Oncolytics Biotech Inc. (ONC) Earnings Call Transcript & Summary

Good morning, and welcome to the Oncolytics Biotech KOL webinar. [Operator Instructions] A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by e-mailing your questions to [email protected]. 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'd now like to turn the call over to Matt Coffey, President and Chief Executive Officer of Oncolytics Biotech. Please go ahead, Matt.

Thanks, Sarah, and thanks to all joining today's webcast. Our discussion today will center primarily around the exciting data reported from our GOBLET trials pancreatic cancer cohort at the SITC meeting last week. These data showed an objective response rate of 69%, including a confirmed complete response in 13 evaluable first-line advanced or metastatic pancreatic cancer patients treated with pelareorep in combination with PD-L1 checkpoint inhibitor and gemcitabine plus nab-paclitaxel. Given the strength of our data and the dearth of novel therapies in pancreatic cancer, we are now planning to present these data to regulatory authorities with the goal of moving expeditiously into a pivotal trial. As you can see on this slide, our latest data have added a second potentially compelling registration opportunity to our pipeline to go alongside our breast cancer program. While our efforts to advance into a pivotal study in HR+/HER2- breast cancer won't be the focus of today's webinar, I will reiterate that this program maintains a strong momentum as we work to build upon our prior randomized clinical data demonstrating pela's ability to drive a statistically significant survival benefit in this indication. The next catalyst for the program will be the readout from its second randomized study, BRACELET-1, which is anticipated to occur at a major medical conference in the first half of next year and is expected to inform the design of a subsequent pivotal trial for breast cancer. Turning back to our pancreatic program. We are pleased to welcome 3 distinguished key opinion leaders to our webinar. We'll first hear from Dr. Andrea Bullock, who is the founding member of the Pancreatic Cancer Center at Beth Israel Deaconess Medical Center and member of the National Pancreatic Cancer Research team network. After providing an overview of the current treatment landscape and unmet need in pancreatic cancer, Dr. Bullock will pass the call off to Dr. Thomas Seufferlein, Professor of Gastroenterology at Ulm University in Germany. Dr. Seufferlein coordinates the German national guidelines for pancreatic cancer, and on today's webinar, will be talking about the failures of prior investigational therapies to improve the standard of care in this indication. Dr. Seufferlein will then be followed by our Chief Medical Officer, Dr. Thomas Heineman, who will provide an overview of our immunotherapeutic candidate, pela, and the design of our Phase I/II GOBLET trial. This will lead into a presentation by GOBLET's principal investigator, Dr. Dirk Arnold, and will present the pancreatic cancer data I reviewed earlier in more detail. Before we move on to these presentations and subsequent Q&A session, I'd like to thank -- extend our thanks to our guest speakers, not only for joining us today, but for their dedication and treating and improving the lives of cancer patients. And with that, I'll turn the call over to Dr. Bullock.

