don't have enough information about this as a biomarker. We do know that individuals may experience pseudoprogression on VERSATILE-002. There was one report from an investigator of an individual that appeared to have pseudoprogression, and the design of the trial is such that individuals are able to be monitored until they meet full criteria for both clinical as well as imaging progression, according to investigators.
I think your comment about how this relates to the real world is an excellent segue, and maybe Dr. Kaczmar, Dr. Mesía, Dr. Price can just briefly comment in terms of where you all are right now in the use of ctDNA, potentially as a biomarker of residual disease or potential recurrence, and how you have adapted it so far in terms of the practice and care of your patients.
Yeah, I'm happy to start. Again, and I think to that question, in terms of pseudoprogression and whatnot, and the sites that are gonna be included in the phase III study, I really think investigators in this day and age are very comfortable with understanding these situations. You know, early on in the immune era, patients might have been taken off study just for simple progression, but there's a lot more nuance to it now. And, you know, and I think I can speak for the other investigators that, you know, we really look at the whole picture, and if a patient seems to be clinically benefiting, we'll generally continue them on study and confirm progression. And in terms of ctDNA, you know, from my practice, I'll use it.
My light went off. I will use it when I'm seeing responses to kind of confirm that. I don't use that for all my recurrent metastatic patients by any means. And sometimes when there's a question where maybe just some lymph nodes are increasing and other diseases stable, to get an early sense, like, are they starting to progress, or are they actually starting to have a response? And I've been able to use that to make, you know, treatment decisions outside the context of a clinical trial. But you know, I agree, in the recurrent metastatic setting, it really is something that we need more data.
This study is gonna be really important, the phase III study, in really correlating that with scans and helping, you know, further the management of patients with ctDNA for HPV.
Great. Ricard, do you have any comments about how you all are utilizing ctDNA over in Europe, and in Spain?
It's on investigation because we don't have reimbursed ct and HPV in our hospital, so we are using in clinical trials or in public investigation, not only in Europe, in all Europe, yes.
Great. Thank you so much. I have—it's now 9:19. I wanna be able to get at least one more question from an audience standpoint, particularly since we started late. So, Kevin, let's have another call.
Sure.
I'm sorry that I'm not gonna be able to get to all of the written-in questions as well as those who may be waiting to call in.
Our next question is coming from Louise Chen from Cantor Fitzgerald. Your line is now live.
Hi. Thank you for the presentation, it was very informative. Dr. Wood, I wanted to ask you how you're thinking about your phase III design, and then how easy or hard will it be to enroll ICI-naïve patients? Last question is just on biomarker: Are you gonna have one in the phase III study? Thank you.
Yes. Okay, so, to answer the three questions in one as quickly and as efficiently as I can regarding VERSATILE-003. Again, we had clearly heard back from the FDA that the pivotal study would need to align with overall survival as the primary endpoint, and we believe the VERSATILE-002 data that we're seeing in both ICI-naïve as well as refractory patients that I've highlighted is aligning that really indeed should be the primary endpoint of the study. We feel that a 2-to-1 randomization will provide the opportunity for us to be able to have individuals access the PDS0101 and Keytruda combination in the VERSATILE-002 study, such that we can maximize the interest and accrual.
You talked about how hard or difficult it's going to be to be able to recruit ICI-naïve subjects. I can tell you that, despite COVID and some delays during COVID, we were able to accrue the subjects in the ICI-naïve cohort within 24 months. We plan a larger global study of 90-100 sites, and with the anticipated screen failure rates that we know have been pretty much tracking exactly as we predicted them, we think we have a very good handle on our accrual timelines, and how the study will progress. Your third question was about biomarkers, and yes, we are gonna have, as I mentioned previously, the exploratory biomarker of ctDNA at sub-study sites, as part of VERSATILE-003, because it's an emerging biomarker, very exciting.
We don't quite know all of its limitations yet, how it may correspond to treatment outcomes, and that's one of the things that we're seeking to answer with the VERSATILE-002 study. It is now 9:22 A.M., and so I do want to be respectful of everyone's time since we did start late. I really want to give my thanks again to Ricard, John, Katharine, and Glenn for your insights and overview this morning. We are in a very difficult space for these patients with recurrent metastatic disease. We really desire that we can impact their lives. All of us are working towards, as John said, helping patients live longer and hopefully live better. I do want to thank everyone for their participation in today's discussion. That concludes our program today.
Again, I'd like to thank everyone, our esteemed panelists, for being with us. PDS Biotech, again, is committed to ensuring that the study of PDS0101 and HPV positive cancers continues to mature so that more patients can potentially access a safer and effective treatment option for physicians as quickly as possible. An audio recording of today's session will be available on the PDS Biotech website for 90 days. You can access that recording at www.pdsbiotech.com. Again, I thank you for your interest and participation in today's session, and we will also try and address written comments with our colleagues who have written in, and we didn't get to answer your questions during the webcast. So thank you so very much, and have a great day.
Thank you. That does conclude today's teleconference webcast. You may now disconnect and have a wonderful day. We thank you for your participation today.