All right, so we can get started. Good evening, everyone, and thank you for taking the time to be here. We're happy to, to be with you today and here, especially at ASCO. It's always a, a great time to see the progress that everybody as a community is making against, cancer. So today is, my pleasure really to, introduce Dr. Diwakar Davar, who's gonna and, and David, actually, who you know, who is gonna, talk to you about, PRAME. You know, look at the data again and frame in the context of, of the platform. So we will be making some forward-looking statements, and without further ado, I'm gonna actually pass it on to, to David. Thank you very much, Bahija. This is my 20th ASCO. Time goes by fast, and 20 years ago, I was very fortunate enough to be working on the team that pioneered the first checkpoint, ipilimumab. But But I'm actually even more excited today to be part of a really talented team pioneering T cell receptor therapeutics. I'm gonna give you some insights from what we've learned from KIMMTRAK, because that's gonna help frame the PRAME presentation that Dr. Davar is going to present. So we are pioneering this new class with the launch of KIMMTRAK, and we have now treated over 2,000 patients. And we've been able to glean insights from these patients that I think really help frame how we should understand efficacy for brenetafusp and for the rest of our pipeline. KIMMTRAK is a distinct mechanism, has a distinct mechanism of action compared to checkpoints. It redirects any T cell into the tumor. KIMMTRAK induces more robust T cell infiltration and activation in biopsies than does checkpoints. So it's not, probably not too surprising then that as we saw in phase I through III, novel measures of measuring full clinical benefit for KIMMTRAK were required compared to checkpoints. And I'm gonna actually show you this data during the presentation. Let's start in phase I. This is a patient with metastatic cutaneous melanoma to the skin wall, treated in the phase I KIMMTRAK monotherapy program. Notice by day 8, there was evidence of benefit in the form of inflammation, redness, and by day 30, there was evidence of benefit by necrosis. Yet by radiographic assessment, the best RECIST response was only stable disease, with a minor tumor reduction of 7%. Now, this disconnect between radiographic assessment, which only measures size and cannot measure underlying tumor immunobiology, has been well known. It's been reported for checkpoints for fifteen or longer years. However, for checkpoints, we know this is really anecdotal, and in phase III trials, this type of disconnect is not really clinically meaningful in terms of percentage of patients. Let's look at what happens to these patients, though, in phase III first-line uveal melanoma trial. This is a spider plot of patients with partial response or stable disease on KIMMTRAK. I'd like to draw your attention to that group of patients in green, who represents the patient you just saw. That is, patients with stable disease and minor tumor reduction of between -1% to -29%. Now, there are two important points I'd like to draw your attention to. First, these patients in green, the minor response, they're not rare. They constitute 13% of all treated patients. In fact, there's more of these than there are patients who had a resistant partial response. But the even more amazing fact is that the median duration of tumor reduction, calculated the same way you calculate median duration of response, that median duration was 11 months for these patients with stable disease, which is the same as the median duration of response for PRs and the CRs. So, and in fact, by the way, we find the same observation in the second-line, uveal melanoma trial, and that will be a subject of a poster tomorrow. So for checkpoints, it's clear. We all know this, that the endpoint you want to focus on is RECIST response rate in heavily pretreated patients in order to predict, is this drug going to work? You can see from the data here, for KIMMTRAK, there's benefit outside of RECIST response. So how can you measure radiographic response if RECIST response underestimates? Well, one way we've come up with is to combine the blue and the green. Look at any tumor reduction because this has the same durability. For KIMMTRAK in first- line, this turns out to be 24% of patients with a blended median duration of 11 months. This same metric of PR or stable disease with confirmed tumor reduction will be shown by Dr. Davar in a few minutes. In addition, we think there actually probably is a better way to capture even more benefit because you'll see in the purple patients with stable disease without tumor reduction, some of those patients have ongoing stable disease for one or two years. Therefore, we believe for KIMMTRAK, and hence also for brenetafusp, the best radiographic early endpoint is disease control rate, which combines PR, CR, and SD. And what we find in phase III randomized trial is that this DCR turned out to be a strong predictor of significant PFS. The DCR for KIMMTRAK, 46%; the DCR for the control arm, 27%. Notice in the KIMMTRAK arm, most of that DCR was actually stable disease, with only a minor portion of it coming in the form of RECIST response. Both PR and SD on KIMMTRAK were very durable, and this is what drove the significant PFS with a