OSE Immunotherapeutics SA (OSE) Earnings Call Transcript & Summary

Hello. Welcome to OSE Immunotherapeutics Key Opinion Leader Webinar. Today, we have the pleasure of catching up with 2 leading providers from different geographies. We will also allocate some time at the end for Q&A. So feel free to tee up your question in the chat during the presentation. First, let me introduce Dr. Stephen Liu, Medical Oncologist from Georgetown University. He'll kick things off and discuss the unmet medical need, as well as overall therapeutic landscape in lung cancer. And then we also have Professor Benjamin Besse, Medical Oncologist, Director of Clinical Research at the Gustave Roussy Institute in France, he'll present the [Indiscernible] study and registration Phase III clinical trial of Tedopi in non-small cell lung cancer. Before we proceed, it would be -- I thought it would be nice if we can have Nicolas Poirier, PhD, CEO of OSE, briefly recap the company's ongoing efforts in addressing lung cancer. Nicolas, you have the floor.

Thank you. So good afternoon or good evening, everyone. Thank you for joining us in this webinar. So I will first briefly introduce the company and then turn to more details in the mechanism of actions of our Tedopi cancer vaccines before leaving the floor to Professor Besse and Professor Liu. So OSE Immunotherapeutics is a clinical stage biotech, we developed exclusively first-in-class immunotherapies. We are developing these innovations, thanks to our innovative R&D engine and collaboration with European and U.S. academic university. Currently, we develop 5 clinical assets from Phase I to Phase III, in both oncology and in immuno-inflammation [indiscernible] or in partnership with some key industrial partners like AbbVie in the field of inflammations, Boehringer Ingelheim in the field of oncology or metabolic and cardiovascular disease as well as Veloxis in the field of transportation. So our most advanced assets is therapy. As you can see in our pipeline, therapies neoepitope engineered -- neoepitope T-cell cancer vaccines, we will see with Professor Basse key data we have generated and published last year in the monotherapy, randomized phase [for trial] and CRC [Indiscernible] and the study design of our next step, next pivotal study in second line still in monotherapy after failure to checkpoints in a non-small cell lung cancers. And we will have you also very briefly how we explore potential of combination of this new drug modality with either chemotherapy or anti-PD-1s in pancreatic cancer, in ovarian cancer, and CRC as well. So if we turn now in the drag in the asset therapy. So therapy is a combination of 9 optimized and engineer T cell epitopes, from different -- 5 different tumorous CT antigens, they are emulsified with a ready-to-use formulations, injected subcutaneously in patients in the [arm of] patients. And then they will be captured and presented by our [indiscernible] cell -- antigen presenting cells to educate our immune system, generate T-lymphocytes, expand the pool of fresh T-lymphocytes capable to recognize this tumor antigens. We have the capacity with the technology I will present to [indiscernible] these tumor antigens, by engineering this T-cell epitope. And then we have demonstrated the T cell eliciting periphery has the capacity to migrate in tissue in particular in the line, when they can exert their functions. They are cytotoxic function, elimination of cancer cells. So we have currently an orphan drug designations of these vaccines, thanks to engineering of the technology for the HLA-A2 molecule. So HLA-A2 was a -- HLA system is an antigen machinery presentations in humans. There is some polymorphisms and HLA-A2 is the most prevalent one, 45% of the population, and we are now selecting these patients, thanks to accompanying diagnostic biomarkers. So if we look now at the revival interest in the feed of cancer vaccines -- Tedopi cancer vaccines, there is 2 different approaches with 2 different clinical positioning. On one side on the left, the off-the-shelf Precision Medicine approach that we are developing, on the right Personalized Approach in the field of neo-antigens, which require to have access to tumor biopsy, sequence genome of the patient, sequence genome of their tumor, identified and predict a key T-cell epitopes in this mutated neo-antigens and manufacturers for each patient, an individual vaccines. So at times, it's costly. Unfortunately, there is some viability in the predictions of T-cell neoepitopes and hence, the immunogenicity generated in patients, but this last 2 years, we have seen