Thank you, Matt. Next slide. So pancreatic cancer, despite advances over the last decade in an almost quadrupling of the 5-year survival rate, remains the fourth leading cause of cancer-related death in the U.S. and has a high impact worldwide. And when we look at pancreatic cancer compared to some of the other malignancies that we treat, while the incidence of disease may be lower, the death rate and the seriousness of this illness remains very prominent. If you look, for example, at the deaths due to pancreas cancer that actually exceeds that due to breast cancer, where, of course, there is quite a bit of attention and research. So there's a tremendous unmet need in improving the treatment options for our patients with pancreas cancer. Next slide. The vast majority of pancreatic cancer cases present at an advanced stage. Majority are metastatic with a high proportion, locally advanced and unresectable. So for the majority of our patients, treatments are palliative and not curative. And there are several reasons why pancreas cancer often presents at this advanced stage. One, there really are no known effective screening tools available to screen for pancreas cancer, The physiology of this disease is one that tends to metastasize early. And for many patients, they don't declare themselves or develop symptoms until it is already at this advanced stage. Next slide. So this is the treatment landscape for pancreatic cancer or for advanced pancreatic cancer over the last 25 years. And we will walk through each of the landmark studies that establish these combination regimens and standard of care therapies. Gemcitabine was established as the primary treatment for pancreas cancer back in 1997. And then for 20 years, there were a number of novel agents or combination regimens that showed some promise in early studies but eventually did not pan out until 2007, when there was a positive study of the combination of gemcitabine and erlotinib compared to gemcitabine. And while this combination had a statistically significant improvement in overall survival, the clinical benefit was really quite modest and very few people adopted this combination. The standard of care really did not change until the advent of the [ FOLFIRINOX ] regimen, now 10 years ago. And again, we're going to walk through each of these therapies. Next slide. So one last slide on epidemiology. And I think that this one is sort of telling. It looks at the death rates of different malignancies, and pancreatic cancer is highlighted in the orange line there. And you can see that while death rates due to most other malignancies are decreasing over time, including, for example, lung cancer, which is the most common cause of cancer-related death among men and women, death due to pancreas cancer is still rising. And much of this is because for many other malignancies over the last 10 years, we've seen a great deal of improvement in the use of targeted and immune-type therapies. And while those -- at least the targeted therapies are beginning to trickle into pancreas cancer, the benefits have been slower to reach pancreas cancer than we've seen in some of these other diseases. So there's really quite a bit of need to be able to expand treatment options within this disease. Next slide. The pivotal study that established gemcitabine again was published back 25 years ago in 1997. This was a small study of 120-some-odd patients who were randomized 1:1 to gemcitabine or single-agent [ fluorouracil ]. And while there was a survival benefit to gemcitabine, the primary endpoint of this study and the reason that established gemcitabine was actually this clinical benefit ratio. And they found that patients who received gemcitabine were less likely to have pain, they were less likely to lose weight, they were more apt to maintain a better activity level or performance status. And those are the findings that established this then as the standard of care. The toxicities were mostly around cytopenias, thrombocytopenia, neutropenia and anemia. Next slide. So we fast forward to 2011, when the ACORD 11 study established the combination of FOLFIRINOX. FOLFIRINOX is a 4-drug chemotherapy regimen, including [ fluorouracil ] and irinotecan. This was a Phase III study that included 342 patients randomized one-to-one to receive FOLFIRINOX or the then standard of care, single-agent gemcitabine. The ACORD 11 study was conducted in a fairly select population. That was primarily conducted at sites in France with a few in Canada. All patients had an ECOG performance status of 0 or 1, there was an age restriction such that all patients were 75 years or younger, and limitations, of course, on lab studies and liver function. There was a -- the primary endpoint was overall survival. And there was a statistically significant and clinically meaningful benefit with the use of FOLFIRINOX. Median overall survival was 11.1 months compared to 6.9 months in the gemcitabine arm with an overall response rate of 32% compared to 9% in the gemcitabine arm. This did come at the expense of increased toxicities. We do see increased cytopenias, including neutropenia with FOLFIRINOX as well as increased GI toxicity like diarrhea and sensory neuropathy. Next slide. Despite these increased toxicities, however, it was found that patients maintained a better quality of life for longer with FOLFIRINOX. And this included improvements in global health status as well as emotional well-being, decreased pain, anorexia, constipation, there was a note of increased diarrhea in the FOLFIRINOX arm. But overall, patients maintained a better quality of life for longer. And I do often explain to my patients that if we can contain the disease, that they will adjust to the toxicities of chemotherapy but that the toxicities of chemotherapy can be better managed oftentimes than the toxicities of the disease itself. And it was felt that quality of life was better with more aggressive therapy because we were maintaining the disease control. Next slide, please. Two years later, in 2013, we saw the advent of the gemcitabine and nab-paclitaxel combination with publication of the MPACT trial. So this was a much larger study of 842 subjects, and it was a worldwide study. Patients were randomized 1:1 again to receive either the combination of gemcitabine plus nab-paclitaxel or gemcitabine alone. And again, the primary endpoint was overall survival. This study was conducted in a broader population, it allowed for any age and a somewhat more lenient performance status. All patients had a Karnofsky performance status of at least 70%. There was a significant overall survival benefit to the combination arm. Median overall survival was 8.5 months compared to 6.7 months in the gemcitabine arm. Toxicities were greater in the gemcitabine and nab-paclitaxel arm but overall manageable, again, seeing greater amounts of cytopenias, like neutropenia, thrombocytopenia, fatigue and also again neuropathy. When we look at the patient characteristics for this study and compare those to those of the ACORD 11 study, 10% of patients in the MPACT study were greater than 75 years of age and about 8% had Karnofsky performance status of 70, which is more equivalent to an ECOG of 1.5 to 2. Next slide. So looking at this evolution of frontline therapy, we can see that there have been modest benefits in terms of prolonging PFS and overall survival, for gemcitabine, 1.24 months gain in overall survival; when we look to the ACORD 11 and MPACT studies, we're seeing greater benefits of 4 and 2 months benefits in overall survival. Next slide, please. There was no standard of care second-line regimen until results of the NAPOLI-1 study were presented about 6 years ago in 2016. NAPOLI-1 study was a 3-arm Phase III study in which 417 patients were randomized 1:1:1 to receive either nanoliposomal irinotecan, single-agent fluorouracil or the combination of fluorouracil and nanoliposomal irinotecan. And the combination and single arms were each compared to fluorouracil, which was considered the standard of care. This was, again, a worldwide study, allowed patients of any age and Karnofsky performance status of at least 70. There was a significant survival benefit with fluorouracil and liposomal irinotecan compared to fluorouracil alone with a median overall survival of 6.1 months compared to 4.2 months. Toxicities included neutropenia, diarrhea, nausea and fatigue. And this established the NAPOLI-1 regimen as a standard of care regimen in the second line for patients who had initiated treatment with a gemcitabine-based therapy. Next slide, please. As stated before, we have not seen many targeted therapies making their way into pancreas cancer. An exception to this is the use of olaparib in patients with germline BRCA-mutated pancreatic cancer. So about 10% to 12% of patients will have an identifiable germline mutation. The POLO study screened 3,300 patients or germline BRCA1 and 2 mutations, and identified 154 eligible patients. All of these patients were treated with first-line platinum containing chemotherapy and has disease stability on that regimen. After a minimum of 4 months of platinum-containing chemotherapy, they were then randomized to receive either the PARP inhibitor olaparib or placebo. There was a statistically significant improvement in progression-free survival from 7.4 versus 3.8 months in those who received olaparib. There was actually no difference in the median overall survival among the 2 arms. But if you do look at the survival curve on the right, we see that they begin to split later at about 24 months. There was also improvements in the time to second line of treatment for those who received olaparib as well as prolonged times on study therapy for those who received olaparib. So we do consider this agent in patients with germline mutated BRCA-associated pancreas cancer. Now there was also a Phase II study that I didn't highlight but which looked at the combination of gemcitabine and cisplatin in BRCA-mutated pancreatic cancer patients. And that is another regimen that we will sometimes consider in this population. Next slide, please. So as we look at the evolving landscape, we can see that there have been improvements in the advent of combination regimens that have improved both progression-free survival, response rate, survival as well as quality of life but still remains a great deal of unmet need in the pancreatic cancer population. And so with that, I think I will be handing things over to Dr. Seufferlein. Thank you.

