Good afternoon and welcome to the Oncolytics Biotech Key Opinion Leader Webinar. At this time, all attendees are in a listen only mode. A live question and answer session will follow the formal presentations. If you would like to submit a question, you may do so by using the Q and A text box below the bottom of the webcast player. As a reminder, this call is being recorded and a replay will be made available on the Oncolytics website following the conclusion of the event. I will now turn the call over to Jared Kelly, Chief Executive Officer of Oncolytics Biotech. Please go ahead, Jared. Thank you very much, and good afternoon to everyone. Thank you all for joining our KOL event today. I want to especially thank our panel of experts here and all the investors and analysts who are gathered here t o s peak about the emerging role of pelareorep in GI cancers, including, of course, pancreatic cancer. I have the forward-looking statement slide we just passed by. Everyone should just take a quick look at that and read it on your own time. The agenda today, the first half of today is going to include presentations from our panel. We're going to start with Dr. Eggermont and go through that again. That's about 30 minutes worth of time. The back half of this event, another 30 minutes, will be a Q and A session that I will moderate. It's questions coming from our analysts and from the investor community, as well as internal questions. We'll get through as many as we can in the time that we have allotted without going over. We really appreciate your interest and look forward to an engaging and insightful discussion. At this time I will kick it over to Dr. Eggermont to lead off our programs. Hello everybody. My name is Alexander Eggermont and I'm a surgical oncologist by training. I'm a Professor of Immunotherapy at University Medical Center Utrecht in the Netherlands. I'm on the board of the largest comprehensive cancer center in Europe, which is in Munich between the two universities there, where they have enormous pancreatic cancer activity. I will give some introductional remarks about pelareorep in the pancreatic cancer program. I will call it PELA from now on, is an oncolytic virus. It's a reovirus and it doesn't require any special handling. This is a great facilitating aspect. It targets cancer cells, not normal cells. One of the biggest advantages is that it is administered IV in contrast to many other oncolytic viruses that are out there, which need intertumoral administration, which is a big stumbling block for widespread applications and certainly not an easy thing to do in peripheral clinics. It delivers double stranded RNA into tumors and causes tumor cell death, expression of antigens, and recognition by the immune system for both angles of the immune system, the innate and adaptive immune responses. Oncolytics has a big experience with the agent in more than 1,100 patients. There are no safety qualms or concerns with this agent, which makes it an absolute first-in-class oncolytic virus agent. It has a clear registration path and strong efficacy signal in both breast and pancreatic cancer. I will focus on pancreatic cancer and it has fast track designation for both indications. As I said, non-genetically modified, non-pathogenic reovirus IV administration. Therefore, it targets both primary tumors, which are usually loaded with T cells, and metastatic tumors, meaning that you optimize the induction of immunologic memory because of your IV administration, because it can infect all tumors and you can work both with primary and metastatic tumors. It requires, as you see in yellow, no special handling. Selectively replicating cancer cells leads to accumulation of double stranded RNA, which leads to more visibility of the tumors. It induces chemokine expression and you need those chemokines for T cell and K cell infiltration of your tumor. It's one of the mechanisms by which cold or semi-cold tumor hot. It induces thereby antitumor cellular immune responses, including expansion of tumor-infiltrating lymphocytes, which they have actually also shown to be circulating and can be detected among the peripheral blood monocytes. How big is the pancreatic cancer problem? It is our biggest unmet need problem. It is in terms of incidence, number 10 on the list of all cancers. Number one is breast, second is prostate, third is lung, fourth is colorectal, pancreatic is 10th, but it's the second cause of cancer death. In 2025, you actually in the United States will have close to 68,000 new cases. More than 52,000 in 2025 people will die of pancreatic cancer. If that is not an unmet need, I don't know what is. What are we doing nowadays in advanced pancreatic metastatic cancer? We give chemotherapy and actually we give combo chemotherapy. It started with mono gemcitabine, which was superior to 5-FU, which was totally dismal. That was in the old days, but still only a one year survival of 18% for gemcitabine versus 2% for 5-FU. That's how bad the tumor is. Now, FOLFIRINOX and what you see here below, gemcitabine, nab-paclitaxel are the two most used standard first-line treatments. FOLFIRINOX was randomized against gemcitabine. It's quite toxic. Median overall survival 11.1 months vs 6.4 for the gemcitabine, the combo with paclitaxel and gemcitabine vs gemcitabine at 8.5 months vs 6.7 months, but is much less toxic than FOLFIRINOX. In second line, here below you see that in second line you basically are pretty much empty handed with median overall survival times of somewhere between four and six months. That's already very, very selective patients because most patients already died. It stands to reason that with a very good initial activity signal of PELA in combination with atezolizumab with an anti-PD-L1, you would explore to see if you can establish a new first-line treatment in metastatic pancreatic cancer. You could therefore