OSE Immunotherapeutics SA ($OSE)

Biotech company listed on market. And we we're lease to [indiscernible]to stand. First let's say it's a global answer I can more on what can bring this this disease -- and mostly are with new initiations for us that present and in age days ago. So in a few words, I would like to make a brief introduction on the company. This is a company I joined less than a year ago. And I'm absolutely convinced that this is a future great biotech company in France and in Europe because we have incredible products. We have this product that we will go into details today, which is TEDOPI. It's an immunotherapy, which is very promising with already more than 700 patients that have been treated. And we expect to have a Phase III readout early '28. So it's very close now. And we have a second compound, which is Luvertikibab, which has delivered positive readout in inflammatory bowel disease last year, in particular, in ulcerative colitis. We are not going to elaborate on [indiscernible] today. This is not the purpose of this webinar. So just if we can share, Thibault, the first slide to give a brief overview of the company's pipeline, of course, a forward-looking statement as we're a listed company. This is compulsory. And then on the next slide, you will have an overview of our clinical assets, which are twofold. We have proprietary assets, which are lusvertikimab and TEDOPI and some partnered clinical assets with Boehringer Ingolam and Veloxis, which is part of Assai, the Japanese company. As you can see for lusvertikimab, we already have delivered Phase II data in ulcerative colitis last year. We're now preparing a subcutaneous formulation that is more suited to the actual market, the actual needs of the patients. And we are planning to launch rapidly now a second indication, which is some kind of subset of ulcerative colitis. The second indication is called chronic [indiscernible]. It has the potential to read out in '27, and we could imagine to launch products in a few years. For TEDOPI, the beauty of our pipeline is that we have this Phase III ongoing Artemia on which [indiscernible] will spend some time. And we also have a series of investigator-sponsored studies, in particular, the one that has been announced and described by Alexandra at ASCO on ovarian cancer, but we'll have additional readouts in the second part of this year, H2 '26 in non-small cell lung cancer in a larger population than Artemia, and we also have long-term readouts of pancreatic cancer trial. So now I'll leave the floor to Stephen, who will give a vision on the pathology itself. And thank you so much to all of you, Stephen, Benjamin and Alexandra for taking the time to make this presentations that will hopefully give more insights to our participants. Thank you so much.