hazard ratio of 0.73. But as we all know, for KIMMTRAK, despite having a significant PFS, that only captures half of the benefit. In order to capture the totality of the benefit, we need to focus on overall survival. And all of these endpoints, DCR, PFS, and survival, will also be presented by Dr. Davar. I'm now going to shift to two really important translational insights that our superb translational medicine team has made. The first is ctDNA, which we showed for uveal melanoma, is a very good early biomarker surrogate of long-term benefit, and you'll see the ctDNA continues to track well for brenetafusp in cutaneous melanoma. But what we learned from the ctDNA is that KIMMTRAK activity is higher in first-line compared to second-line, based on ctDNA clearance, tumor, and ctDNA molecular response. Now, the question is why? Why is it higher? And we think there's probably two reasons. The first, of course, is the tumor. The tumor has undergone less immune editing in the first-line compared to the second-line. Tumor microenvironment appears to be more favorable. That's pretty well understood. What we have uncovered here, and I think it's very important, is that there's a second equal factor, and that's peripheral blood T cell fitness. It's probably not surprising that T cell fitness in the blood is an important parameter of benefit because these drugs work by redirecting T cells from the peripheral blood into the tumor. We have identified a novel gene signature from peripheral blood that we call T cell fitness. This gene signature is highly correlated with naive and stem T cells, and you will see from Dr. Davar's presentation for brenetafusp, there are two key points. First is this T cell fitness identifies those patients who have the most benefit from brenetafusp. And interestingly, when we look at T cell fitness by line of therapy, it continues to improve, increase as we go into earlier lines, and thus, we project in first-line, T cell fitness will be even higher. Interestingly, a similar association between T cell fitness and adoptive cell therapy has been reported widespread in multiple reports. The difference, of course, is that we rely on endogenous T cell fitness, whereas adoptive T cell therapy creates a T cell-fit product exogenously. And I—w e'll be presenting more data on T cell fitness for KIMMTRAK in uveal melanoma, and also for brenetafusp in other tumors as well. So in summary, this platform has a distinct mechanism of action from checkpoints with more robust T cell activation and infiltration, and thus, we believe different measures of response are required. Disease control, including durable tumor reduction, is a hallmark of this platform, and we have focused on high DCR as the best early predictor of PFS for this platform. And we see ImmTAC activity continues to improve in earlier lines, driven in part by T cell fitness. With that, I'd like to introduce Dr. Davar. He is the Director of Melanoma and Skin Cancer at UPMC. He's a world-renowned expert in phase I immunotherapy trials and in treating metastatic melanoma patients. So Dr. Davar? All right. Thank you, David, for that kind introduction. So on behalf of my colleagues, I'd like to walk you through the phase I safety and efficacy data of brenetafusp therapy. You've heard earlier from Dr. Hamid, and this is an oral presentation. These are my disclosures. So essentially, brenetafusp, or Breni for short, is an ImmTAC bispecific T cell engager that's targeting the HLA-A*02- presented peptide PRAME. The ImmTAC platform has already been validated, right, with the OS benefit that was seen with tebentafusp in metastatic choroidal melanoma. What the platform does essentially is redirect polyclonal T cells to target cancer cells by recognizing HLA-A*02- presented antigens that are either intra or extracellular proteins. PRAME is a very interesting antigen to target in this context because PRAME is one of the most widely expressed cancer testis antigens, and also more than 90% of cutaneous melanoma patients actually express PRAME. In fact, when you look at a melanoma patient's tumor under the microscope, one of the first things you try to do if you're trying to figure out if the patient has melanoma or not, is actually look at PRAME. So it's a common IHC stain that we use. This is the study design. It's essentially a phase I/II study. The data presented earlier and today represent an update of the earlier data that was presented by Omid at ESMO 2022. The primary endpoints were essentially MTD and efficacy. As is typical with the ImmTAC platform, essentially, patients receive a step-up dose, one to two step-up doses, before receiving the cohort-defined target dose. All these patients are obviously HLA-A*02:01- positive. Okay, the demographics and baseline characteristics are highlighted here. I think the key takeaway for anybody from looking at this is the extent to which these patients were heavily pretreated. So you know, there are patients who are pretreated, and then there are patients who are heavily pretreated. These patients are heavily pretreated. 