consider PELA plus the combo gemcitabine, paclitaxel plus for anti-T cell expansion, T cell expansion and protection of their effector cell function, atezolizumab for instance in anti-PD-L1 or any anti-PD-1, or you work with the PELA plus the FOLFIRINOX combo plus or minus atezo or any other anti-PD-1, PD-L1. You would see also the analysis of the contribution of component, strong was the signal of activity. This is already my last slide. Look at this. In the GOBLET study that will be discussed in detail after me, there was the observation of a 62% overall response rate, which is somewhere between double and triple what we're used to see with the combo chemotherapies. Even more importantly, I think, is when you look at the spider plot, look at the red lines. Anybody who had a response or a very minor response or just stable disease, it is durable and this is a hallmark of active immunotherapy. Durability is what it brings on top of a 62% overall response rate as a signal. Therefore, this needs to be further developed and further explored. That's where I want to leave it at this point in time. I will be open to any other questions later, but I now first hand over to the next KOL to give his take of the state of the nation. Thank you. Hi, so I'd like to thank Professor Eggermont for his kind introduction into the role of oncolytic viruses and immunomodulatory potential of this virus. My name is Deva Mahalingam. I'm a GI oncologist with an interest in early drug development in a variety of drugs and obviously have been fortunate to work with the oncolytic viruses since I was finishing my fellowship in 2008 and 2009. I've had this kind of been working. It's nice to see this drug come along over the last 15 years. I'd like to talk to you a little bit about what we have done, at least in this space in pancreatic cancer. I'm hoping I can be with you for the Q and A after this. I'm probably in the middle of the Serengeti at the moment, somewhere in Kenya, but I would have loved to have interacted more in person. I hope to be present for the Q and A. My interest in the oncolytic virus stems from the fact that reovirus preferentially infects tumors that are especially KRAS-mutant tumors. What you can see here on the slide is that the human pancreatic epithelial cells, or HPNE cells, when we infect them with KRAS, we see more oncolytic viral replication. Subsequently, when we did mechanistic work, we found that pelareorep actually induces a strong ER stress in pancreatic cells, as you can see here on the figures with ER dilation on electron microscopy and upregulation of stress markers such as CHOP and PERK, and the disruption of ER homeostasis drives apoptosis, supporting the mechanism of action. In this slide, we did it in a variety of pancreatic cancer cell lines. You can see a dose-dependent reduction in cell viability observed, including increase in DNA fragmentation and cleaved caspase- 3 expression, confirming apoptosis. Taken together, these findings suggest that pelareorep induces ER stress-mediated apoptosis and impairs viability of PDAC cells through selective replication. At least when we were working on this in 2008, it was found to be all oncogenic RAS-driven, and hence we focused a lot in pancreatic cancer. This was the basis of our first study, which was an investigator-initiated but sponsored by Oncolytics, known as the REO 017 study, which is a single-arm phase II study, single-arm phase I/II study looking at pelareorep in combination with gemcitabine as first-line trial in advanced pancreatic cancer. Just to remind us that when the study was designed, obviously gemcitabine as a single agent was the standard of care. The trial enrolled 34 patients, mostly patients with metastatic disease. Most of them had liver metastases. The cycle was given as a 21-day cycle with gemcitabine on day one and day eight, and the virus was given on day one, two, eight, and nine. The primary endpoint was actually the clinical benefit rate at 12 weeks, with the secondary endpoints including PFS, OS, and safety. The combination was aimed to assess if there's an early sign of efficacy and tolerability in this chemotherapy-naive population. In REO 017, there were 83% of patients evaluable for evaluation for clinical benefit, and most patients had stable disease. You can see that the spider plot here shows disease stabilization with treatment duration extending up to 26.1 months. For one of my patients, one of the patients actually did achieve a partial response, while 5 had progressive disease. With a disease control rate of 83% amongst all evaluable patients and 71% in the intention-to-treat population, we felt this disease stabilization and this prolonged stabilization in some patients was in particular interesting to look at further studies in this space. One of the things we noted with REO 017 is that when we combined the pelareorep with gemcitabine, we found a median OS of 10.2 months with a one-year survival rate of 45% and a two-year survival rate of 24%. This obviously is a significant improvement to historical controls of just gemcitabine alone. These outcomes are seen actually around that time when we were finishing the study with FOLFIRINOX regimens. We think that this regimen was better tolerated. The progression-free survival was modest at 3.4 months, but we did see this durable overall survival suggestive of a meaningful long-term disease control in a subset of our patients. Around the time when we were finishing REO 017, there was another study that was done through the NCI CTAC known as the NCI-8601 trial. This was Bekaii- Saab's study along with Anne Noonan. Pelareorep was combined with paclitaxel and carboplatin in the first-line treatment. This backbone was acceptable at the time because the only other treatment option at the time was gemcitabine. They did a randomized trial looking at the PELA in combination