Well, thanks for having me. My name is Dr. Stephen Liu. I'm a thoracic medical oncologist at George University in Washington, D.C., where I'm the Chief of Hematology and Oncology and the Head of Developmental Therapeutics. What I'd love to do to set the scene for some of my colleagues is describe the current state of the treatment of lung cancer and how far we've come in and really outline the unmet need. So if we get our slides here, I believe I start with some disclosures. And in the past 13 years that I've been at Georgetown and the 3 lung as we go to the next slide, past 13 years, we've clearly made a lot of advances in the treatment of lung cancer. We've really seen a wide reversal. Lung cancer is a fairly common disease. These are U.S. numbers, where you can see it's the second most common cancer in men behind prostate, the second most common cancer in women behind breast. And if we click ahead, while it is the second most common, it is by far the most lethal. We click a hit the next. So by far the most lethal cancer, you can see the #1 cause of cancer-related death for both men and for women. As you can see, it represents more deaths each year in the U.S. than prostate cancer or breast cancer, for liver cancer or ovarian cancer combined. So it remains a huge unmet need and one of the most lethal cancers that we have. If we go to the next slide. Here, we can see that in red on the left, we see the mortality for men and for women. Lung cancer is on the way down, fortunately, but still far outpacing any other cancer in the U.S. On the right there, you can see the initial stage of diagnosis, these are 2026 numbers. And what we see is part of the reason is we detect lung cancer at a fairly late stage with the most common stage in the U.S. being Stage 4. Outcomes for stage 4 as one can imagine, are clearly worse. And if we look at our survival numbers, while they are better for localized and regional, they're still fairly poor across the board. Our 5-year survival rate of 28% pales in comparison to other cancer types. We look at breast cancer, 5-year survival rate is 92%; prostate cancer, 98%; colon cancer, very important cancers, a 5-year survival rate of 65%; and at lung, we were at 28%. So while we are proud of all the advances that we've made and while these are the best survival numbers we've ever seen, we still have a long way to go, and it still remains an incredibly lethal disease. If we go to the next slide. We've seen advances in the treatment of lung cancer really in the form of 2 different paradigms. One is the development of targeted therapies. Following on the heels of the human genome project and the understanding that certain genomic subsets of lung cancer can respond very well to novel targeted therapies. Here, we see real advances in medicinal chemistry. And if we can identify certain subsets of lung cancer, we can deliver very effective targeted therapies, things like EGFR, ALK, ROS1. When we find these alterations, when we deliver a targeted therapy, we expect responses for the vast majority of patients. While there are some exceptions for most of these patients, we will see resistance in 1 to 2 years, which remains a real challenge in the clinics. But importantly, this is only a subset of patients. For most patients with advanced lung cancer immunotherapy will be the backbone of our treatments. This is appropriate for most cancers and across both histologies. For some, we use monotherapy, PD-L1 or PD-1 inhibitors alone. And for most, we use combinations, either dual immunotherapy or combinations with chemotherapy. But immunotherapy really is the mainstay for most patients with advanced lung cancer. And it's made a huge difference. And not only has it changed how we treat lung cancer. It's changed how we think of lung cancer and really raise the bar in terms of what is possible and what our expectations are. On the next slide, we get into some of the details regarding immunotherapy. And KEYNOTE 024, I think is one of the more important studies that changed our standard of care. This was a study presented at ESMO in 2016. In this trial, we compared a single immunotherapy agent, a drug called pembrolizumab a checkpoint inhibitor and antibody, targeting the PD-1 protein. This immunotherapy agent alone compared to standard chemotherapy, chemotherapy that had been our approach for the treatment of lung cancer for decades, chemotherapy that prolonged survival improves quality of life. Here, we compare that to immunotherapy. And what we saw from that Phase III trial was immunotherapy was better in every conceivable way, better in terms of response, progression-free survival, the durability of control and overall survival. Importantly, it's also better in terms of toxicity. Immunotherapy became our standard of care based on this trial for patients whose lung cancer had high expression of a protein called PD-L1. It's about 1/3 of patients. These are updated data, looking at 5-year survival rates pause there and acknowledge the importance of that sentence, 5 years survival rates. Decades ago, we wouldn't even conceive of anyone surviving 5 years with a Stage IV lung cancer diagnosis. And here, what you can see is almost 1/3 of patients alive at 5 years. This study was presented in 2016. And so we have even longer follow-up. On the next slide, we see 8-year survival data. at 8 years, we have almost 1/4 of patients alive at 8 years. So here we see 24% of patients at 8 years. Notice that there's not a whole lot of difference between the 6-year survival rate and the 8-year survival rate. But I think a better mark is how many of those patients are not -- have not seen any evidence of progression. If we look at the next slide, while 24% of patients are alive at 8 years, we see 13% of patients are progression-free, 13% of patients. So in this study, patients received 2 years of immunotherapy and then are observed. And for 13% of patients enrolled in this trial, 6 years with no therapy, they have still not seen their cancer come back. Now the word cure is a tricky word, it's an emotional word and a hard word to define, but are these patients cured? And I