Yes. Thanks very much, Andrea. And as you've all seen, Andrea has given you a perfect overview on the current landscape in pancreatic cancer, and I will add a little bit to that to show you mostly the failures of strategy but unfortunately, not the success. The next slide, please. These are my disclosures. Next slide, please. And we've hardly made any progress, and that has been already stressed. And you see that in contrast to esophageal, colorectal, stomach or lung cancer. Pancreatic cancer, there is no real progress so far at all in survival in mortality, whereas the incidence is rising. Next slide, please. And we have already -- it's already been mentioned, chemotherapy combinations are still the only standard of care. Next slide, please. We also do modify the FOLFIRINOX protocol often to toxicity being either diarrhea or hematotoxicity. We have now quite good evidence also from adjuvant trials that leaving out a bolus, for example, or reducing oxaliplatin does not really impact efficacy but reduces toxicity, in particular neutropenia, diarrhea and peripheral sensory neuropathy. Next slide, please. So this is the treatment algorithm, as has been already pointed out. Next slide, please. And this is also what is reflected in the situation, this is the German Registry, reflect in this situation in the general practice. So we have about 40% of patients being treated with the combination of gemcitabine and nab-paclitaxel. FOLFIRINOX is a bit more restricted. We have in Germany around about 24%, 25% of patients treated with that. There is still a proportion of patients still in gemcitabine single agent treatment due to the fact that they have comorbidities or are frail, and 11% of patients receive other protocols. The FOLFIRINOX patients are usually younger, a median age of 60 years, and the majority has an ECOG of 0 or 1. The next slide, please. Second-line treatments, as you see, Andrea has already very nicely pointed out to you the protocols available. And you see that around about 40% of patients with pancreatic cancer, metastatic pancreatic cancer receive second-line treatment. This is the data from the U.S., and only 13% received third-line treatment. A lot of patients are followed -- lost to follow up or have died in between. Next slide, please. And this is the sequential treatment. This has been already shown very nicely. This is the data with overall survival with [indiscernible], the only approved second-line treatment so far for metastatic pancreatic cancer. Next slide, please. And this -- now we're coming to the hope for improvement. And there is one approach that actually tried to target the stroma. And you know that the stroma is rich in [ hyaluronic ] acid. And this trial compared to gemcitabine plus nab-paclitaxel plus [indiscernible] compared to gemcitabine plus nab-paclitaxel standard treatment. There was quite a high hope because in the Phase I/II trial, there was quite an interesting signal for the adding [indiscernible] to the treatment with respect to progression-free survival. But as you see here, this is a randomized trial in 494 patients. As you see here, the group with a pegylated [indiscernible] added to the [indiscernible] protocol did not show a significant difference in overall survival with 11.2 months as compared to 11.5 months with the standard of care. And therefore, unfortunately, this interesting concept did not pan out in the clinical trial. The next slide, please. Similarly, we've just seen another trial failing, unfortunately. And here the target were mitochondria, where CPI-613 targets pyruvate dehydrogenase and actually interferes with the [indiscernible] cycle and inhibits alpha-ketoglutarate dehydrogenase. And the addition of CPI-613, was supposed to really have a major impact in the cycle and thereby also metabolically affect the response of chemotherapy in metastatic pancreatic cancer. This was a second line trial with stage 4 pancreatic cancer patients receiving CPI-613 with modified -- first line, sorry, modified FOLFIRINOX until disease progressed. And in this case, the addition of CPI-613 to modified FOLFIRINOX failed to show a significant improvement in response in PFS and in overall survival, unfortunately, as compared to modified FOLFIRINOX on its own. And the data have been presented at this year's ASCO. The next slide, please. Another interesting concept was adding asparagine base to the combination, in this case, a Phase III trial to improve outcome. And this was indeed a second-line trial. And it was -- and the idea was that as asparagine promotes cancer cell proliferation because it's used as an amino acid exchange factor. And by depleting asparagine, this might really lead to apoptosis and the decrease in proliferation. This encapsulated asparaginase was added to chemo combination chemotherapy in the second line setting. The Phase II trial was quite promising. Actually, this led to a Phase III trial. But alas, the Phase III trial in the second line was also a negative trial. There was no improvement in the -- in all endpoints observed, and therefore, the trial alas failed. The next slide, please. The question now is, is immunotherapy efficacious in pancreatic cancer? And we can clearly say that there is no point of treating patients so far with immunotherapy alone or in combination with chemotherapy when the tumor is microsatellite stable. And as you see on the lower left side, the tumor mutational burden is really low in pancreatic cancer. This is only topped by [ ovial ] cancer. And therefore, there is a very low response rate to actually any kind of checkpoint inhibitor. But also the MSI-high tumors, and this is a very low figure, only 1% to 2% of the tumors are microsatellite instable or deficient mismatch repair system. And as you see, this is data from the KEYNOTE-158 study, only a very low number of patients included, a response rate of 18.2%. And you see a median progression free survival of 2.1 months and the median overall survival of 4 months. This is rather poor outcome when you compare this to the other tumor entities examined in the KEYNOTE-158 like endometrial or gastric cancer, where the median overall survival was not even reached, even cholangiocarcinoma with 43 -- 24.3 months. And the only other odd one out is [ outright chemos ] with 5.6 months may be overall survival. Having said that, there are some patients really benefiting from adding immunotherapy, in particular with microsatellite in stable tumors, because you see that there are -- the median duration of response of those really