with carbo- taxel versus carbo- taxel alone. In this study, obviously the primary endpoint was progression free survival, with secondary endpoints being the overall response rate, disease control rate, and safety. There were 73 evaluable patients. Baseline characteristics were balanced. Of note, 17 patients crossed over from the control to the PELA upon progression. This design was to see if there was some synergy between virus and perhaps a platinum based chemotherapy. This slide highlights the key findings from the NCI-8601 study. We see a near fourfold improvement in the two year overall survival in the pelareorep arm versus the control. While the median PFS, OS, ORR was similar between the groups, a delayed separation in the survival curves did emerge, suggesting an immune mediated effect. The two year overall survival rate reached 20% in the PELA arm, with just 9% in the intention to treat control arm. If you exclude the 6% of patients that crossed over, this is certainly meaningful. The late survival advantage without the early benefit supports an immunologic strategy and underpins the ongoing trials that we then subsequently did with PELA with checkpoint inhibitors as well. One of the things we noted is in a lot of the trials that we had done across multiple tumors, including pancreatic, IV administration of pelareorep was detected. We see the virus detected in nearly all tumor biopsies, showing almost 100% presence in pancreatic and breast cancer samples. This demonstrates consistent tumor targeting and replication of the virus. This IHC image you see here is from a breast cancer patient and highlights the brown staining of the virus in the tumor cells but not in the surrounding stroma, confirming the selective localization within the malignant tissue. These data obviously underscore pelareorep's preferential uptake and activity in the tumor microenvironment. This study is obviously the study which I did, which is the REO 017 study. One of my patients on the study had this prolonged clinical response. We did a biopsy and I encouraged him if he would be okay if we did a biopsy from the primary pancreatic tumor because we wanted to see whether the virus can actually penetrate the dense fibrosis and get into the tumors itself. This is what we showed is that like. We can see that the virus is replicating in the tumor. On the top left, we see it causing caspase activation, but importantly, we see this induction of PD-L1, which offers a compelling rationale for combining pelareorep with immune checkpoint inhibitors in pancreatic cancer. This led to the subsequent trial I'm going to talk to you about next, which is REO 024. The plan of this study was to evaluate the safety and feasibility of pelareorep with pembrolizumab and chemotherapy in the second-line setting, given the landscape had changed at the time with gemcitabine, nab-paclitaxel, and FOLFIRINOX in the front-line setting. This was a single-arm study that enrolled 11 patients, median age of 64. A lot of them were female patients. The chemotherapy backbone was physician's choice because it was a second line between gemcitabine, 5-FU, or irinotecan, often depending on what they got in the first-line setting. PELA was given on day one and two, and pembro on day eight on a 21-day cycle. The primary endpoint was safety and looking at the dose-limiting toxicity. Despite the small sample size, we established that this combination was safe, including patients in the second-line setting. In fact, we enrolled these 11 patients very quickly, I think within six months. This is some of the efficacy data. You can see a lot of patients with one partial response, a few patients with stable disease, so certainly we know that when added to PELA and pembro, it's safe. We are starting to see some activity in at least a subgroup of patients that we did here, as you can see in the waterfall and the swim plots outlined here. This led to the next study because one of the questions we had was whether we could drop the chemo and just see the same effects of just the virus and immunotherapy. Thirteen patients were enrolled, 12 were evaluable for efficacy. The treatment involved sequentially using PELA on days one, two, three, and eight of cycle one, followed by pembrolizumab starting on day eight. We wanted to sequence this as well. None of the patients included had MSI-high, and the study focused on overall response rate with secondary endpoints including PFS and OS. Obviously, this study, as you can see here, we found that PELA and pembrolizumab without chemotherapy in the second-line setting, the objective response rate was modest, 8%, but the disease control was about 42% of the patients had a good disease control in this microsatellite stable population. Importantly, immune correlative studies that we had done, which I'm going to show, which we reported in the manuscript, showed that we see T regulatory T regs reduction and increase in PD-L1 intensities, especially in responders. We believe that this provided this kind of immunomodulatory signature that might provide a combination strategy, especially if we decide to move this combination into frontline therapy with chemotherapy. Of note, one of the biomarkers of interest is obviously looking at peripheral T cell clonality. We actually found that in patients after one cycle of treatment, if they had a higher peripheral T cell clonality, they were associated with a better responder and actually improved survival as well. This is suggestive that this reactive T cell clonality assay might be a predictive marker for looking at patients that might actually be the survivor and can be incorporated into any trials that we may intend to do in this space as well. This is my last slide and I would like to thank you for your attention. I'm glad that a lot of the work here led to the subsequent trial, which is the GOBLET trial that