very promising data in the early settings, adjuvant approach to prevent tumor relapse after surgery in combinations in non-randomized Phase I and Phase II, and so we think that it's a really interesting approach to move forward. If we come back to the off-the-shelf, Precision Medicine approach, we have a ready-to-use vaccine with a ready-to-use emulsions. And we can select the patients with a [Indiscernible] diagnostic, not based on the tumor antigen expression, based on the HLA, a genotype of the patients just by a blood sampling. And then we have demonstrated and will show you some data that this approach generates strong CD8 T-cell response in patients and we were able to demonstrate positive data in randomized Phase III in the metastatic disease settings, how we can extend survival for these patients as compared to chemotherapy. So 2 different approaches. We have very interesting positioning in terms of clinical development. One key elements in the field of therapeutic vaccine now is based on the cancer antigen immunogenicity. So a good therapeutic cancer vaccine need to have tumor-specific antigens for sure, but also very strong antigen immunogenicity. So what we have done on the technology of therapy is based on identifications and the identification of validated T-cell neoepitope in the lab from different and shared tumor-associated antigens that have been engineered to break the tolerance, increase their [Indiscernible] and increasing the immunogenicity very close to pathogenic antigens, by engineering the affinity for the TCR or the HLA, so [marginally] which is capable to present or recognize these tumor antigens. This has been -- this is just a summary of the process that have been in performed in the lab more than 10 years ago. So thanks to the understanding of the key residue at the [Indiscernible] in T cell epitope peptides as the interface with the [Indiscernible] a series of thousands and thousands of different peptides and T cell epitopes from 5 different tumor-associated antigens. I was explaining that we screened thousands and thousands of different T cell epitopes from 5 different tumor-associated antigens from [P53, CR2, MH2, MH3]. And then the stronger epitopes for the -- I think for the TCR, HLA have been selected. And you have an illustration on the right part of the slide showing that wild-type epitope in blue T cell epitope from a tumor-associated antigen, can elicit some level of immunogenicity the T-cell [Indiscernible] cytotoxic functions. Just by engineering the epitope which can dramatically create both immunogenicity and cytotoxic profile of the tumor elicited -- tumor-specific elicited T-cells contracting with tumor cells expressing the [Indiscernible] antigen. So several of these epitope has been screened in the lab, in vivo in animals, and then the combination of the best 10 neoepitopes have been selected in terms of synergy and moved forward under clinical development. So this is just some data from our Phase I and Phase II studies where we explore, of course, the safety of the product, also the immunogenicity. You can see on the left, some immunogenicity elements measured by [Indiscernible] response by flow cytometry in cancer patients, very advanced settings where we can see that epitopes that have been engineered for the TCR affinity in green or HLA affinity in red, both are highly immunogenic in patients and the strong [Indiscernible] positive response against the peptide that have been used for vaccination, but also for the wild type corresponding antigens expressed by the tumor cells, validating the concept that TCR cross reactivity is key, we can engineer epitope to break tolerance and induce T-cells that [cross react] with the tumor antigens. On the right, this is the individual data for each individual peptides during the Phase II in non-small cell lung cancer patients, where we can see very robust and very broad T-cell immune response in the majority of patients against individual peptides, either the wild-type, epitope modified for the HLA or for the TCR. And I will just stop after this slide, just illustrating reminding some data -- key data, we generated in Phase II in NSCLC patients, more than 60 patients, Stage 3 and 4, post chemotherapy, where we will sell a very intriguing survival, long-term survival rates in these patients at a time post chemotherapy. And most importantly, we found a strong correlation between immunogenicity [Indiscernible] blood, a list of response and survival, significant correlation between survival and immunogenicity. So I'm done from our presentation. Thank you very much.

