PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

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. [Operator Instructions] 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 Mesia 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. For a discussion of these risk factors, please refer to PDS Biotech's SEC filings. Investors, potential investors and other listeners are urged to consider these factors carefully in evaluating the forward-looking statements and are cautioned not to place undue reliance on such forward-looking statements. Please note that the content of this webcast contains time-sensitive information that is accurate only as of the date of the live broadcast today, October 3, 2023. Except as required by law, the company undertakes no obligation to revise or update any statement to reflect events or circumstances that take place after the date of this call. It's important for all attendees to be aware that PDS Biotech is the sponsor of this roundtable and webcast. 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 Mesia 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-002. 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. Mesia 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 HPV16 targeted immunotherapy PDS0101 delivered in combination with KEYTRUDA, also known as pembrolizumab in immune checkpoint inhibitor naive subjects. Dr. Price will follow with the overview and study design for the planned VERSATILE-00 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. [Operator Instructions] Welcome to Ricard, John, Katharine and Glenn. And with that, I would now like to turn the meeting over to Dr. Mesia. Ricard?

Thank you, Lauren, for your nice presentation. I'm going to introduce the current treatment of HPV16 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 to more characteristic that include tumor burden and PD-L1 value and measure-wise CPS. HPV status is not included up to now in this discussion. So with equally HPV-related and HPV nondirected 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 2 months. In platinum-sensitive patients, we decide according to the PD-L1 value. In CPS, over or equal to 1, we choose between pembrolizumab or pembrolizumab associated with the combination of chemo with platinum or fluorouracil and sometimes in the States fluorouracil is changed by paclitaxel. To choose between pembro or the combination of chemo plus pembro, we usually use clinical criteria such as the tumor burden by adding chemotherapy in those patients who are very symptomatic of what at high risk of some complications. In second line and posterior, we use a different combination of chemo plus/minus cetuximab, who have moved the first line -- the all third line to the second line. For patients with CPS less than 1, we maintain the all standard treatment with EXTREME or TPEx market in Europe, despite we don't know the effect of cetuximab in the HPV-related patients with recurrent metastatic disease. And we usually use nivolumab in the second line when the patient recover. Median OS in patients with a sensitive tumor is 12 to 15 months, depending on the CPS value and medium PFS, it's from 3 to 5 months based on the pivotal KEYNOTE-048 trial. The reason to maintain the combination of chemo plus cetuximab in those tumors with CPS less than 1 is based on the group analysis, the group analysis of the KEYNOTE-048 study with pembro alone. That seems to be regimental in overall survival. You have here in the core of the left and 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 1. Despite HPV-related and non-related tumors are clearly 2 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 nonrelated. Like in the KEYNOTE-048 study where represented about 20% of the patients include in the all-comers patients. Up to the introduction of immuno-checkpoint inhibitors, we use the schedule with cetuximab regimen or TPEx regimen in Europe. The main goal here was a palliative in 10 of our treatment. And we try to improve overall survival by increasing the response rate, symptom control and of course, improves 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% to 18% of the patients who get these 5 years overall survival in patients with CPS over 1. So I think some patients could recur with ICS associated or not to chemo. So now one of the new goals of this treatment is to increase these long-term survival of our patients. Analyzing the figures of what happened in second line in the 2 most important Phase III trials in the recurrent metastatic setting KEYNOTE-048 and CheckMate 651, only about 50% to 60% of patients who started a first line with chemo received a second line therapy based on what they have received fares. This 40% of patients who do not receive a second line include the own survival that never record, but also those patients who progress and deteriorate very fast at 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 KESTREL 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 progress independently of the study arm, durvalumab or EXTREME. And those who had a stable disease have an intermedian 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 2, PFS 2 is the measure the time from the start in 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 in combination with chemotherapy seems to weather on dose for receive chemotherapy alone in the first line. The conclusion of these 2 trials is that we should select the best treatment for the first line. And to summarize the unmet needs in the first line recurrent/metastatic HPV16-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 recurrent/metastatic setting. The rest option of treatment should be administered in the first line because up to 50% may not receive the second line. And to date, today, standard of care chemotherapy or OS alone is not enough in most of our patients with an HPV-related disease. Thank you very much.

Thank you so much, Ricard. John, will let you take it from here.