Dr. Arnold, I'm looking forward to listening to his updated data on the study as well. Thank you very much. Dear colleagues, my name is Dirk Arnold. I'm Director of the Asklepios Tumorzentrum in Hamburg, Germany, as well as one of the main investigators of the AIO, which is a collaborative study group. I do have the privilege to present you some of the most recent GOBLET data with specific attention to pancreatic cancer, which we have presented at the European Society for Medical Oncology Congress in 2023. What is GOBLET? GOBLET is a basket trial. It's a pan gastrointestinal cancer trial. We are now looking specifically to the cohort which is examining first-line metastatic pancreatic cancer. PELA plus gemcitabine plus nab-paclitaxel plus atezolizumab. It's a full drug combination. Two immunotherapies, PELA plus atezo, and two chemotherapies, gem and nab-pac. It's a single-arm cohort and the primary endpoint of this combination is to assess objective response rate. Secondary endpoints are progression-free survival, overall survival, and disease control rate, of course, as well as safety. Let's have a look to the study population. So far, what we can report, they do have a median age of 63 years. They're predominantly male and notably all patients had metastatic disease. Nearly 7 out of 10 patients had liver metastases. What are the efficacy summaries before we go more into the granular data? Let's have kind of global overview. The response rate has been 62%, the disease control rate 85%, and 45% of all patients were alive at one year. There were no treatment-related safety concerns. We will also, let's say, lose some thoughts about potential biomarkers, specifically on the expansion of the tumor-infiltrating lymphocyte clones which seem to correlate with response. Going to more granular data. That's response, so that's objective response and the 12-month survival rate. You can see in this spaghetti plot as well in the waterfall diagram on the right-hand side the really stimulating data of overall response rate of 62%, disease control rate of 85%, and as I have said before, the 12-month, excuse me, overall survival rate is 45%. Really great signals for efficacy. Let's look specifically a bit on patients and responding patients. We haven't seen a clinical pattern of any patient group which benefits more or less. Of course, it's still a limited number of patients but we can see responses across all metastatic sites, liver, peritoneum, lung, and also lymphangitis. Therefore, very difficult to say. Obviously, liver metastatic sites seem to respond as well as others and that's important. The overall response rate in liver metastases only is 56%, nearly one-to-one correlating to the overall response rate. Looking at toxicity and safety signals, the predominant toxicities are immunotherapy-related, low-range or low-class acute reactions like pyrexia, chills, and also some temporary fatigue. There have fortunately been no higher grade three or four treatment-emerging adverse events, maybe except neutrophil count decreased. Please have in mind that this is a four-drug combination of two immunotherapies and combination chemotherapy. The most common adverse events are flu-like symptoms and GI symptoms, and most of them are grade one and two or transient. Coming to the biomarker aspect, that's a graph showing the tumor-infiltrating lymphocyte expansion in patients' blood. What we can see here is that the pre-existing tumor infiltration expansion in blood increases at cycle two to four compared to cycle one to two. Obviously, the expansion in blood is a result of the treatment for a certain time, and interestingly, this corresponds with the decrease of tumor size. It's not a perfect biomarker because we don't see these before we start to treat the patient, but it may be correlating to the mechanism of action as we can see that the TIL expansion in blood continues at least through cycle three of therapy, and the TIL clonal expansion in the blood seems to correlate with a reduction of tumor volume. Thank you for attending. Hi, thanks for having me. I'm Sanjay Goel. I'm a medical oncologist at the Rutgers Cancer Institute in New Jersey. Just as a brief introduction, I've been working with pelareorep for probably close to 20 years now, and I'll briefly explain our work in colorectal cancer. Just to give you a brief idea about the burden, it's the second most common cancer among men and women, responsible for close to 53,000 deaths in the U.S. alone. 96% of metastatic colorectal cancers are what are considered microsatellite stable. I'm not going to go into the details of pelareorep because that's already been discussed by prior presenters. I'll delve right into the work that we've done. We started working on this several years ago and I've highlighted some of the important results. We looked at several colorectal cancer cell lines that were both KRAS- mutant and KRAS- wild type, and we were also fortunate enough to have a cell line that is isogenically similar, except for the KRAS gene, and the parent cell line is HCT 116. The cell line that is lacking the KRAS- mutant gene is HKE3. This is essentially KRAS wild type. Through a series of several experiments, what we discovered was that when we expose a panel of cell lines, several of them to pelareorep at different concentrations, we find that overall, cells that carry a KRAS mutated gene essentially are more susceptible to pelareorep than wild type, as is shown on this graph. To the right is the susceptibility of these isogenic cells to increasing doses of pelareorep as we go from the left to the right, and again, what we can see essentially is that even though mutant and wild type cells are susceptible to pelareorep, the mutant cells shown in blue have a greater degree of inhibition as compared to the KRAS- wild type. Similarly, when we look at TUNEL staining, which is a marker of