who did response were 13.4 months with up to [ 60 ] months in the range. So there are some people or some patients responding, but we haven't really got the features yet that are required to achieve this response, and it's not really achieved in the overall population. The next slide, please. And it has been tried to even improve that by adding another compound. This is a CD40 agonist to combination chemotherapy in this case, gemcitabine-nab-paclitaxel and a checkpoint inhibitor nivolumab. And this was a 3-arm trial that either examine gemcitabine nab-paclitaxel plus nivo or the gemcitabine nab-paclitaxel plus the CD40 agonist, sotigalimab, or the combination of all gemcitabine nab-paclitaxel nivolumab and sotigalimab. This was a smaller trial in total 105 patients, so around about 35 patients in each arm. And the primary endpoint of this trial -- this was a trial of patients with no prior treatment for metastatic disease and a good ECOG performance status of 0 to 1 was more than 35% 1 year survival rate as compared to historical control. There has been quite nice data with a CD40 agonist in some patients with pancreatic cancer leading to huge tumor shrinkage, and this led to this trial. The next slide, please. And as you see, here there was indeed of the -- no benefit of the triple combination, gemcitabine nab-paclitaxel plus nivo plus sotigalimab. And the 1-year overall survival target, this was the significantly better than the 35% historian comparison. There was no comparison arm in this trial, was only achieved by the gemcitabine nab-paclitaxel plus nivolumab group. And the reason for that is really unclear because you see that also on the right side, the triple combination didn't really perform well here in the yellow curve. There might be an antagonist between different IOs, in this case, sotigalimab and nivolumab. We didn't know that because we have a lack of really good biomarkers that might guide us to really have a better understanding of how these compounds work together. The next slide, please. And there are, of course, quite interesting novel approaches. And this, you might have seen, that is a recent paper in the New England Journal where the authors choose a different approach and they took autologous T cells and modify these T cells to express 2 allogeneic HLA-B608.02 restricted T cell receptors that really target mutated KRAS G12D and added, of course, tocilizumab and cyclophosphamide and other [indiscernible] to enhance to boost the effect. And they could show a 1-month partial remission of 62% and, at 6 months, a partial remission of 72%. And they still could show these modified T cells in more than 2% of all circulating T cells. But this seems to be a very interesting, however, a highly complex procedure that is restricted to these HLA phenotypes on top of that. But it shows that immunotherapy, under certain circumstances, might be really efficacious in this disease that seems undruggable and really untouchable by immunotherapies before. The next slide, please. When we actually want to identify vulnerable targets, this might be a way forward to do really a genomic approach, and this is just an approach where there has been done on the whole [indiscernible] subsequencing and where 48% RNA sequencing, and 48% of cases really showed a relevant genomic observation; and in 30%, even this led to a potential change of clinical management. The next slide, please. And the [indiscernible] registry trial really could show that when we actually identify those patients with actual [indiscernible] and we do target these actual mutations, then we can really achieve a benefit in median overall survival. And you see here with a match treatment, median overall survival was 2.5 years. Of course, this is not a randomized trial, but there might be a way forward to select these patients. Next slide, please. And this is maybe choosing a subgroup of patients, which has targeted alterations and this is the KRAS [indiscernible] trial subgroup. This is just one trial from China that is recently represented that examined the combination of gemcitabine plus [indiscernible] antibody as compared to placebo in a KRAS wild-type only group, first-line treatment in this case. And you see the data on the data on the next slide. I just want to briefly mention that in the KRAS wild-type population, there might be a benefit of adding anti-EGFR to gemcitabine in this case, and will meet an overall survival of 10.9 as compared to 8.5 months. So there is a way forward, small improvements in selected subgroups, but the hazard ratio was quite nice. It was 0.5%, but the curves separated rather late. It's a clinically interesting trial. The next one, please. So in other KRAS one type subgroup has other features. We have NRG1 fusions that can be targeted, for example, by [ sinacutuzumab ] in other alterations that might be interesting for further approach. But it only comprises 10% of all pancreatic cancers. The next one, please. And this has already been mentioned. This is just the group with [indiscernible] germ line mutations in pancreatic cancer. And Andrea has already shown you very nicely that the POLO trial. I just want to point out that this is as important, that only 3 of these 33 patients in this group that have been identified with germline mutations in BRCA, for example, or other target genes of -- for the DNA damage repair system. Only 3 of these 33 patients had a family history of pancreatic cancer. So you need to sequence these patients nevertheless because family history doesn't always give it away, whether you have a familiar pancreatic cancer with BRCA ATM or PALB2 mutations. Next slide, please. And Andrea already mentioned platinum responsiveness of these tumors that might sometimes lead us in first line to use a gemcitabine cisplatin combination when we don't use FOLFIRINOX to target these cancers. And this is a very nice paper showing out that the responders are all on the platinum-based treatment site when you have an HRD efficiency tumors. Next slide, please. So in conclusion, we have the treatment is still largely chemotherapy-based. We have many innovative approaches that had failed, targeting [indiscernible] metabolism, for example, or targeting asparagine in the overall population. There might be approaches, but only for small subgroups, BRCA 1/2, KRAS wild-type or the KRAS G12D which I did mention for time. And immunotherapy is, so far, not efficacious for a larger population. And you will see now what it could be another novel approach. Thank you very much.