believe that some, if not all of these patients are cured. And so we are able to cure some patients but notice, it is a small minority of patients, only 13% of patients. But it is possible. And now, so to speak, we've bit me Apple. Now this is really the bar. This is what we're capable of. And what we want to do is deliver this to more patients, more than 13%. But also remember, that this study was done in patients with high PD-L1 expression, which is about 1/3 of our patients. What about the other 2/3, whatever most people with advanced lung cancer. And again, this is only a small subset. If we look at the next slide, we see long-term follow-up from a regimen called KEYNOTE-189, which was immunotherapy with chemotherapy. This regimen looked at standard state-of-the-art chemotherapy, platinum plus pemetrexed either with placebo or pembrolizumab. And what we saw was adding immunotherapy to chemotherapy improved progression-free survival and importantly, improved overall survival. And as we saw with the prior trial, it led to a chance of long-term survival. Here, the 5-year survival rate, almost 20%, almost 1 in 5 alive. And this includes all PD-L1 status, really an entire all-comer population within a non-squamous histology. On the next slide, how many of those patients are progression-free at 5 years, it's the minority. It's about 7% to 8%. And breaking it down by PD-L1 expression. For PD-L1 high, 13% of patients progression-free at 5 years. For PD-L1 low, about 7% of patients progression-free. For PD-L1 negative, only 2%. It's a small minority of patients, but what we've seen with immunotherapy strategies and recapitulated across many different immunotherapy agents is long-term survival and long-term progression-free survival is possible. It is not most patients. It is certainly not enough patients, but it is some patients. Now this is what we're chasing for all patients. All of our patients deserve this opportunity. And so immunotherapy remains our standard of care. For every non-small cell lung cancer, it does not have an actionable target, which is most lung cancer. All patients deserve that opportunity. Most will not achieve this result. And what our job is, what our vision, our goal, our hope, our treats is to deliver this to all patients. And how do we get there? If you look at the next slide. The overall summary here is that most patients do not respond to immunotherapy, a small subset do achieve durable response, but another subset achieve a transient response. And this, I think, intellectually is very intriguing. On the next slide, we see follow-up from that KEYNOTE-189 study. And in dark green, you'll see the course of therapy 2 years with pembrolizumab. If we click ahead to the next slide, in dark green here, we see a 2-year course of pembrolizumab. And what we see with the black dots, those represent progression events. While some patients have progression of their cancer early, some patients do have it late. Some don't have it at all. That's certainly what we hope for, but some do progress late. These are instances where we feel we're very close to getting that immune response where we were able to engage our immune system, but not in a durable way. This is really what we want to achieve more durable immune responses. And for patients whose tumors initially responded, but lose response. We really want to recapture that response. Because what is our alternative here? For patients who initially received chemotherapy and immunotherapy and then progress. The current standard of care is docetaxel in the U.S. docetaxel with ramucirumab. This is a tough regimen in the outcomes report but it is a regimen that we have not been able to surpass. When we look at the outcomes with standard docetaxel and ramucirumab, the response rate is 23%, only a fraction. And with docetaxel alone, which is the global standard, only 14% of patients will respond, 14%. The progression-free survival with docetaxel alone was 3 months, which is really the first scan. Any benefit is fairly transient and the survival remains between 9 to 10 months. Outcomes with docetaxel are very poor. And the safety leaves a lot to be desired. Patients do not feel well with this treatment. Fatigue is seen in most patients with 14% having Grade 3 or very severe fatigue. Patients do not feel well. Neutropenia or low white blood cell count seen in 55% of patients, most of those, almost all our grade 3 febrile neutropenia dangerous complications seen in 16% of patients. And about 1/3 of patients require some dose hold or reduction or adjustment in some way. This is a regimen that we do not like prescribing. It has a ceiling on how well it can do. Patients do not feel well with treatment. We need something better to offer to patients, but we haven't seen anything better for quite some time. We're longer due for an advance. And while we appreciate the advances with immunotherapy, we're ready for something more. And so to wrap up on the next slide, where we see things currently with non-small cell lung cancer without a driver alteration immunotherapies are standard of care, clearly, superior to chemotherapy alone and importantly, offers the potential for long-term survival. We celebrate this advance. We offer hope to our patients. But for most, the likelihood of long-term survival is quite low. So we can celebrate the advance while still acknowledging the unmet need is pressing and looms large, progress has stalled. While immunotherapy is state-of-the-art, the KEYNOTE-024 was FDA approved in 2016, chemotherapy with immunotherapy in 2018, almost a decade since some of these have been approved, and we still haven't improved upon that. The pursuit of transformative change really lies in finding durable survival. And what we do not want, what we do not need are incremental benefits with cytotoxic molecules. What we want for patients are more immune mediated antitumor responses that have meaningful durable survival and progression-free survival. This is really what we're chasing and our hope is that this program will get us closer there. And so with that, I'm happy to turn things over to the next part.