apoptosis, looking at the isogenic cells, on the left is the KRAS- mutant panel that shows a greater degree of apoptosis as compared to the wild type cell. Finally, mechanistically, we found through Western blotting and other experiments that it induces apoptosis in a caspase dependent manner. We also then look to see whether we can demonstrate synergy with irinotecan again with the objective of developing the drug in colorectal cancer. What we essentially found is that in 12 of the 13 cell lines, using a test called the combination index, we found that 12 of the 13 cell lines were the combination was synergistic except in one. The synergy was mediated by p21 as shown in the western blot on the top right. The synergy was also visible when we tested for apoptosis, showing that the combination has a greater degree of apoptosis again both in the wild type and in the mutant cells. This represents wild type, this represents mutant. Finally, taking this into xenograft models with the CT116, this is a classic model. I'm not going to elaborate, but we clearly see a greater degree of tumor control with the combination. Based on this, we hypothesized that possibly pelareorep can sensitize microsatellite stable colorectal cancer to the effect of immune checkpoint therapy. Essentially, we began a series of experiments. We had two syngeneic models: CT26, in which CT26 cells are injected into BALB/c mice. This is KRAS mutant and microsatellite stable. MC38 cells injected into the C57BL/6 mice. This is KRAS wild type and microsatellite unstable. To summarize, what we see is that when we use the combination it is synergistic as shown in the purple line. Here the combination is synergistic in the cell line that is KRAS- mutant and microsatellite stable, whereas in the cell line that is microsatellite unstable and KRAS- wild type, the checkpoint inhibitor is highly active as shown by the green line, that the combination really achieves nothing more, so there's no real combination activity in the microsatellite unstable cell line. Similarly, we did other experiments showing the synergistic effect in induction of dendritic cells, monocytes, and in suppressing macrophages by the combination. Going on further, we show a decrease in Ki67, an increase in cleaved caspase- 3, and an increase in TUNEL staining in the combination, but only in the cell line that is microsatellite stable and KRAS- mutant as shown on the left panel. Cells that are microsatellite unstable and KRAS- wild type, we do not see the synergistic effect. To conclude, I would say that pelareorep is active in KRAS- mutant and wild type cells, but more so in mutant. It is synergistic with gemcitabine and it's mediated by p21, and pelareorep sensitizes microsatellite stable cancers to the effect of checkpoint therapy and is synergistic with immune therapy. Going on to a clinical trial. In brief, this was a combination of FOLFIRI and bevacizumab in oxaliplatin-refractory KRAS-mutant colorectal cancer. We performed a phase I study looking at escalating doses, and even though initially we saw two dose-limiting toxicities in patients who had had prior exposure to FOLFIRI, we amended the protocol to only include FOLFIRI-naive patients. At the highest dose of irinotecan, which is 180, and the highest dose of pelareorep, which is 3 x 10^10, out of the 6 patients, no DLTs were observed. Interestingly, in these patients the overall survival was 25 months. Historically, one would expect only 11 months, and the progression-free survival was 15 months. Historically, we'd only expect 6 months. In terms of some correlative studies, we saw that there's a clear induction of dendritic cells as shown by an uptick in CD123 at two days, followed five days later by an increase in what is called CD8 CD70. These are activated CD8 lymphocytes or really the active T cells. This is just a comparison of the three randomized phase III trials of FOLFIRI plus an anti-VEGF agent. Comparing them to the data that we observed, as I said, we've seen 25 months survival. All the others are between 11 and 13. Our PFS was 15 months at best. What was seen before in this phase III trial was seven months, and our response rate was 50% whereas previously the best response rate was 20%. Even though our data is limited, I think there's clear evidence that the combination of FOLFIRI, bevacizumab, and pelareorep is highly active. I'm going to skip through this. Essentially, what I hope to do is launch a randomized phase II trial of metastatic microsatellite-stable KRAS-mutant metastatic colorectal cancer to randomize them into either FOLFIRI, bev, and pelareorep, which is really the clinical trial that I just presented in terms of the phase I, and randomize them to either the combination of standard of care versus the combination plus a checkpoint inhibitor, with the primary endpoint being response rate. Essentially, we would need 28 patients in each arm, and we expect a response rate of about here. The null hypothesis is a response rate of 15% in the control arm and 39% in the ongoing checkpoint inhibition. I'll end there. Thank you everyone. Thank you for those presentations. A lot of really interesting information, obviously. I think right now we want to jump right into the Q and A. Some people call it fireside chat. I sort of dislike that term, mostly because there's no fireplace around. I want to get into questions. I think we have the first one coming in from an analyst, Michael Freeman from Raymond James. Sort of a broad based question for Dr. Arnold here, sort of based on the data we have today with PELA in the first line of PDAC. You know, does it follow that PELA should be explored in a registration enabled study in the first line? Good question. I think that's the key question. We have seen this really for us also promising and unexpected efficacy. Given the unmet need in pancreatic cancer and the need for