Great. Thank you, Nicolas. Apologies for the slight technical difficulty, but let's transition to our first KOL speaker, Stephen Liu, as I briefly mentioned earlier, he is the Associate Professor of Georgetown University's Lombardi Comprehensive Cancer Center. He has extensive training, starting at Johns Hopkins University and then the University of Southern California, and he focuses on innovative treatments for lung cancer and related malignancies. He leads the thoracic oncology efforts, and the Phase I development therapeutic group, and he has published -- he's been published in numerous recognized journals, including the New England Journal of Medicine, Journal of Clinical Oncology, Journal of Thoracic Oncology, Lancet Oncology and Cancer Discovery and Clinical Cancer Research. Without further ado, Dr. Liu the floor.

Thank you Sue, I want to talk a bit about non-small cell lung cancer, Professor Besse and I, both focus on this subtype. And in our lifetime, we've seen a dramatic shift in not just how we manage lung cancer, but really how we perceive the disease. It has happened in a relatively short period of time. And coming from the U.S., when we think of lung cancer, lung cancer is by far the leading cause of cancer-related death in the U.S. shown here are estimates for 2024, and you see for both men and women, a leading cause of cancer death, outnumbering breast cancer and prostate cancer combined, that peaked in the late '90s, early 2000s. And while we have seen progress due to some innovative new paradigms, still far and away, the leading cause of death for both men and women. In the '80s, '90s, even the early 2000s, lung cancer was known for a tremendous and profound sense of nihilism. And many community oncologists, which is where most lung cancer care is delivered in the U.S., really weren't deciding between which treatment to give, but whether to give treatment at all. As recently as 25 years ago, we were still publishing analyses comparing treatment to placebo in the frontline setting to best supportive care. Because at that time, our drugs did not work very well. They were fairly toxic and often the treatment worse than the disease. We've come a long way in disrupting that sense of nihilism with some important advances. And with platinum doublet chemotherapy, better supportive care, chemotherapy did become our standard of care. I show this study ECOG 1594. This was a study, a cooperative group study in the U.S. that compared the 4 main chemotherapy doublets in use at the time. So they were all roughly equivalent. But I showed this to show how limited the outcomes are with chemotherapy alone. If we look at the left in progression-free survival, we see the median progression-free survival somewhere around 3 months or so, meaning that when we start treatment by month 3, month 4, most patients have seen their cancer start to grow. The benefit of chemotherapy really is a transient one. If we look at survival on the right, a median survival well under 10 months, by the time we get out to 2, 3 years, we see that survival number very close to 0. Chemotherapy alone is of benefit, improves quality of life, extend survival, but there is a very low ceiling as to what chemotherapy can accomplish. This was our standard for many decades. We didn't think we could do much better than that, and it really did plateau. It changed with the integration of immunotherapy. Immunotherapy changes the paradigm in a dramatic fashion, very quickly replacing docetaxel as a second-line therapy. It has since emerged as part of our standard frontline treatment, either alone, in combination with other checkpoint inhibitors or in combination with chemotherapy. Now in 2024, our standard after radiation before surgery, after surgery or both immunotherapy really lead into our paradigm in every step of the way. The advantage of immunotherapy is clear. It has generated tremendous enthusiasm from most scientific and lay press. And justly so, it is the durability of response. The potential for long-term survival maybe even cure. And on top of that, a much more favorable safety profile. If you look at the study that really changed our paradigm in 2016, we saw KEYNOTE-024, shown here the 5-year survival updates. This was for patients with high PD-L1 expression, which is about 1/3 of our patients with non-small cell lung cancer receiving pembrolizumab alone on that blue bar, we see 30% alive at 5 years, 1 in 3 something we could not fathom just a decade ago. In addition, if you look at that blue curve, you get the sense that it flattens out that there is a tail, a plateau, suggesting that if you alive at 4 years, very likely to be alive at 5, 6, 7 and hopefully beyond. Are these patients that we are potentially curing. Now this is a very elite population, but we've seen in real-world analyses, this work done with Dr. Solange Peters and myself, showing that in very large data sets across all PD-L1 strata, about 20% of patients are surviving to 4 years in the real world with all the comorbidities and constraints, that population intends. This is real, patients are surviving, patients that would not be alive with standard therapy are alive now. And just a few days ago, we saw the update from CheckMate 9LA. This was our most