Thank you, Professor Seufferlein. The insights that you and Dr. Bullock provided on the need for new treatments in pancreatic cancer set the stage nicely for Professor Arnold's upcoming discussion of the GABA clinical trial results. However, before we get into that discussion, I'd like to first provide some background on Oncolytic's proprietary immunotherapeutic agent, pelareorep, and the scientific rationale underlying the treatment approach used in the GOBLET pancreatic cancer cohort. For those who are new to Oncolytic story, pelareorep is a first-in-class nonpathogenic oncolytic virus that selectively replicates in tumor cells. Unlike many other oncolytic viruses, it's delivered intravenously rather than intratumorally and it also has a [ BSL II ] classification, which means that it does not require any special handling for cautions. Therefore, it can be administered easily and reproducibly in a standard outpatient setting. Also, the intravenous delivery means a pelareorep can directly target primary and metastatic tumors wherever they may occur in the body. So pelareorep works through an immune-mediated mechanism of action that positions us to solve one of oncology's most prevalent and long-standing problems, which is the inability of the immune system to recognize and for immune cells to infiltrate and attack some tumors. This problem stems from multiple complex biological processes within tumors that collectively blunt the effectiveness of many different classes of cancer therapies across a wide range of indications. Pelareorep's potential to overcome these obstacles has been demonstrated in prior clinical studies in pancreatic cancer, breast cancer and other cancers. Data from these past trials have shown that pelareorep can induce the expansion of new and existing anticancer immune cells while simultaneously remodeling tumor microenvironments to make them more accessible to immune cell infiltration and activity, including the upregulation of PD-L1 expression. Collectively, these effects position pelareorep as a platform agent that can synergize with a broad range of cancer therapeutics, including checkpoint inhibitors and chemotherapy. So on this slide, you can see summarized some of the prior clinical results that helped form the rationale for the treatment approach used in GOBLET's pancreatic cancer cohort. These data shown here are from the [ REO 17 ] trial, which was a single-arm Phase II study that evaluated pelareorep in combination with gemcitabine in chemotherapy-naive patients with advanced or metastatic pancreatic cancer. As you can see from the table, this combination led to a median overall survival of 10.2 months and 1- and 2-year survival rates of 45% and 24%, respectively. These values are all substantially higher than those observed in 2 prior clinical trials of gemcitabine alone in pancreatic cancer, where median overall survival range from 6.8 months and the 1- and 2-year survival rates range from 20% to 22% and 2% to 5%, respectively. So although this study showed a clear survival advantage, for the combination of pelareorep and gemcitabine compared to the historical results, progression-free survival is actually similar to the earlier studies. Results such as these in which there is an overall survival benefit but limited impact on progression-free survival is typical for immunologic agents such as pelareorep. Okay. Turning our attention to the right hand -- to the bottom of the slide, rather. We can see additional evidence of pelareorep's immunologic effect. Shown here are images of pre- and posttreatment tumor biopsies from that trial, with the dark brown coloration indicating PD-L1 expression. As you can see, PD-L1 expression is dramatically upregulated by treatment with the pelareorep gemcitabine combination. This suggests the potential for synergy between pelareorep and PD-L1 or PD-1 inhibitors in pancreatic cancer. Based on these findings, a subsequent Phase II trial was conducted to further explore pelareorep's ability to act synergistically with checkpoint inhibitors in pancreatic cancer. This trial evaluated pelareorep combined with the anti-PDL ED1 checkpoint inhibitor, pembrolizumab, in pancreatic cancer patients who have progressed after first-line therapy. The results of this trial showed a strong anticancer signal as a 42% disease control rate was achieved despite the absence of chemotherapy in this very difficult-to-treat patient population. Moreover, tumors from patients treated with this combination that increase PD-L1 expression and the correlation between clinical response and increased activation of anticancer CD8 T cells was observed. Collectively, these data strongly suggest that the observed anticancer activity was a result of therapeutic synergy between pelareorep and the checkpoint inhibitor. We are now working to further explore this apparent synergy by collaborating with Roche and AIO on the Phase I/II GOBLET trial, an overview of which is shown here. As you can see, from the graphic, GOBLET's first cohort is evaluating the combination of pelareorep, the PD-L1 checkpoint inhibitor, atezolizumab and in the chemotherapeutic agents, gemcitabine and nab paclitaxel in first-line advanced or metastatic pancreatic cancer patients. We chose to study first-line patients in this study as both pelareorep and atezolizumab work through immunologic mechanisms of action, and the immune systems in first-line patients may be more able to respond to these agents than those of the more compromised later-line patients. You'll also notice from the graphic that GOBLET is a multi-indication trial with additional cohorts in 2 different colorectal cancer populations as well as anal cancer. While we won't be speaking about these cohorts today, enrollment into these cohorts is proceeding as planned. Looking ahead for this program, we plan to discuss our results with regulators with the goal of enabling advancement into a registrational study rather than into GOBLET's optional Stage 2 expansion phase, we believe this approach represents the best strategy to address the urgent needs of pancreatic cancer patients given both the strength of our data and the limited efficacy of currently available therapies. With that introduction to pelareorep and our pancreatic cancer program, I'd like to now turn the webinar over to Professor Arnold. We have Professor on the line, please?