improvement which Professor Eggermont has nicely introduced in his talk, I think we all would really die for having a kind of registration trial which is aiming to improve overall survival and also symptom control for patients with pancreatic cancer. I think that's one of these beauties of the GOBLET trial. We have seen this great one year overall survival rate which is really stimulating. I think the most stimulating thing is these shrinkage of tumors. We'll say the lowering of the tumor burden and this is in most patients associated with relief from tumor related symptoms. Therefore we would in any case like to offer patients with metastatic pancreatic cancer a great and hopefully very efficacious treatment. Therefore I would give a thumbs up for this thought and I would dare to do this and to see this. Thank you. Yeah, thank you. One quick follow up, Dr. Arnold, and then others can jump in too. Dr. Heineman, Tom, interested in your take on this. What would be the sort of just a couple of key points of that study, primary endpoint, maybe hypothesis on the size of the study. What are your takes on that, Dr. Arnold? Traditionally, when we see registration of trials in first-line pancreatic cancer, it's always an overall survival endpoint. I think that's really the challenging thing that we have to show in a randomized trial, that this combination can improve or will improve the overall survival likelihood. Therefore, we talk about, let's say, many hundreds of patients. I don't see, let's say, thousands of patients, but it's clearly more than 200, 300 patients, which we have to see, which we have to invest. We also have to see that the treatment landscape in pancreatic cancer will be evolving over the next few years. We will have all of these RAS inhibitors coming up, also, let's say, coming into the market of first-line treatments. Therefore, we have to, let's say, discuss the environment where we evaluate this. It's a randomized phase III trial. We have to have randomized phase III in pancreatic cancers due to the methodology the registrational agents or agencies are asking for. It has to be an overall survival endpoint. Great. Yeah. We'll get to the treatment landscape shortly. Tom, on this point, you know that we have this GOBLET data with the checkpoint inhibitor, which would bring into this component contribution components thesis here. You know, our data, we have strong data with just a chemo plus PELA backbone. Quick thoughts on two arm versus three arm study, Dr. Heineman. Yeah, so I think that the data we have are actually promising, show promising efficacy for pelareorep either both with and without a checkpoint inhibitor backbone, I mean, component. Right. I think you could make a very, a good case for investigating going either pathway. Of course, if you go without a checkpoint inhibitor, it makes a simpler and probably smaller study. If you go with a checkpoint inhibitor, you would have to add additional patients to sort out the actual contribution of the checkpoint inhibitor component. I think it's actually a good problem to have. There are a couple different ways we could go and I think both of them are valid and we'll just have to see, y ou know, we'll have to agree on the best design with our experts and also internally. We have two good options, I think. Yeah. Thank you. Thank you, Tom. Dr. Mahalingam, it looks like you might have technical difficulties, but if you can hear this question, I wanted to throw you a quick follow up. You know, what is the, you know, we have 1,100 patients worth of safety data. What does that tell you about PELA safety profile? I think he dropped off. Okay, we lost him again. How about Dr. Goel, you know, 1,100 patients worth of safety data in PELA across multiple tumor types. What takeaways can you make on the safety data? Yeah, I mean, I think I've had experience with this starting from the single agent phase I and to several other trials. Of course, looking at all the data, it really seems that the drug, if you call it a drug, is really overall quite safe. I would not attribute any major additive toxicities to the drug other than what you'd expect when you get a viral infection, like just some fever, mild diarrhea, et cetera. I think overall it's tolerated very well. Yeah. You know, how often do you have a late-stage biotech with 1,000 patients worth of data before a drug approval? How often do you see? Yeah, I would say not often at all. Yeah. Transition on here. This is another question from an analyst. This is Albert Lowe from Craig Hallum. The question to Dr. Eggermont here. If PELA were to be approved in the first-line of PDAC, where would it fit in as a therapy option in combination with chemo, and would oncologists welcome it as a treatment option in the front line? I think the answer is relatively simple here. The answer is yes and would be readily incorporated if it shows the likelihood of being able to show not just the PFS, but an overall survival benefit. The number of patients you need when overall survival is so low is actually lower than the big phase III trials that we are used to think about when we're discussing colorectal or other diseases, let alone breast cancer. Right. I think the total number of the phase III trials that we would have in mind would be somewhere between 300 and 500 patients to be able to show these overall survival benefits, and they are very doable. Secondly, this oncolytic virus is not hampered by procedural toxicities and problems, which is otherwise a problem for the intertumoral delivery oncolytic viruses. Therefore, the preparedness of not just academic centers and big hospitals, but also peripheral hospitals would be very great because this is an intravenously delivered agent that seamlessly is then being incorporated in the combo chemotherapy of your choosing. That can be FOLFIRI, it can be the less toxic