aggressive regimen for drugs, nivolumab, ipilimumab plus 2 chemotherapy agents, and we see here 18% of patients alive at 5 years. Now when we often celebrate this 1 in 5 alive at 5 years, if we flip that curve around, it means about 80% of people are not alive at 5 years. Our goals here are to extend that survival for people that are responding, but really to get that type of quality durable response for more patients for all of our patients. That is our goal and we've taken a very important first step. I think it's clear that we have a long way to go. The unmet needs for lung cancer, we know that a small subset will achieve that long-term survival. The vast majority will not. And after chemoimmunotherapy, in 2024, our standard is docetaxel-based treatment. Shown on the right are the outcomes from the REVEL study, looking at docetaxel plus ramucirumab or those curves fairly close together, the adoption of ramucirumab, very inconsistent given its modest benefit. But overall, in this setting, we see a response rate of 14% to 23%, most patients not getting a response. The median progression-free survival of 3 to 4 months, the median overall survival is 9 to 10 months. This was published 10 years ago, and we're embarrassed to say this remains our standard now. We've tried to do better and there have been a number of Phase III studies looking to improve upon docetaxel. This seems like a low bar, but one we have not been able to clear, small sampling here, a very highly publicized and highly talented Phase III trials that failed to improve survival over docetaxel, CANOPY 2 looking at an IL-1 antibody Canakinumab, no difference in overall survival. The CONTACT-1 study in the [Indiscernible] trial, looking at VEGF and multikinase inhibitors, Cabozantinib, Sitravatinib, no difference in survival. The [Evoke I] presented a week ago today, looking at the TROP2 antibody drug conjugate, sacituzumab govitecan, no difference in survival by press release, the CARMEN-LC03,tusamitamab ravtansine will be presented later this year, but we know no difference in survival. What do these have in common? These were built on solid science led by various steamed investigators. And what these combinations showed was an improvement in outcomes, better response rates, better progression-free survival in smaller studies, very promising. But when put to the test of overall survival, they did not improve survival. People didn't live longer. And if we look a little more closely at the EVOKE-01 trial, again, this very disappointing Phase III trial. We thought there was no improvement of this ADC over docetaxel. But again, look at a modern day rendering of docetaxel and how it's performing, 18% patients responding, meaning 80% plus not responding, a median progression-free survival of 4 months of survival of less than 10 months. And what is perhaps most vexing with docetaxel, is it is a very difficult medicine to give. 40% of the patients, nearly, with a dose reduction, 14% stopping therapy just due to toxicity. The median duration of exposure, only 2.3 months, median time to deterioration based on quality of life 2.1 months. I can tell you, it is very hard to have numbers that are worse than that. People are voting with their feet. This is a real-world analysis of U.S. practice patterns published by Dr. [Indiscernible] and myself, looking at real-world treatment sequences after chemotherapy and immunotherapy. If you look at that blue bar at the top middle, we see nonplatinum-based chemotherapy represents less than 30%. This is our only standard in the U.S. And when we are free to choose what we like, we do not choose docetaxel. Even though this is our standard of care, simply a medicine that we do not like to give patients do not like to receive. What doesn't show up on our toxicity tables is the deterioration is the overwhelming fatigue and the low overall quality of life, really choosing between this treatment and no treatment often patients and providers choose no therapy. When we look at our current status in lung cancer, the use of immunotherapy has changed, not just our standard of care or treatment algorithms, it's changed what's possible. But along the way, it has raised our expectations, and we are no longer satisfied with regimens that offer modest response and transient benefit. What we want is long-term benefit, what we want is survival. In addition, we also want tolerability to maintain that high quality of life and the toxicity of docetaxel prevents it from being used. It is our standard of care in Phase III trials. It is not our standard in clinic. People choose to offer anything else. And when we look back at the practice patterns, we see about 30% of patients receiving a checkpoint inhibitor, second line after progressing, on a first-line checkpoint inhibitor. There is no data that this is of any benefit, but we choose that because of the prospect, that minute hope that we can offer a long-term survival without overwhelming toxicity. I think that speaks volumes for what we need in lung cancer. Most patients don't achieve durable benefit. What we need is safe and effective treatment for those patients that give us at least a prospect of something better and long term. With that, I'll turn things back over to Sue.

