Thank you so much for joining us. We've got iTeos here, Michel Detheux, and Matthew Gall here joining us from the company. Thank you so much for coming down to Miami. Thank you, John, and good morning, everyone. Right, so we've got plenty to talk about, but let's start with some recent developments in the space. Obviously, we've all seen SKYSCRAPER-01's failure. I'd love to get your thoughts on what's going on here. We already saw some data from the second interim. It looked like there was a nice OS benefit developing. You spoke about this being validating, potentially validating in the past, but the trial ended up not hitting despite that early signal that we all saw, so what are the learnings here, and what are you hoping to bring away from that failure? What is fascinating is that Roche started eight different phase III based on the data of 29 patients, the CITYSCAPE. And the CITYSCAPE was trending very nicely with a fantastic difference between monotherapy and the doublet with response rate, PFS, and OS. What we learned from CITYSCAPE and SKYSCRAPER-01, and indeed we learned a lot from the leak in August 2023, is that quality of component will matter, indication selection, and the design of the study. One of the traps in which Roche fell is the fact that in CITYSCAPE, there was a clear difference between the two curves already after three months. In SKYSCRAPER-01, the difference only started after six months. That was a major impact on the statistical design, and they cannot anticipate that. Then it was one of the limitations. SKYSCRAPER-01 interim last year showed HR of 0.81, and everyone was expecting that this trial will be slightly positive or slightly negative. We've not seen any final data, then we don't know how much is negative, but what we learned is that statistical design can be improved, is what we have done in our phase III. In terms of quality of component, the Roche SKYSCRAPER-01 has been crippled from the beginning because they've used atezolizumab as a comparator. We believe it's super important to use pembrolizumab, and it's what we are doing in our phase II and our phase III. And finally, in terms of quality of component, atezolizumab is a major limitation compared to the other PD-1. With dostarlimab, the PD-1 from GSK, we know that we have a best-in-class, which is as good as, if not better, than PD-1. Now, I totally agree with you on the viability of using atezolizumab as a combo, but it's not as relevant in a commercial setting. Even if they'd hit the trial, it's tough to get folks to use atezolizumab as a combo. But do you think that the contribution of TIGIT would be less visible on top of a PD-L1, on top of something like atezolizumab, than it would be on top of something like pembrolizumab? No. They've shown that they are able to add six months in overall survival, which is significant on top of PD-L1, and we expect to see at least the same benefit over any other PD-1 like pembrolizumab or dostarlimab. Entirely a stats issue, not to do with the degradation of OS or anything like that. No. Okay. That sort of roundabout 20% benefit that we thought we were seeing in that second interim, assuming it was maintained for a near stats miss on the final, is that about where you think optimal TIGIT could add on top of good PD-1 backbone? Is that the sort of OS benefit we should be expecting from randomized studies with better combos? We believe that six months improvement would be a significant win, and we believe we could go up to 10 months. Interesting. In overall survival in the high PD-L1, non-small cell lung cancer. So obviously, turning to your data, at ESMO, we saw really robust ORR benefits from the addition of TIGIT, more than we've seen on ORR from competitive programs, from anybody, I think. So maybe let's start there. From your perspective, what are the key mechanisms that are driving you to see such robust ORR delta or ORR contribution from TIGIT, I should say, on top of the backbone? As I said, quality of component is super important, and one thing that iTeos has been able to develop over these past 12 years is this expertise in tumor biology to develop a differentiated asset. We've developed a best-in-class TIGIT. We have shown that in terms of affinity, potency, but also activation of Fc gamma receptor, we have an antibody which is highly differentiated, and we believe that this preclinical differentiation has translated into a clinical benefit with the significant ORR benefit that we have seen at our data in ESMO in September. Now, I noticed, though, there was not much, anyway, dose response on that ORR benefit. Would you expect to be in a similar position from PFS OS, where you're sort of capping out on the benefit from the dose you're giving? Two things. First, in terms of receptor occupancy and PD readout in our dose escalation in phase I, we have shown that we were already reaching a maximal level of receptor occupancy at 70 mg. In our dose escalation dose optimization that we have presented at ESMO at 100, 400, and 1,000, we were expecting to be already at the plateau that we have seen. However, we need to keep in mind that we have also a multifaceted mechanism for our TIGIT antibody, both in terms of binding to TIGIT, but also with the Fc gamma receptor. And we have seen, for example, that in the ctDNA measurement, we have seen a dose response with 100 being less effective than 400 and 1,000. Okay. Now, the market obviously reacted very strongly to the safety signals that were observed, especially on the high dose in the ESMO data. And presumably, that is at least partially driven by that Fc active construct that you have, by that strong Fc gamma receptor activation that you see. So where do you-- you've been very defensive on that safety profile, but where do you see the benefit-risk balance being on Fc activation driving toxicity? Yes, indeed. It's an important component. Yes, we have been defensive because when we presented the data at ESMO, the feedback of the audience, the feedback of the clinicians, and the feedback