gemcitabine, nab-paclitaxel. We have all seen based on 1,100 patients that there is no toxicity problem. There is some light flu-like type of symptoms, and that is basically it. There is all the space. It doesn't take space, this oncolytic virus in the toxicity profile. Therefore, it also allows very easily for the further combo with an anti-PD-1 or anti-PD-L1 that protects the effector cell function of your T cells, which you have just diversified in terms of T cell clones and have expanded. If you add the anti-PD-1 or anti-PD-L1, meaning that I don't see any major hurdle or stumbling block for a three or four drug combo. The chemo-immunotherapy that would have two chemo components and two immunocomponents would be very palatable and feasible. Yeah, and follow up there is, you know, RAS inhibitors are mentioned but those are a few years away from the first line, at least as far away as PELA is. In terms of the near term chemotherapy in the front line, Dr. Arnold, you know, what's your take on, you know, where we'll see chemo as a frontline treatment and you know, how difficult is it just to add an immunotherapy right onto that chemo backbone in the front line? Yeah, excellent question. I think we do have to accept, unfortunately, chemotherapy will be a mainstay of one of the background treatments. We do have two standards of care treatment, which is gem, nab-paclitaxel as we have been shown here, and as well it's FOLFIRINOX, we'll say a triple chemotherapy regimen, which we are currently, let's say, investigating in cohort number five of the GOBLET trial. We didn't have a, let's say, decent readout because the trial is still ongoing. We're comparing this triple chemotherapy also with this immunocombination, and we will get a good picture about tolerability also with this. Then it's a three-drug chemotherapy backbone plus two immunotherapy, so it's really multi-drug, whatever, and we will find out what is the best chemotherapy backbone. Let me allow me to lose a few words about also these specific RAS inhibitors. Even if they will enter first-line treatment, they will not overcome the problem of developing resistance against this specific inhibition. That's what we have learned with these RAS inhibitors as they are available in lung cancer and other tumor types. We will not, let's say, solve the problem of development of resistance. Immunotherapy can contribute to overcome resistance or can prolong the response and the durability of the response. Therefore, even if this will be at some need as a component of the treatment, this will not make immunotherapy unnecessary, and I think that's the environment of the thinking. We have to see what is the best landscape, what is the best backbone. Maybe a targeted agent may be also contributing. However, we have to find s olutions f or the immune system, it's really great to have further investment, further insight on these combinations with various first-line combinations as a backbone. Yeah. We're speaking of first-line PDAC here. Dr. Goel, similar question to you with chemo as a frontline treatment and potentially mixing PELA into a frontline or even second-line treatment in colorectal cancer, since that's where your interest and specialty lies. What's the treatment landscape look like there, and what do you think about chemotherapy in the frontline going forward in CRC? Yes, as our study showed, combining pelareorep with bevacizumab and FOLFIRI, the activity seems to be quite strong and encouraging. The trial design I talked about was planned as a second line. That's only because at least in the U.S., the majority of the patients receive FOLFOX or an oxaliplatin-based regimen as frontline. If it's a worldwide study, then it doesn't necessarily have to be that way. Essentially, what clinical data has shown us is that pelareorep may not really work that well with an oxaliplatin-based regimen. At least one clinical trial has shown that. Also, I've not seen any preclinical data to support synergistic effect of pelareorep and oxaliplatin. I would really place my bets on combining it with irinotecan rather than with oxaliplatin. I think going in first line or second line, both may be options, just depend geographically where the trial is done. From a practical perspective and based on the data we've seen, I think combining PELA with bev and irinotecan-based schema is going to be active. To test the question, what we saw preclinically, that we do see synergistic action between pelareorep and checkpoint inhibition, especially in the KRAS-mutant microsatellite stable model, which accounts for about 50% of all colorectal cancer patients. To answer that question and whether to take the combination of chemo with PELA with checkpoint inhibition forward, I think a better step would be like what I was saying. Maybe first do a smaller randomized phase II, pick the winner. It may be PELA with chemo or maybe PELA checkpoint with chemo, and then take that forward into a phase III. Yeah, that's something you could be interested in doing as maybe an investigator sponsored type trial. Yeah, that's correct. Yeah, that's where my effort is right now. Yes. Switching gears, a little question for Dr. Heineman. This is from Patrick Trucchio from H.C. Wainwright, another analyst covering Oncolytics, thinking of PELA as a platform and a product option. What does the consistent translational data tell us about the mechanism of action and the potential across tumor types, especially in GI, as we just discussed, CRC and PDAC. Yeah, yeah. Excellent question. PELA, as I believe one of our experts mentioned earlier, actually can replicate in many different tumor types. It's been shown to replicate in breast cancer, colorectal cancer, and of course, pancreatic cancer and several others. That obviously speaks to its potential as an effective therapeutic across multiple cancer indications. Even beyond that, its mechanism