Great. We really appreciate your effort in this challenging area, Dr. Liu. Next, we have Professor Benjamin Besse. He's a recognized medical oncologist specializing in thoracic cancer, currently serving as the Director of Research of Clinic, Gustave Roussy with expertise in personalized treatment approaches and early drug development, he's authored over 250 peer-reviewed articles and has led numerous clinical trials. Besse holds leadership roles and prominent scientific councils and networks, including Chair of the EORTC Scientific Chair Council and Coordinator of RYTHMIC, the French network for malignant thymic tumors. Professor Besse, I'll hand it over to you.

Thank you very much. So given better key set up the challenge we have in second line treatment after chemo immunotherapy in non-small cell lung cancer. And this is where the cancer vaccine therapy or OSE2101 was developed. I will briefly review the data we have generated. So as Stephen said, upfront when you diagnose the patients with the metastatic non-small cell cancer, you have to look at the targets, and we know that the Caucasian population, probably 15 to 20 of these patients have a target that will change the standard of care that will -- and will receive first-line targeted therapy. But for 80% of the patients, immunotherapy or chemo immunotherapy. And the main unmet need today is, as Stephen said, the second-line treatment. I just summarized some studies that Stephen already presented, on the left side one strategy that is to give immunotherapy plus VGFR inhibitor and it's totally negative against docetaxel second line. And on the right side, the very, very disappointing curves, a new family of drug, the antibody drug conjugates in which 2 years ago, a lot said this will be the new standard of care second line, while the figures are not good enough to make it a standard of care, and we are still using docetaxel, and it highlights the need for alternative strategy to ADCs or oral drug. Therapy has been tested against docetaxel in a randomized Phase III trial called [indiscernible]. We enroll patients with HLA-A2 positive profile. What is HLA-A2? It's like the -- your type of blood A, AB, O -- your blood type. It's a different type of immune system. It's not good, it's bad to be HLA-A2 positive or negative, roughly out of the Caucasian are HLA-A2 positive, it's only those patients that can process the vaccine and then develop a reaction against the vaccine and the cancer cells. So we enroll patients that were pretreated with chemotherapy and immunotherapy. At the time this trend was started, it was not a standard of care to this combination of chemo and immunotherapy. So some get first chemotherapy and other chemotherapy followed by immunotherapy, and other the combination of 2. Brain mets [Indiscernible] without control. And there was a 2:1 [Indiscernible] between therapy, subcue or docetaxel or [indiscernible] 1 or the 2 chemotherapy that was allowed. And the similar [indiscernible] point was OS. The trend started before the public. So we aim to enroll 323 patients; but because of the COVID time, and the vaccination against COVID that was a bit concentrated with the vaccination with [indiscernible] . We decided to stop the study. And as you can see, only 219 patients was enrolled in the study. Of interest and analysis of this population show that only the patients with similar resistance to immunotherapy, derive a good benefit from the vaccine compared to the chemotherapy. It means that these patients with at least 6 months of immunotherapy were more likely to benefit from the vaccine as if I was responding to an immunotherapy, I will respond to the vaccine. If we look at a group of patients with secondary resistance, you can see the overall survival goes from 7.5 months with the docetaxel to 11.1 months with therapy, with other nature of 0.59, which is quite strong because lower than 0.6. So there is really here a signal of efficacy. If we look at the difference of group, may be innovations with brain metastasis had no real benefit from the vaccine, although it's a very small subgroup. But you can see that most of the patients, whatever their stage, their smoking status had a benefit to the vaccine. The good part also is the vaccine with a side effect that are lighter than for docetaxel. So the time for the worsening [Indiscernible], which is the time from the start of the treatment to, let's say, nearly chronic fatigue and the fact that you are not able anymore to lead your daily life, this period is extended with vaccine. It has two causes, first of all, the vaccine is much well -- much more tolerated than the chemotherapy. If you look at the severe side effect related to the study drug, it's 3x more severe side effect with the chemotherapy compared to the vaccine. And on the right side, you have the quality of life that is better, but in some use, if you can control the disease and then decrease the side effect of the tumor, obviously the quality of life will be better. It's only a subgroup of a study that was stopped for recruitment. So it's a signal of efficacy that we have to confirm in the new [Indiscernible] Phase III study, and this is the [academia study] that I will present now. Before starting the study, OSE Immunotherapeutics met the FDA and agree on the population. So HLA-A2 positive non-small cancer with secondary resistance to immune checkpoint in either [Indiscernible] the docetaxel, which is [indiscernible] , the other drug didn't make it. They agreed on the primary endpoint, which is overall survival, really strong in that setting, the main secondary endpoint, in particular, the quality of life of the patients and their reported outcomes and a biomarker designed for the selection of HLA-A2 positive patients. So the trial has already started. The U.S recruitment is now open. The design is really similar to what we have seen with [indiscernible] , which is remission to do one between therapy or docetaxel in roughly the same population, but restricted to the patient with secondary resistant immunotherapy. So all these patients had the degree of benefit to their first immunotherapy. Obviously, HLA-A1 has to be positive and all histologies and nonsquamous and non-squamous are enrolled. There are other efforts with therapy in the -- in other type of disease and this is the other cancer area where therapy is dead-locked. There is an ongoing study of therapy combined with endotherapy as a second-treatment plus chemo-immunotherapy. And there are 2 trial with met [Indiscernible] therapy, after [indiscernible] one that is currently recruiting in the ovarian cancer and one that is close to recruitment in paretic cancer and the readout is expected this year, although the readout of 2 other trials is expected in 2025. And with that, I will give back the floor to Nicolas.