Yes. Thank you. So 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. Mesia 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 carrying 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 smoking and alcohol versus the virally the ology of HPV. Importantly, when we're developing new standards of care, we're often layering treatments together. We have KEYTRUDA as the foundational 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 cell. 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. Let's 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 nonrandomized study, they 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 HPV16. 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 2 years. And then the PDS0101 was given cycles 1 through 4 and then a booster dose at cycle 12. End points 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 in the modified intention to treat population 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 PFS negative. And the majority of patients were CPS 1 to 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. And 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. And I think this is the WOW slide. We're really looking at the overall survival of 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 1 year and which is impressive, even more impressively, almost all those patients were still alive at 2 years, which is, as we'll see, is 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 and paralyzing about 30% higher on the 002 study and 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 everyone looking at a study 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 patients, a partial response for a stable disease is a little bit in the eye of the beholder. So you have a 30% reduction is needed for a partial response for 1 had a patient who was about get a 25% response who seem to have excellent control in 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 live 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 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 were only at 5 months. So looking like a better progression-free survival potentially compared to any of those modalities. And 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. And the nice thing here is we're seeing only 13% of patients had grade 3 treatment-related adverse events. And 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. Flu vaccine probably have very similar adverse events if it was reported. And 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 to 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 to highlight, we're seeing in the Phase II study, a great increase in the 24-month overall survival, significantly more than double than the historical control and historical standard of care. And similarly, at 1 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. So 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 naive subjects with recurrent or metastatic HPV16-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 to 100 sites planned across the globe. The targeted indication will be for the treatment of recurrent or metastatic HPV16-positive head and ex limos 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 a patient get to decide which treatment arm they go in. This is determined by computer algorithm. You can also note that there is no crossover allowed in this study, meaning that subjects who have received the pembrolizumab alone and 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 in stable disease. And 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. Mesia. 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 ctHPV DNA. I will defer that discussion to my colleague, Dr. Hanna. We will have robust immune correlates and look at changes in HPV16-specific immune responses. And very interestingly, we will be looking at health care 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 health care 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 3 weeks, along with standard dosing of pembrolizumab 200 milligrams intravenously every 3 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 as 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 HPV16 positivity as this is the target of our investigational agents, 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 time line 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, and we have started initiating site activation and related clinical and operational activities with the goal of enrolling our first patient by the end of the year. And 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 prepared -- available from a proprietary standpoint at this point, which is the NavDx or Naveris assay. This is a tumor tissue modified viral HPV DNA pro towards the 5 high-risk subsite 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 has summarized the TTMV-HPV DNA NavDx assay work that was done by Bhish Chera 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 4 or 5, 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 nonepisomal 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. And 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 rates and that translates into lower recurrence-free survival. And so even though this is 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 bill patients with low-risk disease who are never smokers were often focused on de-intensifying 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 de-intensified on prior trials because they're considered high risk, but we use the DNA cutoffs of higher copy number and clearance to allow modest de-intensification 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 the 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 a HPV DNA score of about 232, which was above our threshold for low copy number integration. They did not clear at week 4, 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 gray 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 that presentation who got chemoimmunotherapy 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 from a clinical response the patient is having, but getting them 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 declined to undetectable when the tumor is removed and the baseline 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 recurrent 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. And 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. And many of us have those stories of our own patients. And 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 complement paper to that positive predictive value data showing that, I think the key is really the survival curve. 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 curve, the survival is much worse. So 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 relapsed in the HPV curative setting. And 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. 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? And so are there high-risk patients like men with certain number of risk partner or sexual partners in a certain age range, you've never been vaccinated where screening for HPV DNA testing may lead to identification of cancers and improvement in outcomes. And that's going to take a courier's worth of time to answer, but it's something that many of us are interested in.

Great. Thank you so very much, Glenn. I appreciate it greatly. In addition to the ICI naive 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 naive 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 to 4 months. So the observed survival outcomes to date really can help us understand PDS' 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 immuno-cytokine NHS-IL-12 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. And for this cohort, KEYTRUDA monotherapy is not approved or indicated. Importantly, again, it's about how much of treatment patients are able to receive, 48% of subjects received 4 doses of PDS0101 and 1/3 of these subjects received 5 or more doses of KEYTRUDA. In agreement with our data monitoring committee, we will not progress Stage 2 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% to 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. Mesia reported that for those patients who don't receive any salvage chemotherapy in the second-line treatment setting, the expected 12-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 the predominance of local injection site reactions and then the most common systemic adverse event being fatigue, which is not unexpected in delivery with immunotherapy. So these really survival and safety results to date support the initiation of our proposed VERSATILE-00 Phase III trial in the first-line treatment of ICI naive for current metastatic head and neck cancer. I just want to note that we are -- 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 support of 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. And 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. So 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 going to 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 want to highlight is that the FDA's project front-runner 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 treatments. So Glenn, I'll start with you and then John and Katharine, you can also weigh in as well as Ricard. Thank you.