of everyone was super positive. In the 16% immune-related discontinuation that we have observed, half of them are related to grade I or grade II that we believe we can control. It could come back to a level of discontinuation which is in range with other IO therapies. We believe that it could show that the significant benefit that we see with our best-in-class TIGIT can overcome the tolerability issue that we've observed in this first dataset. Okay. So there's two things going on here. One is dose selection, and we should talk a little bit about the selection of 400 milligrams going to phase III. But there's also a management component where physician comfort and management of these toxicities will bring discontinuations in. Yes. So when we think about that 400 milligram dose, obviously, at 1,000, you saw materially higher discontinuations on that dose. How confident are you that you're striking the right balance in the phase III dose that you've selected, and how much are you leaning on physician management versus the dose selection? You must keep in mind that this dose optimization, which was due to Project Optimus from FDA, has been defined based on multiple modalities. You have seen some of the data at ESMO, but we have dozens of other data points which have been used by GSK and iTeos to define what would be the optimal dose. By using this approach, we have found that 400 was the best balance between efficacy and tolerability. I think, too, without Optimus, 400 was, based on all the modeling we'd done from phase I, from other combo studies, was going to be the phase III recommended dose. Without Optimus, we wouldn't be having this conversation. We had a 16% discontinuation rate in the combo that Michel mentioned. We are pretty confident it can be managed down via steroids, via doctor communication versus why were patients ever pulled off from a grade I, grade II skin reaction in an IO combo. And again, this would not be a topic of discussion if not for Optimus pushing us up to 1,000 to show a level of tox. Okay. Fair enough. In phase III, though, you were also using pembrolizumab as a compound, and I'd love to discuss that choice. We've seen from others trying to do development in the IO space, even in the PD-L1 high population, it's tough to enroll patients on pembrolizumab. There's a strong demand still for chemotherapy availability for those patients to deal with early relapses or early progression events. So can you talk me through the choice of pembrolizumab as a compound and maybe how the feedback has been from physicians on ability to enroll such a study? Yes. That's a very interesting, I would say, belief. When we go to market research, and we've done multiple of them in parallel with GSK, today, 70%, 70% of patients are treated with PD-1 monotherapy when they are high PD-L1. Then it's a majority of the population. The combination with chemotherapy is used for bulk tumors that need to be decreased before to give the immunotherapies. Then we still believe there's a major interest from the physicians to get access to a chemo-free regimen for these high PD-L1 patients. There's also been no challenge in enrolling 201, which is the same dostarlimab mono, pembrolizumab mono, and the dostarlimab belrestotug. Although that was a couple of years ago, though. No, 201 is still. Still long way. Yes, this is our phase II, which is still running, and it's interesting because many of the clinicians of the 201 studies are asking to be part of the 301 studies, which is the phase III. Then we feel there's a significant interest from the physician to be part of this study giving patients a chemo-free option. Is that true across all geographies? We have started today. We are sites open in Europe and Asia and also rest of the world. U.S. will come soon, and this is the case for all the geographies so far. So far, the U.S. is where I'm most curious because this is where I hear the biggest feedback that a chemo-free regimen, while everybody wants a chemo-free regimen, it's tough to enroll those patients in the U.S. I believe what is tough is U.S. is more the competition for this patient population. There are so many trials ongoing. Again, the market analysis that I refer to has been conducted in U.S. Okay. Fair enough. Let's then skip to talk about Head and Neck, where you're ahead of other TIGIT players. Relative to other TIGIT players, you've gone into Head and Neck maybe a little bit more aggressively. Looks like a pretty substantial couple of datasets on track for the first half next year. So maybe what are your key hopes to be able to show in those readouts next year, and what do you need to see there to push aggressively into phase III? This is also super interesting because Roche has started a series of phase IIIs, I told you, based on no data from phase II or even phase Ib. And some of these indications like small cell lung cancer in terms of biology doesn't make any sense. Head and Neck is a biology which is similar to the non-small cell lung cancer. On top of that, in Head and Neck, you have a higher percentage of Tregs, which is these immunosuppressive T cells that we can deplete with our TIGIT antibody. And then we believe that based on the biology and the Treg presence, our TIGIT antibody could really make a difference. Interestingly, we were not the first to start there because Roche started a phase II called SKYSCRAPER-09 years ago. In the meantime, this phase II disappeared from the charts, and Roche is not anymore communicating on that. Then we've decided to start our own randomized phase II, the GALAXIES Head & Neck-202. Indeed, we're going to release a significant set of data next year. Now, do you want to discuss about the competitive landscape and what we want to see in order to move forward in a phase III? Yeah, I think broadly, and he said SKYSCRAPER-01 and SKYSCRAPER-09 was the Head and Neck study that disappeared. Look, we're aware of the challenges that have been in the TIGIT space. We need to see a compelling signal, particularly in Head and Neck