Thank you, Benjamin. So thank you all, again, for joining us today in this webinar. So we are really happy and really proud to develop one of the most therapeutic cancer vaccine, in terms of clinical development. In off-the shelf cancer vaccine we've -- what we think are very differentiated, but complementary mechanism of actions after PD-1 figure. When the immune system is not strong enough to kill element of cancer, we need to form -- we need to train new troops, from new fresh soldiers and send a new wave of immune soldiers in the battlefield. So we are highly convinced, thanks to the data we have generated and published last year that -- there is a place for cancer vaccines in this advanced metastatic settings. Patients need innovations, I think Professor Liu explained that we need to increase survival in these patients. We need to have drugs that are well tolerated for our patients. So we are eager to start this Phase III, this pivotal confirmatory Phase III in second line in this population of secondary resistance or [Indiscernible] resistance after PD-1 failure. And to hear more about the Phase II exploratory studies in combinations to see whether there is broader potential in other indications or when we combine this new drug modality with chemo or anti-PD-1. Thank you very much for joining us today.

Thank you, Nicolas, and thank you, Professor Basse. We look forward to the -- any updates on the Tedopi results. This concludes our prepared remarks.

So we'll proceed to Q&A. I'll give a minute just so we can queue up some questions. [Operator Instructions] I will read one off here. I think this is more for the KOLs. Could you share a brief overview of the current treatment plans for non-small cell lung cancer, including success rates as well as the presence of various mutation influence choices of the treatment?

Yes. So I can start with that. As Benjamin mentioned, we first subject these tumors to biomarker testing. And if we find an actionable target like a mutation in EGFR, Fusion and ALK and we go down the targeted pathway. The targeted agents work for nearly everyone profound, rapid deep responses. They can work for quite some time, but they do not work forever. I mean we do expect resistance. If we don't find one of those actionable alterations, which is still the majority of the time, then the standard treatment is immunotherapy. And we have a lot of different ways to deliver immunotherapy, either a PD-1 or PD-L1 inhibitor alone with a CTLA-4 inhibitor or with chemotherapy. And while we're waiting for results from direct head-to-head comparison, long-term results between all these strategies are, I think, pretty similar. A subset of patients with long-term survival, not the majority. And really, we need something better for those patients that don't achieve that. Benjamin, I'm not sure if you have a different approach.