100% of them had prior checkpoint inhibitor therapy. The median number of prior PD-1-containing regimens was not one, but two. 80% of patients had prior CTLA-4 therapy, almost all of whom had received this in combination with Opdivo. Forty percent of patients additionally had another prior checkpoint inhibitor in addition to PD-1 or CTLA-4. The combination pembrolizumab arm had heavily pretreated patients as well, who even more heavily pretreated with a high number of patients with BRAF prior exposure and primary resistance to checkpoint inhibitor therapy. Primary resistance is important because primary resistance represents a proportion of patients who have no prior response. These are patients who receive a checkpoint and whose next scan shows tumor growth, so no prior response or what is termed primary progression to a checkpoint inhibitor agent. 90% of these patients in the monotherapy cohort were PRAME-positive, and the PRAME, PRAME expression was actually quite high across cohorts. As you can see, the median H-score in the monotherapy cohort is approximately 215. From a safety perspective, this drug was exceedingly well-tolerated. Brenetafusp monotherapy resulted in, well, the most frequent adverse event observed was, you know, basically low-grade CRS, the vast majority of which was Grade 1, so relatively easily managed. There were no Grade 3 or Grade 4 instances of cytokine release syndrome. And typically the management algorithm for this involved IV Tylenol, IV fluids and Tylenol. The most frequent Grade 3 treatment-related adverse event was lymphopenia, and this is actually a class effect. Essentially, when you give somebody a, you know, T cell bi-engager, you're gonna bind lymphocytes. And when you bind lymphocytes, the lymphocytes leave the blood, go into the tumor. So seeing this actually is a PD biomarker, so, you know, you have to report it as an adverse event, but it's not truly a clinically significant adverse event. So it's a— But beyond that, you know, clinically insignificant treatment-related, Grade 3 event, which is transient, we did not see significant other treatment-related adverse events outside of that. A couple of instances of patients with grade three rashes and fevers that were easily managed. This is the swimmer's plot that essentially talks about the extent of durable disease control in the monotherapy patient population. There were 36 patients that were evaluable, and the vast majority of the point, the vast majority of benefit is actually seen in the middle. As you've heard earlier from David, what you see here is different from what you see with a checkpoint inhibitor swimmer's plot. So in a checkpoint inhibitor swimmer's plot, you see early rapid regressions in tumor. You can see about 10%-15% of patients with delayed responses over time, but that's not what you see here. What you see here is a classic closed umbrella plot that we've seen with tebentafusp, where you see a large majority of patients having durable disease control, durable disease control over time. Also, patients with durable disease control as, for example, that patient down there with a -30 at 22 months, who converts from having durable SD to a PR after not one, not two, not three, not four CAT scans, but at two, almost two years. Multiple patients had SD without tumor reduction, but also many patients had SD with tumor reduction that did not hit the 30% threshold required for RECIST response. This is very distinct from the PRAME-negative patients highlighted in the dark blue or almost black on the screen, who did not appear to have significant benefit at all. The overall DCR rate for the trial was 56%, with the proportion of patients with PR and confirmed tumor reduction, meaning PR or SD with confirmed tumor reduction, being 28%. The response rate was only 11%, but as you've heard earlier, and as we've seen with both this platform and this related drugs such as tebentafusp, the overall response rate significantly underestimates the proportion of patients with durable benefit. The very interesting thing here is the validation of the platform in the PRAME-positive patient population. In the PRAME-negative patients, of whom there were only five, we do not see any partial response or any SD with tumor reduction, and the response rate is unexpectedly, is, unsurprisingly 0%. So certainly, this is a drug that primarily works PRAME-positive patients. Tumor reductions were observed, as mentioned, in PRAME-positive patients, including in patients who had prior BRAF/MEK inhibitor therapy. And that's a very important thing because these prior BRAF inhibitor-treated patients tend to be very, very refractory patients with very rapid disease kinetics that oftentimes do not do well on, for example, even cellular therapies. We also observed patient clinical benefit tumor reductions in patient populations that are known to be refractory or have poor prognostic features, including patients with high tumor burdens, such as shown here. These are patients with tumor burdens that are greater than 10, 100 mm. That's 10 cm of tumor, so that basically is tumor that is greater than 2 grapefruits inside your body. So, you know, generally speaking, these are bad actors. You also see benefit in patients with extensive tumor burden in certain vital organs that are known to be adverse from a tumor microenvironment perspective, including patients with liver and brain mets, in whom actually the checkpoint inhibitors actually do not work quite as well as they do in patients without this setting. So this is again, clear evidence that the drug