Professor Arnold is joining right now.

Oh, excellent. Thank you.

Hello. So dear colleagues, let me present some of the interim data we have been in pleasure to present in the Annual Meeting of the Society of Immunotherapy of Cancer coming from the first cohort of patients haven't been treated within the GOBLET trial. Next slide. So we do report safety and efficacy of the cohort patients with pancreatic cancer with, say, patients which underwent combination treatment of combination chemotherapy, gemcitabine plus nab-paclitaxel the PD-L1 inhibitor, atezolizumab, plus pelareorep. So patients which entered this cohort, and I do report efficacy of [ 13% ] and toxicity of up to 18 patients, have all metastatic disease. Predominantly, we had male patients average or, will say, mean age has been 62 years, and all patients had good or even excellent performance status. So metastases or shape of metastases was predominantly liver met. That's what we expect in pancreatic cancer. On the next slide, We see out of the 18 patients which entered the cohort in which available for efficacy analysis, you can see the summary of all treatment-related adverse events. So of note, this is a 4-drug combination: 2 immunotherapies and 2 chemotherapies. So toxicity can be coming from chemotherapy or from immunotherapy or from the combination of both. But what we can see is a fairly low rate of any [ Grade III/IV ] treatment-related adverse events. Overall, pyrexia has been the most commonly observed adverse events being commonly mild and self-limiting, occurring 11 out of these 18 patients. But 0 patients had higher grade pyrexia. Also other immune-related -- acute immune-related adverse events like chills or maybe also some acute fatigue has been observed in one out of 3 patients being treated, but also no higher grade toxicity. And if you look, let's say, down the road to -- down the table, to typical chemotherapy-related toxicity like leukopenia or any kind of hematotox or dyspnea and diarrhea or mucosal toxicities, again, there's surprisingly low rate of high-rate toxicities with a fair rate of low-grade toxicities. So I would say this is clearly unlikely that we will have a synergistic toxicity profile. Coming to efficacy. We had the pleasure to have 13 patients which underwent treatment until week 8. So therefore, this is the per protocol-defined efficacy treatment group. And out of these 13 patients that have been observed until week 8, 6 patients had a partial response, 5 more patients had stable disease and only 2 patients did not respond. Those patients, which were having stable disease or partial response, then I also had confirmation of their response at week 16. And we also had some follow-ups for patients up to week 24 to date. Of course, longer follow-up will be provided. But as you can see, we have still a higher range of patients being still with disease stabilization or even partial response. So if you follow this from left to the right, you can see that out of these 13 patients at week 8, 9 of these 13 still had partial response at week 16, and 6 have this even maintained up to week 24. So we'd say, we have high response rates -- surprisingly high response rate higher than with chemotherapy and this lasting up to 24 weeks. Well, this is another graph of displaying efficacy profile. This is showing in this kind of swimmer plot per patient efficacy analysis. The blue squares represent partial response and the light blue dots represent even the single patient with complete response, we'll say, with complete, let's say, vanishing of metastasis. And in the orange triangle shows patients with stable disease. So this is representing, let's say, the long-lasting control of the disease with then of those patients being in partial response up to end of treatment. Well, to support the theory that pelareorep works as a part of this combination, not only by clinic efficacy but also by its specific mode of action, we have some data of T cell repertoire turnover or rearrangement of T cell repertoires. We can see that this is correlating obviously in responding patients and maybe this biomarker is, let's say, best indicating which patients are responding and have a sustained response as a result of this treatment. Okay. Thanks for attending. Any further questions or any questions at all?

Great. Thank you, Dr. Arnold. At this time, we'll be conducting our question-and-answer session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by e-mailing your questions to [email protected]. Please hold for a brief moment while we poll for questions. So our first question comes from John Newman from Canaccord.

Thanks for putting on the event. Just had a question for Dr. Arnold but also all the physicians on the call. The question is the GOBLET 1 study had a number of patients that at week 8, I think, initially showed stable disease and then at later scans actually showed partial responses. And I'm just wondering if the physicians could comment on whether that type of finding is something that's more common with immunotherapies or something that can also be seen with just chemotherapy treatment on its own.

If I may start, I think that's not surprising to see, and that's not related or specifically related or associated with immunotherapy or with immunochemocombinations. I will say we do have the situation that patients do not yet reach the criteria for partial response after 8 weeks. And with continued shrinks to metastasis, they do reach this then at week 16. This is seen with chemotherapy but also with immunotherapy. But personally, I'm surprised to see so many patients already responding at week 8, which is quite an early assessment for pancreatic cancer. So therefore, I'm more surprised to see the high rate of patients already showing up at week 8. We compare to seeing this kind of stable disease at first imaging and then having partial response at second imaging after longer treatment duration.

If Professor Seufferlein or Dr. Bullock would like to comment, please feel free.

Yes, I can only agree with that, in particular, also for immunotherapy, it's a very early response. So I'm pretty surprised about the high number of early responders after 8 weeks in this combination and also on the maintenance of the response over a longer period of time. That's something I'm really surprised about, to be honest.

I was equally impressed and surprised, but I would echo what Dr. Seufferlein and Dirk said, that the immuno chemo combinations, I think sometimes not infrequently, those responses may be delayed. So we may not see that partial response until beyond the 8-week scan.

Our next question comes from Patrick Trucchio from H.C. Wainwright.