and Lung, where the competitive landscape continues to evolve. So we look at prior datasets, our own datasets that are being generated, and then concurrently generated datasets in the field to make sure our phase III go forward decisions are rational and data-driven. But you're not giving guidance on what those bars for go/no-go might be? No, for the moment, no, because we have also an evolving landscape into Head and Neck. First, with KEYNOTE-048, the reference data are not super clear. PFS is more important than response rate clearly. But we have also Merus and Bicara progressing with the bispecific that could define a new threshold, which is still undefined. And we really want to understand how our data will position in which specific population, subpopulation type in order to take our final decision. Makes sense. Why do you think other TIGIT players haven't been as aggressive in head and neck, given, as you say, the biological similarity of the lung where the signal seems most robust? It's a good question to ask them. Fair enough. The Head and Neck landscape, as you say, also continues to evolve. You're clearly looking beyond PD-1 for both the competitive landscape and for your own combinations. What are you hoping to see from CD96 contribution? Are there other combos you're also considering moving forward? So what really attracted us to GSK three and a half years ago when we did the deal was their commitment to TIGIT triplets and exploring the CD226 axis really aggressively. The data that's been generated so far, this is preclinical data that was their rationale to go into these combinations. It's very encouraging. We're still yet to see the first clinical signals. Those will come next year to see what those triplets could add and is it a really meaningful kind of game-changing type of regimen. But clinical data has not been generated yet. That's in process now, and it'll be part of the data disclosures next year, both in Head and Neck and in Lung. TIGIT is the most important component of the pathway. What could be interesting with CD96 and PVRIG is that these immune checkpoints are expressed on complementary cells compared to TIGIT. Then we could see some additional benefit on top of TIGIT. Yeah. When I speak to folks who are very enthusiastic about the PVRIG components, it's a lot about duration of therapy and forestalling resistance or escape pathways. We still have some data to see to really be convinced that this additional immune checkpoint will bring a benefit. Makes sense. Maybe in the last few minutes, let's talk a little bit about the adenosine pathway. You did give a small update from that program at ESMO. Obviously, market enthusiasm for adenosine is minimal, and people don't like to talk about it. But you and a few others are very committed both to A2A and, in your case, also to ENT1. Some folks to CD73. So there's still some interest from biotech in this axis. Can you compare and contrast these different mechanisms a little bit? What's still driving your interest here while the market has moved on? Yes, and well, John, we are going to present our data at ESMO IO in two weeks in Geneva for our A2A program. It's another example where understanding the tumor biology of this mechanism is super important. Adenosine has been validated decades ago. It's a major component of immune control. The SCID patients, which are deficient in an enzyme degrading adenosine, is the perfect example of the role of adenosine in the immune response. And when we started this program eight years ago, we realized that there are multiple mechanisms to produce adenosine. Then shutting down one mechanism like CD73 or CD39 is not sufficient because we will have other mechanisms to generate adenosine. Then we targeted the ENT1, and we've been the first to realize that if we want to compete with the huge amount of adenosine produced in the tumor microenvironment, we need to come with a different antagonist. We developed a unique antagonist, which is called insurmountable antagonist, which is able to compete with any concentration of adenosine found in the tumor microenvironment. Among all the players, we've been the only one able to derive this program into clinics. We are going to see in a few weeks data in second-line non-small cell lung cancer, the chemo-naive post-IO patients. This data will allow us to decide if we move forward into this specific indication or if we believe that there are, I would say, no sufficient data to really invest into this specific indication. Now, when we've characterized this A2A antagonist, we realized that it was super powerful to reactivate T cells, but there is no effect on T cell proliferation. Our scientific team has found that another protein called ENT1, which is a transporter, is super important to control the proliferation of immune cells in presence of high adenosine concentration. We've been the first one to develop an ENT1 inhibitor to be developed in oncology. This program now is moving into phase IB in combination with PD-1, and we will release data next year about this phase I, phase IB. Okay. One thing I would love to, in the last couple of seconds here, you mentioned this insurmountable inhibitor, and I'd love to get just biochemically a little bit deeper into that. This is still an adenosine competitive inhibitor, yes? Yes. How is it that is it just a difference in affinity to target? How do you see insurmountable? Residence time. Residence time. Imagine you have 500 people entering the room trying to take your seat. You don't move. That's the way it works. It's a long residence time antagonist that we have optimized with our knowledge of the biology of the system. Makes sense. And did you mention you said chemo combos? When do we see data from chemo combo in this program? No, it's a chemo-naive population with chemo in two weeks at ESMO IO. Right. Okay. Fabulous. All right. Well, we are out of time, but thank you so much, Michel. Thank you so much. Thank you, John. Matthew, for joining us. Thank you very much. I appreciate it.