Many thanks, Stephen. Now we're pass to [indiscernible].

Sure. I'm happy to be there. I'm Benjamin Besse. I'm a medical oncologist, mostly to our sechocologist and Head of Clinical Research at [indiscernible]. And now we will talk about therapeutic vaccination and therapy in patients with non-small cell lung cancer. So there are 2 main kind of vaccines, those that are ready to use of the shelf, which are vaccine already prepared, that can be based on protein on RNA and therapy is one of them with mixture of epitopes, and it is dedicated to patients that have an HNAstivefenotype. Other vaccine are personalized. Usually, they are aeronvaccines. They are quite costly and difficult to make with turnover time that is usually between 6 and 7 weeks because you have -- you need a biopsy or surgical assessments of the tumor, and then you generate the vaccine, the personalized vaccines. So we will talk about therapy that is ready to use one, as I said. So next slide. What is therapy? It's a combination of new epitopes. It's 9 optimized neoepitope that will cover roughly 100% of non-small cell lung cancer -- so you don't have to adapt the vaccine to the expression of the epitopic ready to use to any kind of nonsmall cancers, squamous or non-squamous. There is a binding to HLA 2. So we have to restrict the population to HLA-A2 positive patients, which represent 45% of our patients. The -- so it's a ready-to-use emulation that is given subcut each 3 weeks. Next slide. The first Phase II study was done in 64 patients with non-small cell and counter and all these patients were chemo pretreated. And the overall survival of the vaccine is quite impressive in this pretreated population, 17.3 months. It's obviously restricted to HLA to positive patients. But interestingly, in this sub-analysis, look at the benefit of the vaccine based on the epitope response. So you measure in the blood the immune response to each of the 9 epitops. And the more response, immune response you have against epitope the better is the survival, which is a strong indication that the activation of the immune system, the specific activation of the immune system by therapy leads to a disease control and a benefit of overall survival. The second point is, you remember all these curves on immunotherapy in first line that Stephen showed. All these curves, as he highlighted, a plateau. So the shape of the curve is really that have long responders these patients. And interestingly, even in the patients with lower epitope response, you can see the shape of the curve with low responders. So next slide, this drive to the development of the first Phase III trial in patients with nonsmall cell lung cancer, pretreated with chemo and immunotherapy is the Phase III ATALANT-1 trial. Next slide. So the trial was done in second line. As Stephen presented, now when he diagnoses a non-small cell lung cancer, he had to look at the targets that make the patient eligible for targeted therapy, that will be roughly 15% of the Caucasian population. And all the other ones will receive immunotherapy or chemo immunotherapy. But at the time of progression, there is only one standard of care that is docetaxel, a standard single-agent immunotherapy, quite toxic, I have to say. Next slide. There have been a lot of attempts to beat docetaxel as a standard of care. And a few years ago, we had a lot of expectation with 2 type of strategy. VGFR inhibitors, and this is example of 2 Phase III study that have combined an immuno 3 plus of VGFR inhibitor and [indiscernible] is against docetaxel. The 2 trials are negative for all survival, but there are randomized trial with 4 different combination of IO plus VGFR inhibitors and all these studies are negative. The other class of drug that is really under the spotlight is the ADC, the antibody drug chemotherapy. So these are agent that were given single agent and combined head-to-head with docetaxel second line, again, post chemo immunotherapy and none of these drugs made it even if some of the trials were statistically significant, the clinical benefit was not enough to have an FDA or EMEA approval. So that now standard of care, even with all this development of new drugs, standard of care is still docetaxel for the second line. Next slide. So in the ATALANT-1 trial, Top was runomized 2:1 to docetaxel, the standard of care in exactly this population or we just