is working in patients with adverse prognostic factors. The ctDNA molecular response was seen in 42% of PRAME- positive patients. The patients who had a molecular response had at least a half-log reduction in their baseline ctDNA, as you've seen on the slide. These molecular responders also tended to have a more longer, more greater, more durable progression-free survival, as well as overall survival. It's important to note that the line at the bottom, which is that molecular responders were seen regardless of the RECIST response. So you do not have molecular responders only in PR patients. You had molecular responders in PR, SD, and sometimes even in PD patients, and four patients had almost near complete ctDNA clearance. Additionally, molecular response was also seen in patients with primary PD-1 resistance. That's another very important point because that indicates a non-overlapping MOA for this agent, which is kind of what we'd expect. The exciting survival data is shown on the slide. Again, in the evaluable patient population of 47, we saw a median PFS of all patients of 3.3 months, but in PRAME-positive patient population, this was 4.2 months. And again, a 6-month OS rate of 95% in PRAME-positive patients. So why is this exciting? Well, the reason it's exciting is because, again, although the data is immature, overall survival is improved with this agent. And the dark blue patients who are PRAME-negative represent an internal control that clearly differentiates that the drug is having activity in a very defined patient population. It's also worthy to note that in similar studies, so for example, SWOG S1616 trial, right? So that was essentially CTLA-4 versus CTLA-4 plus PD-1 in PD-1 primary refractory melanoma, published by Ari VanderWalde and Antoni Ribas in Nature Medicine last year. What you'd see in that study is that the median PFS of Ipilimumab, an FDA-approved agent, was three months. So what you're seeing here, non-FDA-approved agent, median PFS in PD-1, and in this case, potentially CTLA-4, vast majority of patients, CTLA-4 refractory melanoma, with an endpoint, in this case, PFS, that does not even represent the true benefit of patients who are doing well, 4.2 months. Suggesting that the likelihood of this drug potentially seeing success in different lines of therapy, particularly earlier, might actually be greater. The combination, the initial data of the combination shows that the safety profile is when you add pembrolizumab, is very favorable. The addition of pembrolizumab did not appear to alter the safety profile in a significant fashion. Brenetafusp can safely be combined, and the safety profile suggests that this is something that is likely to be very well tolerable further as we treat more patients. As you've heard from David, we are very excited about this novel biomarker that was developed internally by Dr. Koustubh Ranade and his colleagues. And this idea that the phenotype of peripheral blood T cells, which could be recruited by the agent, may be important for clinical activity, is an emerging theme that is not just specific to this particular drug, but specific to this particular class of agent, but also other agents that are T cell therapeutics, including allo products. So the whole hypothesis in this instance is that there's— If you're looking at a T cell engager, which essentially is binding T cells, that there must be some T cell subsets that are a little bit more favorable for the drug to bind or at least elicit benefit as opposed to other T cell subsets. And the subset that you'd probably be most interested in if you didn't know anything, a priority looking at the data for the first time, is the stemness phenotype, so the IL-7 receptor expressing T cells, stem-like T cells, that appear to be very important for generating that, durable antitumor immune response. So the method was essentially RNA-Seq, right? It's a whole blood RNA-Seq, using PAXgene stored blood, looking at a couple of key subsets. What they observed was that when you looked at the molecular benefit, looking at the monotherapy benefit, looking at the T cell signature, defining high and low based on the median values, the median PFS, the objective response rate, the disease control rate, were all greater in this biomarker patient population. When you look at T cell fitness, the reason why we think it's so important is because when you think of this as a predictive marker of benefit, it clearly appears to be segregating people who do much better compared to people who do significantly worse. The other interesting thing about the T cell fitness, it's certainly observed at a higher value, earlier lines of therapy, where it's more strongly correlated with the presence of naive and central, stem-like, central memory-like cells, clearly indicating that the probability of the drug working in earlier lines of therapy in less pretreated, heavily pretreated patients might be greater as well. So in conclusion, brenetafusp is exceedingly well-tolerated, with the most frequent treatment-related adverse event being reversible and manageable, low-grade CRS. Safely, it can appears to be safely combinable with a checkpoint inhibitor, and the promising monotherapy efficacy of, brenetafusp in heavily pretreated melanoma clearly supports a PFS endpoint. The benefit appears to be