I very fully agree. The issue is that I would say, [Indiscernible] drug has been moved to first line, depleting the second line. I mean, 5 years ago, we used immunotherapy in second line that is so effective that it's now in first line. And it's true that -- this is really in the space where we made improvement. And as we said, there were strong competitor in the field Tedopi [Indiscernible], ADCs. And in fact, they are -- well, we realize and I think we are all surprised that the docetaxel is after treat [Indiscernible] care, and we need an alternative option to [Indiscernible].

Yes. No, it's really great. So we recognize that the non-small cell lung cancer treatment market, it's super competitive, both in terms of what's available and those in the pipeline, in your view, what sets to Tedopi apart from the rest?

Well, I would say, the landscape in second line is not that competitive. Well, it's, I would say, is not anymore compared to 2 years ago. We will have other Phase III trial with ADCs and we're waiting for the readout that the top 2 ADCs were disappointing. There are attempt to use ATR inhibitor in second line, [Indiscernible] inhibitor, let's say, and there is a Phase III ongoing. But the possible options that we see are quite limited and therapy is quite unique in the way we can activate the immune system and the fact that you are targeting a population that had a degree of sensitivity to immunotherapy makes sense. So the idea is really to reverse the secondary resistance to immunotherapy. So this is about -- we have promising data from the first study.

Yes, I agree with that. I think that -- what I like about the agent is that it is, as Benjamin pointed out, very different. We're not relying on cytotoxics, which we know offer only a transient benefit. And while antibody drug conjugates have a different design, they exert their effect through cytotoxic means. And so I do think the ceiling is lower there. What sets to Tedopi apart for me is really in the early signal was survival, not responsor to PFS, it was overall survival. I think that there's no clear surrogate for it in this day and age. In addition, I think that one of the curves that Benjamin really pointed out that resonated with me was that sort of time to worsening performance status. And while some patients may derive benefit transiently to docetaxel, we can see others where you get the sense you're almost deteriorating things faster. Tedopi is much better tolerated. And by avoiding the toxicity of chemotherapy, I think we offer the prospects for a much more meaningful treatment.

Yes, that's great. Maybe a quick follow-on to that, Nicolas, maybe you could give a brief overview of how the Tedopi works from a mechanistic perspective?

Yes. As I think all cancer vaccines, we have 2 key properties, which is oxygen selectivity, but most importantly I think antigen immunogenicity and there was a lot of effort, and there is still a lot of efforts to identify the best source of cancer antigens, mutated or not. But the difficulty is immune tolerance, we need to have antigens, tumor antigens that are trained enough in order to make sure that our immune system will see them, really recognize as strangers, foreign, and then amplify the immune response and then kill the tumor. So -- this is not something that is easy. We have succeeded in generating highly mutagenic cancer antigens, epitope by engineering this epitope. And to use intrinsic [Indiscernible] the immune system to be cross-reactive. There is not one T-cell for one antigens. Our immune system is fantastically cross reactive against different pathogens, self-antigens and cancer antigens. So we can design foreign antigens and engineer cancer antigens to increase the level of difference to the self, [indiscernible] educate T cells and then cross reactivity with the tumor antigens and elimination of these cancer cells, [Indiscernible] in our technology.

Yes, that's great. So how about for the KOLs, I think this is more appropriate. We look forward to the following the progress of the confirmatory pivotal trial for Tedopi, especially after the encouraging results from the [Indiscernible]. Could you recap any differences in terms of trial design focus between this and the Phase III trial?