of action more specifically is not limited to any particular tumor type. Its mechanism of action really derives from its ability to make the tumor and microenvironment hot and visible to the immune system, along with its ability to stimulate both innate and adaptive immune responses, including the expansion of tumor-infiltrating lymphocyte populations. All of which is relevant across multiple tumor types. In fact, PELA's cross-tumor potential has been empirically demonstrated by its strong efficacy signals, as you've heard today, in both pancreatic and colorectal cancer, but also above and beyond that within breast cancer and anal cancer as well. We do have good evidence for its cross-tumor potential. In fact, it's become clear through these studies and others that PELA can be combined with multiple different chemotherapies, as you've heard discussed today, as well as with immunotherapy, such as checkpoint inhibitors. Mechanistically, Dr. Goel alluded to this, but its synergy with checkpoint inhibitors is driven at least in part by its ability to upregulate PD-L1 expression in tumor cells. All of that speaks to its potential to be an effective therapeutic in combination with either chemo or immunotherapies across multiple tumor types. Thank you. Thank you, Tom. Dr. Mahalingam, I'm not sure if you can hear us now, but hopefully you're able to. A follow-up question on the mechanism of action: you know, PELA as an intravenous delivery system. Thank you. Yeah, it might be on a delay. Question about the mechanism of action. How important is it that PELA is intravenously delivered instead of intratumorally delivered, you know, to hit metastatic disease and other really difficult things in the GI tumors? You know. I think that's one of the advantages of it as an oncolytic virus. A lot of the kind of oncolytic viruses we are dealing with now are given intratumorally just so that you allow for access. I think we have showed multiple kind of on-treatment biopsies that the virus reached the tumor, both the primary as well as the metastatic sites. I think that's key. It's easily delivered with all the patients that have been treated with multiple trials. I've not had a safety issue with the virus both in the short-term setting and the long-term setting. The typical innate immune system activation of fevers, chills, rigors are expected and usually self-limiting. These are well-tolerated treatments and easily applicable both in academic settings as well as community settings. I think it's time to do a registration or even a phase II, III adaptive design way, but it's time for a randomized trial in this space. Been working on this for 15 years in pancreatic cancer and I'm hoping to see this and I'm glad that the GOBLET study has proven that we can move it forward to randomized that it. Thank you very much, great transition. We just have a few minutes left here. Question for Dr. Eggermont. Thinking ahead, can you just speak specifically about the potential for PELA as an immunotherapy platform, just looking forward and where we go from here? Obviously, regulatory work is needed to be done and ongoing partnership discussions, obviously with a biotech of our size. What's the potential for PELA as an immunotherapy in GI cancers specifically? Wouldn't even limit the discussion to GI cancers because by definition we're discussing here a trans tumor type mechanism of action. As long as the virus gets in, replicates, it will kill tumor cells both in the primary, in the lymph node mets, in the distant mets, wherever the tumors are. Because by intravenous route it will find all those tumors. Now, primary tumors have the wrong tumor microenvironment that allows tumor progression and all this, but so do metastases, right? The fact that this mechanism of action releases the chemokines, brings in the T cells, and then you can further work with those T cells with an anti-PD1 and anti-PD-L1 means that you have two transversal common denominator immunity mechanisms working hand in hand. The fact that in a number of these tumor types you will not say goodbye to chemotherapy for a while, talking about pancreatic cancer, talking about colorectal cancers, it means that we have this world of chemo-immunotherapy. Now, finally, we have immunotherapy that works. It can work hand in hand with chemotherapy, provided the chemotherapy is of the right type, especially if it is chemotherapeutic components that induce immunogenic cell death. That's a detail. The other point, looking forward, is that the ongoing immunotherapy revolution is the neoadjuvant immunotherapy revolution. If you see effects in advanced metastatic pancreatic cancers, if you see effects in second line or third line colorectal cancer patients, that means that there's a whole new angle of activity that's now being mobilized and that we can sail with and sail on. That also means that, quite honestly, but secretly, I'm already dreaming about a neoadjuvant chemo pelareorep plus anti-PD1 pancreatic cancer trial to induce responses as early on as possible, working with the primary tumor and creating the biggest immunologic memory moment that you can capitalize on. That is very true for the colorectal cancers and not just for the MSI colorectal cancers. It's also true for the MSS colorectal cancers if you come in early and you do it the right way. I think there's tremendous potential and tremendous synergy potential on the immunological side, as well as on the interactive side with the chemotherapy for the tumors that still need chemo at this point in time. Thank you very much, Dr. Eggermont. I think that's all the time we have today for this event. I want to again thank our panel and all the investors and analysts who tuned in today to watch this. This will be recorded and will be up on our website for further viewing. Thank you all again for attending our event, and good day to you, everyone.