prescribed, so patients with advanced or metastatic nosecone cancer with an HLA-A2 positive test EDoFmutation and AlFusion were excluded. Any PD-L1 stated could be enrolled. All the patients had to progress under chemo immunotherapy, given sequentially or both combined, but the last line had to be the immune checkpoint blockers. So the patients for randomized between therapy and the [indiscernible], the primary endpoint was overall survival. Next slide. So the trial came to recruit almost 320 patients, but because of the COVID pandemia and the new vaccine for COVID, the trial was stopped after inclusion of 219 patients. These patients had first or secondary resistance to immunotherapy, meaning that they received less or more than 24 weeks of immunotherapy. The primary population that we define was those patients with secondary resistance. So all these patients that receive at least 42 weeks, 6 months roughly of immunotherapy, and that represents 118 patients. Next slide, so in this primary population, if we compare to the intent-to-treat population, the patient's characteristics are overall quite the same, the percentage of squamous, in particular on the T&M stage at study entry or the rate of brain or liver metastasis, it was roughly similar. Next slide. So in the primary population, these patients with secondary resistance to immunotherapy. You can see a significant and clinically significant improvement of the overall survival, 7.5 months in the control arm, what is what you expect versus 11.1 months in the TEDOPI arm with another ratio of 0.59. Next slide. If you look at the subgroup where you could see a benefit, the only subgroup where there is zero benefit apart from the Stage 3. But as you can see, it's a very, very small population, so difficult to have any conclusion. It's the patients with brain metastasis. So in the current trial, these patients are excluded. Next slide. If we look at the time to worsening of the performance status, it was much better in the TEDOPI arm compared to docetaxel arm and this is related to both the efficacy and the toxicity. Next slide. If we look at the toxicity of the docetaxel or TEDOPI, it's striking to see that you have 3x less severe Grade 3 to 5 adverse with the vaccines compared to docetaxel. So in terms of toxicity profile, the vaccine is much better in a lot of parameters, hematologic toxicity, but also very important parameters such as alopecia, docetaxel-induced alopecia, where a vaccine doesn't. And this is also why the quality of life was better in the TEDOPI arm compared to the chemotherapy both because it's more effective and because you have less toxicity. Next slide. So as I said, this trail was stopped because of the pandemic and the subgroup analysis of the secondary responder shows a strong benefit, but it was not enough to put the drug in the market. It was enough to have a very strong hypothesis to build a new Phase III trial in a much more precise population, the patients with nonsmall cell lung cancer pretreated with chemoimmunotherapy, HLA-2 positive and with secondary resistance to checkpoint in users. Next slide. So this is the main characteristic of the trial, the population, HLA to metastatic non-sponsor lung cancer with secondary resistance to immune checkpoint inhibitor, defined by at least 24 weeks of immunotherapy. Docetaxel was accepted by FDA as a standard of care for the comparator arm. The primary endpoint is overall survival. This is really meaningful and convincing for such trials. Among the main secondary end point, the patient reported outcome and quality of life was accepted by FDA. There is a central HLA-A2 testing with a component diagnosis test. And this lead to next slide, these designs. So in the artemia study, an ongoing Phase III study, therapy is again compared to docetaxel, but in this well-defined population HLA-2 positive squamous and non-squamous non-small cell lung cancer, pretreated with chemo in immunotherapy and with secondary resistance, so at least 24 weeks of immune checkpoint inhibitor. And as I said, because of the subgroup analysis, the brain mets were excluded. Primary endpoint is overall survival, and there is a stratification on histology, squamous and nonsquamous and performance status and the trail is now ongoing. And while I will stop here and give the word to Alex, that has presented the results in the ovarian cancer.