Yes. I mean, I think it's an exciting time. And I guess my thought here just stepping back and thinking a little bit broader is that, 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, could we think about giving them chemo radiation as a standard, and then separately in the adjuvant setting, giving them something like a therapeutic vaccine, that has a lot of appeal. 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 a patient scenario where they have HPV DNA that's detectable like 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 presurgical or preradiation 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. And 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 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 not just head and neck cancer, but other solid tumors that moving immunotherapy earlier in the disease course seems to have a greater magnitude of benefit. So it makes a lot of sense. And patients are really excited about this type of treatment. I just also wanted to comment just to kind of give a flavor for 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 in chemotherapy or surgery, followed by radiation, and radiation and chemotherapy. So 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 after first line potentially. So, there's a lot of excitement, patients come looking for alternatives to chemotherapy. So this isn't just an interesting science question. It really is meeting an important need of our patients. And the use of ctDNA I think, is just going to add a level of understanding to help us because we've 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. 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. We had an inquiry, a question regarding data that was released as -- and presented yesterday at ASTRO that examined ctDNA declines in subjects receiving PDS0101 along with standard of care chemo radiation therapy for cervical cancer in the Phase II IMMUNOCERV 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 would receive PDS0101 in combination with standard of care chemo radiation. In contrast, and not a direct head-to-head trial comparison. This is just utilization of samples, individuals who only had standard of care chemo radiation therapy at week 5; 53% of them were still positive. And the specific question was, "Oh, well, could ctDNA be a biomarker that could be used for accelerated approval?" And 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 and copies per mL. And then in prospective studies, monitor treatment outcomes and see that declines in HIV1RNA -- or 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 an accelerated biomarker for accelerated approval?

Yes, I totally agree, Lauren, that it's -- we're not quite there, but I do think the momentum is gaining at this point. I think there are a number of prospective trials going on at several institutions, including some of our own for 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 started 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. I think that's probably a couple of years out on the horizon. I do think VERSATILE-003 can be a 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 we're seeing in the ICI naive subject population when we looked at individuals who had CPS scores 1 to 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 2 subpopulations that are in the ICI naive cohort. So, it appears that individuals who have a lower CPS score of 1 to 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. And 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, will 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 wanted to let you know, there are some questions over the phone as well. So whenever 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 that are coming in, that are typed in. And so, let's go ahead and hear from our first listener who wants to pose a question.

First question is coming from Joe Pantginis from H.C. Wainwright.

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 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, other potential issues with responses, scar tissue being one of the examples, 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, how prepared is the clinical -- I'm sorry, the site investigators as well as the broader doctor population to deal with these kinds of "issues" 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 want to 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. Mesia, 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?

Yes. I'm happy to start. Again, I think to that question, in terms of pseudoprogression and whatnot and the sites that are going to be included in the Phase III study. I really think investigators in this day and age are very comfortable with understanding these situations 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 I think I could speak for the other investigators that we really look at the whole picture and if the patient seems to be clinically benefiting, we'll generally continue them on study and confirm progression. And in terms of ctDNA, from my practice, 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 disease is stable to get an early sense like; are they starting to progress? Or they actually are starting to have a response? And then I've been able to use that to make treatment decisions outside the context of the clinical trial. But I agree in the recurrent metastatic setting, it really is something that you need more data. This study is going to be really important, the Phase III study and really correlating that with scans and helping further the management of patients with ctDNA or HPV.

Great. Ricard, do you have any comments about how you all are utilizing ctDNA over in Europe?

Yes. It's only investigation, because we don't have a [ report ] ctDNA and HPV in our hospitals, so we are using in clinical trials or in public investigation only in Europe, and all of Europe, yes.

Great. Thank you so much. I have -- it's now 9:19. I want to be able to get at least one more question from an auditory standpoint, particularly since we started late. So Kevin, let's have another call.

Sure.

I'm sorry, because I'm not going to 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.

It was very informative. Doctor, what 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 naive patients? And last question is just on biomarker. Are you going to have one in the Phase III study?

Yes. Okay. So to answer the 3 questions and one as quickly as efficiently as I can regarding VERSATILE-003. Again, we were -- 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 that VERSATILE-002 data that we're seeing in both ICI naive as well as refractory patients that I've highlighted is aligning that, that really indeed should be the primary endpoint of the study. We feel that a 2:1 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 naive subjects. I can tell you that despite COVID and some delays during COVID, we were able to accrue the subjects in the ICI naive cohort within 24 months. We plan a larger global study of 90 to100 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 time lines and how the study will progress. Your third question was about biomarkers. And yes, we are going to have, as I mentioned previously, the exploratory biomarker of ctDNA at substudy 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 in 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.

That does conclude today's teleconference and webcast. You may now disconnect, and have a wonderful day. We thank you for your participation today.