The main difference is that we have restricted to the population with secondary resistance to immunotherapy. They have received at least 6 months of immunotherapy and when you give a chemo immunotherapy, for example, first line, usually, you assess, well, you give chemo plus immunotherapy during 3 months and roughly after just the immunotherapy. And during the first 3 months, you don't really know who is the good guy, if it's immunotherapy, chemo or both. But after 6 months, if the patient still in response, it's probably the immunotherapy that maintain this response for a long time. So it's a very simple criteria, but quite solid, and it's an international criteria, find by the immunotherapy society, that's the main difference. We are a bit restricting also on the brain mets because there is no signal of activity there, the patients must have -- keep their brand meds, they must be completely controlled.

Yes. To me, it's just a natural sort of following the science and really where that signal was strongest and where it made sense because as Benjamin pointed out, the world is different now than it was when [Indiscernible] was conducted. So I think it's a natural continuation to really find where this agent is going to provide the most benefit.

Great. That makes sense. Nicolas, maybe you can help with this one. Can you provide some more details on how the companion diagnostic streaming will be used as part of this trial protocol?

It's a very easy task. So just a blood sampling, no need of tumor biopsy, tumor resections, just blood sampling and then its new next-generation sequencing technologies, just to identify what we call the genotypes. So the allele that is expressed for the HLA gene. So if the patient is HLA2 which, as explained by Benjamin, roughly 45% of the Caucasian population. So patients will be select, just by this blood sampling. And while we select this HLA 2 because the vaccine or the epitope have been engineered to increase affinity. And we know that HLA2 patients are the biological responders to these vaccine. So we need to have patients that really biologically respond to the vaccine to make sure that at the end, we may have a clinical benefit.

Yes. And maybe another one for the KOLs. Tedopi certainly has promised in non-small cell lung cancer as a monotherapy. Could you comment on the potential synergies between the cancer vaccine with immunotherapy?

I think it's a very natural combination and certainly you want to show a benefit here, but the potential -- the combined ability, I think, is quite vast. This is a drug that does not have sort of overwhelming toxicity, can be combined very well. And most combinations that we use in lung cancer are additive. But I do think that in this particular instance, based on antigen presentation, there's the potential for true synergy. So one could certainly see a world where this has moved into different settings in combination. I'm not sure if Benjamin is a different perspective.

No, I fully agree. And the combination is part of the development of Tedopi, yes, since there is this trial ongoing combining therapy plus immunotherapy without safety signal that would have stopped the study, which is a good sign. And there are also a study in ovarian cancer and combined with chemotherapy in pancreatic cancer. So yes, it made complete sense to combine the treatment.

That's very good. And then for Nicolas, following this, could you share some further details on the Tedopi potential in other cancers, such as pancreatic cancer, maybe ovarian cancer?

So this is ongoing study, so I will not be able to share any information for sure. I think as explained by Benjamin, Stephen, we have a very good safety profile, which is important if we want to combine, with another molecules. Otherwise, you increase biological risk [Indiscernible] toxicity. And what is, I think, important also is a complementarity in terms of MOA. So it's a very differentiated mechanism of actions, very different from the anti-PD1, very different from the chemo or the other drug modalities. So if we want to look for synergy, we need to have for differentiated mechanism of action. So that's really important. That's why we explore combination with anti-PD-1, how pushing on the gas pedal with the vaccine and raising the break with anti-PD1 can clearly unleash the anti-tumor immune response. But there is also rationale to combine with chemo, for example, in our pancreatic cancer study, where we need probably to slow down the rate of tumor growth in order to have time of our immune system because the T cells need time to kill one cancer cell. But when you think that the patients are progressing, the number of tumor cell is growing, and so we need to probably reduce the rate of tumor growth in order to make more time for our immune system to eliminate these tumors.

So I think that -- those are all our questions. I know you took the time to answer so many here. So thank you, everyone, for joining us here today. We appreciate it's been a really busy week with ASCO and the late hour in Europe for our audience. If you would like more information on the company, please do not hesitate to access their website, oseimmuno.com. or [Indiscernible], OSE Immunotherapeutics. This recording will be shared in the next coming days. Thank you all.