Many thanks, Benjamin. Up to you, Alexandra.

Thank you. So I have a first slide. So I'm [ Alexandra Learey ]. I'm a medical I'm a medical oncologist at Gustav use and Deputy Head of the Department of Medical Oncology. And I'm also the President of the National Intergroup for clinical trials in Gyn/Onc. Next slide. So before I jump into the trial, because we've talked only about lung cancer so far, I'm just going to give like a 30-second introduction on ovarian cancer. Ovarian cancer is not as frequent as lung cancer, but it's deadly as well. 80% are diagnosed at an advanced stage where we do chemo and surgery. And for years, the 5-year survival without disease in ovarian cancer was less than 2%. So when we're talking about cure rates, even in upfront surgically resected ovarian cancer, a cure rate was 2%. So absolutely, horrible prognosis. This has clearly evolved with better surgery and the advent of targeted therapies, such PARP inhibitors and bevacizumab. And actually, today, I -- but in chemo, surgery and using these maintenance options, we've dramatically improved survival with now 5-year disease-free survival close to 40%, which is great. And that's excellent news. For years, when they relapse, we would do platinum again and platinum again and platinum again, that was our favorite chemo. It worked every time you put it in again. Unfortunately, by doing much better in first line. Those were not cured in first line and progress under the pressure of something like a PARP inhibitor or after bevacizumab. In years, over 5 years. And this is despite huge [indiscernible] own with bevacizumab with PARP inhibitors, all negative. And as I said, these patients who progress post-PARP have poor response when you reintroduce the platinum. And even if you manage to get some platinum in, we stop it usually after 6 cycles, the relapse really shortly thereafter. Next slide. So I'm not going to give again the background on this vaccine, which has been very well introduced. It's relevant in ovarian cancer because 80% to 90% of ovarian tumor express one or more of these tumor-associated antigens. And it's important. They're not just tumor-associated antigens. These have been modified to increase their binding capacity to the T cell receptor and/or to HLA-A2. And given the positive results in lung cancer with acquired immune checkpoint resistance and the fact that so far, immune checkpoints alone or with PARP or bev being efficacious in ovarian cancer, we thought we would use this vaccine to turn what is frequently described as an immune cold tumor into immune hot, okay? And that was the aim of the study was to evaluate the benefit of combining this vaccine with an anti-PD-1 as maintenance after platinum and it's very difficult to treat patient population. Next slide. So the design was rather simple, basically any patient, but relapsing an eligible for platinum doublet received a platinum doublet 4 to 6 cycles and had at least their disease controlled with stable disease, partial response or complete response, who had previously had a PARP, previously had bev or had a contraindication. Therefore, there's no maintenance options for these patients. Then if they were HLA-2, they were randomized to the standard of care, which unfortunately is watch and wait or best supportive care versus the vaccine on its own versus the combination. And the randomization was 1:1:2. Next slide. Without going too much in the statistics -- there was a 3 arms that we designed the trial to have with a sample size of 185 patients to have the power to detect an important difference between the combination of the vaccine and pembro versus pet supportive care, okay? Next slide. The patient characteristics I probably won't go into too much for those of you who are not particularly ovarian cancer specialists, but they're as we expect, they were very pretreated with PARP future with that, roughly half of them had stable disease, half of them were in complete or partial response to the chemo when they were randomized. Next slide. And these are the primary results, okay? The combination of vaccine with pembrolizumab as maintenance after platinum significantly decreased the risk of progression by 50% compared to standard of care. The hazard ratio of 0.53 and a highly significant p-value. So the trial is positive. We achieved the results we're hoping to get. So that's for the primary endpoint. Next slide. So although we weren't powered to do this, we couldn't help but look. So when you compare the 3 arms between each other, there is an incremental benefit for the combination compared to the vaccine on its own and there's an incremental benefit for the vaccine on its own versus best supportive care, although this did not reach statistical significance. Next slide. The safety was actually interesting. So the vaccine had been previously tested and very well tolerated, as Benjamin said. We did have more immune-related toxicities in the combination. And we know an anti-PD-1 alone -- vaccine alone, and we're seeing more immune-related reactions with the combination than we expected, which we -- actually, while the trial was going on, considered a good sign that we were actually -- we were stimulating the immune system. The most common grade 1 or 2 were local site injections, okay? And having seen some of Benjamin's patients who were men and women at least in my women-only population, it seems they get more local site reactions. Grade 1 or 2, but they're there. The intriguing one was the cytokine release syndrome. They were very rare with a vaccine alone in previous studies was very rare in our vaccine alone arm here with 9%, mainly Grade 1/2. But we were seeing more mainly Grade 1, 2, cytokine-release syndromes with a combination of vaccine and an immune checkpoint, okay? Again, at least proving that we were achieving what we wanted to achieve. But therefore, halfway through the study, we said, okay, we're going to put just very simple primary porphyry access with basically paracetamol and nonsteroid inflammatories. And with that, we significantly decreased the risk of Grade 1,2 CRS. Next slide. When you look at the subgroups, the benefit was seen across the subgroups. If you look at HRD negative all the way at the bottom, it suggests no benefit. There's 13 patients, I think you should -- and in a multivariate was no -- it was negative, and there was no interaction. On multivariate analysis, the only group that appeared to have especially great benefit were the patients who were in partial or complete response to chemotherapy, where there, the hazard ratio was 0.31, which is really quite remarkable. Next slide. So in conclusion, we present the first trial, providing a proof of concept for the benefit of a vaccine approach in ovarian cancer. This is also the first positive randomized trial in the platinum-sensitive setting of ovarian cancer in years. And the combination of the vaccine with pembro as maintenance after platinum significantly reduced the risk of progression by 50% and by almost 70% in those in CRPR. There was a little bit more toxicity, but it was mainly Grade 1,2, and quite manageable once we introduce really simple prophylaxis. And this study, its control arm confirmed that these patients who relapse, they get another platinum. Their prognosis is terrible if they have prior PARP exposure. Once you stop the platinum, their PFS is less than 3 months. And we really feel this supports a Phase III confirmatory registration trial. And then last slide, do I have any more? Next one. And this was sort of the lay summary. Just a reminder that women with ovarian cancer who received platinum-based chemotherapy when the cancer comes back after prior bev and PARP have a poor prognosis, okay? And that's on the, let's say, the flip coin of the fact that we're doing such great treatment in first line. Unfortunately, if that doesn't cure them when they relapse, they're harder to treat. The TEDOPI trial showed that giving a combination of an antitumor vaccine with immunotherapy as maintenance after platinum significantly delayed cancer progression. As I said, this is the first positive randomized trial in years for this patient population and the first proof of concept. So we're really excited about this data, and we can't wait to go to the next step. Thank you very much for your attention.