My first question is just for the panel. On Slide 46, there's a discussion around PD-L1 expression levels. And I'm wondering if these levels of expression was brought across all of those patients that were enrolled in the GOBLET program or if there was a cutoff of expression levels that correlated with complete or partial responses seen so far in the program.

Yes. I mean, I'm happy for the -- our KOLs to respond. Tom Heineman here. I can tell you that the PD-L1 expression was not assessed in patients on treatment in the study as these patients did not have biopsies subsequent to entering the study. So I -- so the data that was shown from an earlier study, but in the context of this study, we cannot correlate PD-L1 expression on treatment to the responses directly.

To be precise, not yet since we do have, let's say, access to tissue patients. But however, that's not the hypothesis behind because we have seen that there is a poor, we'll say, nearly no correlation of PD-1 or PD-L1 expression to any checkpoint inhibitors in pancreatic cancer. So I ask the other expert, Thomas Seufferlein also working in this field preclinically. Thomas, I think to my knowledge, there is no correlation. Is there?

Indeed, there is no correlation. I would expect actually to be -- the expression to be rather low as it is usually in pancreatic cancer. So I would not -- I won't be surprised to see it otherwise. There might be a change when you treat the patients with pelareorep, I don't know yet. But the baseline, I suppose, would be just as we would have expected from all the other trials. Andrea, what do you think?

I would agree thus far, PD-L1 levels are usually known to be lower in pancreas cancer, and it hasn't proven to be a predictive biomarker. I'm not an expert on the design of the GOBLET study, but my sense is that was looked at retrospectively and not identified as a predictive biomarker for this combination, at least not yet.

Yes. That's helpful. And then just a few follow-up questions on the clinical path forward from here. First, just wondering what some of the gating factors may be for advancing this program to the registrational study and what we would need to see in this next data cut to kind of give confidence the program is on track to advance your registrational program. And then separately, what would be needed to be demonstrated in the registrational study to support approval in pancreatic cancer?

Thomas here. I can comment from oncolytics perspective that we view this study as to -- as already demonstrating a signal for this treatment regimen in this population, right? And so we would view that the next most efficient and scientifically most valuable step would be to generate data in a randomized study in which this combination was compared to appropriate controls in order to further confirm the signal and move most efficiently to a registrational study. Of course, I would be very happy to hear the opinions of any of our experts on that proposed path forward.

I am so much involved in this discussion. So I'd like throughout the other 2 to give the first word to see what do you think from your perspective? Is this encouraging enough to -- and how would you advise to follow on the registrational path?

I mean, I think that the response rate and the durability of those responses is very impressive and unlike what we have seen in other pancreatic trials and regimens. So it certainly looks very promising and encouraging. Ultimately, of course, we want to see that we are extending survival, reducing toxicity, increasing response rates with the regimens that move forward, The bar is, unfortunately, not that high in pancreas cancer because of the limited treatment options that we have to date.

Yes. And I think definitely, in pancreatic cancer, we need a randomized Phase II trial at least to show that this is better than standard of care. We had so many failures in this disease. Actually, we had mostly failures in this disease that I think a randomized approach is necessary. I think this is also absolutely justified given the responses and the duration of the responses. And of course, we would like to see the PFS and the OS confirmed as we have these now the sensitive data from the smaller trial. And to see this in a larger trial, I think that would be fantastic, yes. Absolutely. I would really like to see a randomized trial.

And if I could just follow up with our experts to the second part of the question. In this population, first-line pancreatic -- metastatic pancreatic cancer patients, what magnitude of treatment benefit do you think would be ultimately meaningful as a treatment option in the future, assuming the toxicities are manageable. Perhaps Dirk, you could comment first, but I'd like to hear from everyone if people are...

Well, since -- yes, since we discussed it a bit, let's say, the question is always in clinical development and clinical goals in metastatic pancreatic cancer, can we trust in progression-free survival or do we have to wait for overall survival data? What is considered to be the more relevant perimeter? If you think of metastatic disease, I would say that progression free survival give, let's say, a good hint that there is a stronger activity if we combine something to a standard care. And I personally numerically would say that I would like to see an improvement of at least 30% or 25% for overall survival around that to really confirm that this is a meaningful -- and yes, this is a meaningful benefit or meaningful improvement.

Dr. Bullock or Professor Seufferlein, I think that would mean about a maybe a 3-month overall survival benefit or something. Would you consider that appropriately meaningful for a next-generation treatment?

I mean, yes, other regimens have been established with even more modest improvements in overall survival, more in the range of even 2 months benefit and that has been considered clinically meaningful.

Yes. I would think 3 would be fantastic because we're now seeing better data from real-world data on gemcitabine nab-paclitaxel combination. So the bar is a little bit higher than we used to have from the MPACT trial. And still 3 months would be fantastic. Absolutely agree.

Our next question comes from Douglas Miehm from RBC Capital Markets. We will go to the next question. So our next question comes from Paul Stewardson from iA Capital Markets.

I guess I'm just wondering a little bit about in this clinical setting for a larger trial how difficult is it to recruit patients? Can you talk about sort of the recruitment side of things from the clinician's perspective, what that's up against and then how competitive that is.

I'll take this since I'm dealing with this every day. And I think out of the portfolio of all the trials we are running at our cancer center, this cohort, let's say, there is really a fight to get seats on this cohort since patients are desperately waiting for improvement. Patients do know about their prognosis with metastatic disease and do know about the limited, let's say, efficacy of chemotherapy and are really enthusiastic about being on trial with standard chemotherapy plus immunotherapy as the hope for improvement. So it's a high unmet need, and promising signals from immunotherapy and the positive interpretation of immunotherapy make it from me, from my perspective, really super easy to recruit patients through this cohort.