Many thanks, Alexandra. So now we are moving to questions. First, I would like to thank, in particular, Valerie Gaba, our Head of MSL; and Thomas Gidoin, our CFO and Deputy CEO, who have prepared this webinar. So I think that we have the first question coming from Aron. Aron ask the question. So I'm not so familiar with that. So maybe I will read the question. When we look at the population of interest for tedopis evaluation in non-small cell and cancer Don't you think that we addressed Top at a very restrictive population to a very restrictive population with the double restriction of HLA-A2 phenotype and secondary resistant to checkpoint inhibitors. Benjamin maybe can you answer this question?

Sure. So since more than 20 years now, we are easily used in non-small cell lung cancer to treat subgroup of patients that have started with EGFR inhibitors and then Al and then Ron, and we have now 10 targets that we have to screen in all the patients. And some of these targets like BRAF inhibitors, BRAF mutation is 1% of our population, and that's enough to develop a randomized trial and to approve drug in the market. So in lung, we are very, very used to screen for markers and treat subgroups. So no, we think that this population will represent roughly 15% of the patients that progress after chemo immunotherapy, which is a huge number for you. So I don't see that as a limitation.

Thank you for that. So -- sorry, Stephen. Sorry.

Yes, I echo Benjamin thoughts here. We're used to dealing with small populations. I'll mention in the U.S. H2 is 40% to 50% of patients. This is the most common noise as well. And you have to start with where the drug is going to perform best and follow the science. And I think that's the starting point. But if this really confirms our suspicion is that this is an effective treatment. I think that it opens the door to further modifications, which can sort of expand its use in different indications. But the HLA-A2 is the most common subtype.

Thank you so much for that. I think that Aron is connected. Would you like to ask oral questions. If we can do that technically, I'm not familiar with that. So I'm not sure it works like this. Thibault?

Can you hear me?

Oh, yes.

Excellent. Fantastic. Curious to learn if the Artemia trial results are positive. How quickly do the KOLs think that dope could fit into the second-line treatment pathway? And what, if any, physician education or diagnostic infrastructure would be needed?

I can start with the U.S. answer. Very quickly, again, the endpoint here is overall survival, and we are eager for something to replace docetaxel as Benjamin outlined, there have been many large Phase III trials that have simply failed to improve outcomes. And so if we do demonstrate an OS advantage, I think that they would be a very enormous appetite to move this forward fairly quickly first on guidelines, and then certainly through the FDA process. HLA subtyping is done pretty routinely as part of our -- most of our commercially available next-generation sequencing panels. So in the U.S., we often know that information upfront, and we didn't have to have big changes in terms of our current testing practices, at least for most institutions. Certainly, the time lines would be a little different in Europe, I imagine.

Regarding Europe, HLA 2 is a very simple blood test. So I don't see any issue to have HLA 2 as a reflect testing. It's not -- I mean, it's something that is intrinsic to the patients. So it's not something that appears at resistance, for example, so you can screen upfront when the patient is diagnosed or start is first-line chemo IO and when you have a doubt of progression, so the testing will be something very easy. And as Stephen said, we all want to give something else than docetaxel. So I think the uptake of such vaccine would be very massive.

Thank you for that. Aaron, do you have additional questions?

Yes. One more question for me, perhaps for Alexandra. Looking at the ovarian cancer program, the data was really encouraging. So thanks for presenting that. Please could we hear your thoughts on what's a credible subsequent study might look like in terms of design and how it would build on from the prior trial?

So that's a very good question. It is a matter of discussion because we just got these results. So -- when we designed this trial, the acceptable standard of care, the only available standard of care in this setting was best supportive care. Today, it's becoming increasingly unacceptable not to give any maintenance, okay? Even though we don't have reimbursements, which is a bit of a problem. So one idea would be to say, well, there is data to support putting an anti-angiogenic and people who are previously exposed to bevacizumab and would that be appropriate to add an anti-angiogenic component both in the control and the experimental arm. PARP inhibitors, we don't have any data, but we have a large Phase III study that supports bev after bev or antiangiogenic after atiangiogenic. So that would be one site modification, which I think, ethically and even just it makes sense.

No more questions for me. I look forward to following the progress.

Thank you for that. So we have written questions. With the rapid emergence or other approaches like ADC bispecifics. -- next-gen immunotherapy. Where do you see TEDOPI fitting into the treatment algorithm in the coming years? You'll see -- do you view TEDOPI primarily as a stand-alone therapy -- or do you believe it greatest potential could be coming from combination strategies with checkpoint inhibitors, ADCs, other immunotherapies.

Well, I may start. When we design Artemia, a lot where thinking that ADC would be the standard of care, and it's not on the Phase III are negative. But other strategy also now there, you're talking about the specific Genmab had a randomized study with GEN1046, which is a PD-L1 4-1BB specific antibody. -- and they stopped the Phase III study. It seems to be for -- not based on data, if I understood correctly, but I stopped the program. Latifi was also a very promising study with ceralasertib, an ATR inhibitor combined with IO in second line compared to docetaxel and to trial is negative. So the signal that we have from ATALANT-1 is quite strong in a situation, in fact, where all the Phase III so far failed and I don't see -- and maybe Stephen, you have other ideas, but I don't see an asset that has -- well, it's, let's say, much more activity than the one that I just alluded to. So no, I don't see in the upcoming years, the standard of care changing.

Yes. I think that ADCs have shown a lot of promise really across tumor types. But at their heart, they are still cytotoxic molecules somewhere they can offer responses. They still share a lot of toxicities that we see with standard chemotherapy. So I think that will be a challenge to a lot of patients, particularly in later line settings. I think that the difference with TEDOPI is it really is an immune-based strategy. It can really make a big difference both in terms of quality of life and overall survival -- these immune strategies offer, I think, a potential of much more durability than we might see with something like a cytotoxic agent. So ADCs, there are a lot of the credit field. I suspect, just by sheer number, that one of these studies will be positive, but how much of a huge impact it will make it remains to be seen. I still think that there's an appetite for an immune-based strategy -- in terms of monotherapy versus combinations, I think once you demonstrate this offers a survival advantage is monotherapy, then you open the door to all sorts of combinations. And whether that's with bispecifics or with checkpoint inhibitors, could that further long-term survival odds. And could that really enhance those immune-mediated antitumor responses is something that I'm very optimistic for. Of course, first, we have to demonstrate clear efficacy as a single agent before we explore combinations, but I see no reason why this wouldn't be able to be combined with other strategies.

In terms of the ovarian cancer space, I sort of have the same answer. As I said in my introduction, people have tried to get a new standard of care in maintenance, platinum sensitive, and they have not managed with immune checkpoint inhibitors on their own when they combine them, what we thought was the best such as PARP inhibitors didn't add anything. So there's not so much out there. There are ADCs that are being explored everywhere. They're putting them in every indication and a lot of them is maintenance. Let me tell you, an ADC as maintenance is not the same thing as an immune therapy as maintenance in terms of quality of life, okay? And so for now, it will be a while before we get even the opportunity of a positive study with an ADC in the platinum-sensitive setting. And we do believe in combining it because we've already combined it with an anti-PD-1. And I think it might be worth thinking about running it with an anti-VEGF. But I think it's nice to have a maintenance that doesn't have a cytotoxic in it.

Thank you for that. An additional question regarding to Dova. The patients presenting CRS benefit better from the treatment from TEDOPI than others.

It's an excellent question. No, we couldn't see that. And one of the reasons is that in the early part of the trial, we didn't expect CRS and Gyn/Oncs haven't done a lot of CAR T cell therapies and TCR-modified T cells. So when they saw CRS a lot of the investigators were a little shocked, and it actually my concern was they were going to stop the treatment. That's why I introduced the prophylaxis, okay? However, when we look at prophylaxis, people who came in sort of in the effective phase where the patient .

You mentioned a prognosis, Alexandra. And what is in your, let's say, globally, the current median overall survival? And what would be something that you would define as clinically relevant, assuming that you will get this data, I don't know, probably next -- later this year or next year. What would be the median overall survival improvement, let's say, clinically relevant for you?

So demonstrating improvements in overall survival in ovarian cancer in clinical trials has been challenging, okay? Finally, we've arrived there for the first time in, I think, 3 decades a couple of weeks ago in the resistant setting, okay? So the resistant setting is not where I am here. It's patients, they've become resistance to platinum. And here, the standard chemotherapy doesn't work. It's a little bit like the docetaxel, right? And so they don't have subsequent lines of therapy. And so if you have a PFS benefit in that setting, it is easier to translate oto OS. And so finally, we have 2 positive clinical trials in the resistant setting that showed a OS benefit. But all of our studies in first line were subsequent sensitive setting we haven't been able to translate PFS benefit in OS benefit because subsequent therapies still work. Now again, this might change because here in the post-PARP setting that might change. And so I don't like to talk about numerical benefit. But here, we have a hazard ratio of 0.53 PFS. If we get a hazard ratio that's positive, 0.7, 0.8, no one has ever achieved that in first-line or platinum-sensitive relapse. So any impact on OS to me would be a great success.

Very clear. More sophisticated question. I'm sorry, I will try to read that carefully. I gave that TEDOPI targets multiple-specific antigens to turn cold tumor too much hot, have the translational data from TEDUVA shown any evidence of epitopsprading to nontargeted antigenes.

So the work is ongoing. So we have collected PBMCs. We're working with an academic lab to do all of this. And I haven't yet seen the data, so I'm not hiding anything from you. We'll be very interested to see some of the data that was already generated by Benjamin in the previous lung trials suggest that the [indiscernible] response might be relevant. As to the rest, I don't yet know, but we have a very comprehensive translational program as well as targets and the expression in the tumors themselves, the tech P53 mutations. We have 2 types. One, there's a loss and the other 1 is overexpression. That's probably relevant. So there's a lot of work still to be done, and we look forward to presenting that in subsequent presentations and publications.

Fantastic. I think we're coming to the end of this webinar. Thank you so, so much to the 3 of you for all your dedication to patients first and to science globally. And we're very, very enthusiastic at OSE to move forward with TEDOPI, of course, in non-small cell and cancer in the very short term. And assuming that we have financial capacities in ovarian cancer and maybe another indication. So I thank you so much, and I thank all the participants to this webinar. It will be -- it is recorded. So this will be available probably for the next few weeks on our website. And I wish you a great day, and see you and talk to you soon. Thank you again.