I'd also say it's a piece of cake. The trouble will be to randomize these patients and probably would have to use DFS into a crossover to really offer patients something to really make them happy to participate because they all will say, "I'll participate but only if I get the immunotherapy, and I'm not going into the standard arm." So one probably will have to think about something to really entice the whole cohort to really stay on trial even if they are in the control arm.

I wouldn't see any barriers to enrolling patients on this study. Less patients with advanced pancreas cancer, many are coming looking for trials and particularly immunotherapy studies.

Okay. That's great to hear. And one more from me. Just in terms of the -- looking at the secondary endpoints of particularly overall survival. Is there any way based on historical clinical trials to get a sense based on the earlier endpoints like ORR, which [ has ] been very impressive, can we reliably use that to expect where we're going to end up on OS? For example, with a complete response, is that a pretty clear signal that OS is really going to have a positive result? Or is that something that when you've seen data like the PARP inhibitors, you really just can't take it seriously until you get the number out of the trial. Just wondering your opinions on that.

Yes. I don't know. I guess any of our experts could jump in. But again, maybe, Dirk, as a PI for the study might...

Yes. I will say response is really the promise here. But the proof of the trial has to be progression free survival or even overall survival. And we do have to see that we will really profit to this prolongation of overall survival likelihood. Responses are unexpectedly -- are really unexpected in this disease. So we would be also super happy in having many patients with stable disease and long progression-free survival and long overall survival since the correlation is not super clear. But however, with this high rate of objective responses, I would, let's say, I would wonder when -- or I would be extremely surprised this wouldn't be resulting in also a very promising PFS and overall survival. But proof has to be done on a randomized basis.

I can only agree on that. In pancreatic cancer, response by itself is very difficult because we've seen responses that did not translate. In here, we have a combination of response and duration of response, which I find probably encouraging, that response by itself. But it needs to be shown in a randomized trial, the superiority, particularly with harder endpoints. And I think it's also for authorities important to have a harder end point like PFS and preferably OS.

Our next question comes from Matt Biegler from Oppenheimer.

I was hoping the physicians could comment on the patient baseline demographics and just kind of how representative those were of the broader population, obviously, as we think forward to a Phase III trial, trying to limit any surprises where Phase II results diverge from randomized trials. So any kind of color you could give there would be great.

Perhaps we can run things around a tiny bit and let Dr. Bullock go first on this one.

Would we be able to pull up the table outside?

Can you pull up the table on the demographic side so that Dr. Bullock can...

I might not be able to comment.

No, I'm sorry.

I'm sorry. I didn't mean to throw you under the bus, Andrea.

No, that's quite all right. I would say, look, yes, this does look like a typical patient population, median age in the 60s, predominantly liver and lung with a high amount of liver metastases is actually kind of sizable target lesions. And ECOGs of 0 to 1, I think that is -- this is a very similar population to what has been looked at in other larger scale Phase III studies.

Thank you, Andrea. And Dirk or Professor Seufferlein line, please feel free to add your thoughts.

No, just to add, in clinical routine, you may see more patients with ECOG 2. So that's still a trial population. We have to be a bit cautious here. However, also ECOG 2 could mean potentially that the deteriorated ECOG performance status is related to tumor-related symptoms, and this could come from the massive tumor -- the bulk of tumors. So therefore, it could be also interesting to have, let's say, a patient with a poorer performance status and with the high likelihood of tumor shrinkage here by partial response also being treated. But that's speculative for the moment being, I'd say, and I completely agree with Andreas saying, this is a standard trial population.

The other thing that it's probably a little bit -- at least for German relations, it's a little bit a younger population than we usually would see at our centers because we usually see a median age of 68, 70 years of age. But that's a trial population. However, this combination, given the side effects Dirk has shown, it's not something which I would be afraid to include all the patients into this trial. It's not like a FOLFIRINOX protocol, where we really have to be afraid of very high hematotoxicity for example. So I personally think this is really -- you can extrapolate the population to a general one, particularly because age is not a limit to include patients in this particular -- for this particular protocol.

I'll now turn it over to Tim McCarthy of LifeSci Advisors to read the remainder of the questions.

Thanks, Sara. One remaining question that hasn't been covered in the discussion so far is to shine a little bit more light on the complete response, how common that is? Anything about that, was the detailed question?

Well, I think, Dirk, you are probably best positioned to comment on that specific [ patient ], if you're able.

Yes. Well, generally saying complete response is a rare event, and I wouldn't, let's say, necessarily say that this is a realistic goal to try to reach complete responses since it's so uncommon. However, we have seen it. We have seen this specific patient. So this patient presented with liver metastasis. And we can clearly object them to good imaging, and we can -- and this confirmed that go stepwise from shrinkage to complete disappearance of the metastases. So therefore, surprisingly, it went well and it's there. But I wouldn't expect this, to be honest, in also a randomized trial or a larger scale trial occurring in many patients.

Okay. And that's it from here on the written questions.

So I think that concludes our question-and-answer period. Let me conclude by once again thanking the 3 KOLs for their time and the important work that they do. We very much enjoyed hearing from them and look forward to advancing our breast and pancreatic cancer program towards registration studies. I'd also like to thank all who attended today's webinar and wish everyone a good day.