enriched in patients who are PRAME-positive, as you would expect, with a DCR rate of 58%, confirmed tumor reduction of PR and confirmed SD, with tumor reduction of 32%, molecular response in 42%, and a median PFS of 4.2 months, which as I tried to contextualize earlier, is very promising given the context. These endpoints all appear to capture brenetafusp benefit best, and they also platform, you know sort of contiguous with the, efficacy of the platform. The T cell fitness signature, developed internally, appears to be associated with brenetafusp benefit and is clearly, present in earlier lines of therapy. This emerging association that is, platform-specific but has also been reported for other T cell therapies, is also supporting migration of this drug early into the life cycle of the patient. And this data certainly support a idea of combining this drug with checkpoint inhibitor in an earlier line of therapy. So this is the design of the phase III trial evaluating brenetafusp that we'll be evaluating brenetafusp. Just a couple of, you know, sort of quick notes about it, and we can talk about it more later if you'd like. But essentially, it's a frontline phase III trial evaluating the addition of brenetafusp, the combination of brenetafusp plus nivolumab against the control arm of either nivolumab or nivolumab- relatlimab, administered every four weeks. The inclusion criteria include patients who have PD-1, previously untreated advanced melanoma, who will have to be A*02 restricted. There's no prospective PRAME testing for the reason that I alluded to earlier, which is that PRAME is expressed in greater than 90% of cutaneous melanoma. The stratification factors are the typical that you would, allow, and there's a very important, you know, We have to, you know, credit Immunocore with allowing patients to have prior adjuvant PD-1 therapy because this is a nod to the fact that if you don't allow prior adjuvant PD-1 therapy, it's not realistic to enroll a trial of this current landscape. And this is also supported by the fact that you're seeing efficacy in this nth- line setting in patients with prior primary exposure to PD-1. So the fact that prior adjuvant PD-1 is enrolled is firstly a nod to reality, but also I think, supported by the non-overlapping MOA of this drug relative to other agents, which certainly gives you confidence in this, in this trial design. The primary endpoint is BICR-defined PFS, with key secondary endpoints being overall survival and ORR, objective response rate, and then the ctDNA being an exploratory endpoint. So, you know, we thank all our colleagues. This trial is actually a phase III trial. I think, we are happy to note that the first patient of this trial is actually randomized today, actually, at the University of Pittsburgh. We're hopefully treating the patient in the next couple of days. And so with that, I'm going to stop and turn it over to my colleagues. Thank you. Thank you very much for that, really clear explanation. Much appreciated. I'd now like to put this into context because there are multiple lines of evidence that have given us confidence to start this PRISM-MEL trial that Dr. Davar mentioned. Number one, a high disease control rate, which, as we've talked about, is what we believe the appropriate metric for this platform of 56%. This is higher and relatlimab plus nivolumab from the RELATIVITY-020 trial, which is relatlimab plus nivolumab, but in a similar population, and there the disease control rate was 40%. That's point number one. Number two, we believe that all the activity we see here, PFS, disease control rate, response, all of that will increase as we move into first- line, based on the T cell fitness rationale that we shared and based on the ctDNA, increase in clearance as we moved KIMMTRAK from second- line to first- line. We believe that's a platform. It's also not, it's not surprising. In fact, all immunotherapies improve as they move from second-line to first-line, even relatlimab plus nivolumab, which went from a 3.2-month PFS and 40% DCR to a 10-month PFS and a 60% DCR. The third factor is that when we move into first-line, we will be in combination. We will have brenetafusp plus nivolumab, two agents, each with different mechanism of action, each with known monotherapy activity. This dual, we expect this to have at least additive activity. Thus, we expect this to be superior to nivolumab alone because we have monotherapy activity in heavily pretreated patients. And once again, based on the apples-to-apples comparison of brenetafusp monotherapy to relatlimab, this gives us confidence in the first-line, brenetafusp plus nivolumab will be superior to relatlimab plus nivolumab. i would now just like to update you on a really additional exciting announcement that we made earlier this week about our KIMMTRAK cutaneous melanoma trial. Now, we have always had confidence for KIMMTRAK in cutaneous melanoma. Obviously, there's a fantastic survival benefit in a different type of melanoma, uveal. In two different phase I trials, we've had promising survival in cutaneous melanoma for KIMMTRAK monotherapy and for KIMMTRAK plus checkpoints. This is what led us to start the phase II/III trial. Now, we did the phase II portion originally because we were not sure which regimen to advance to phase III, either KIMMTRAK mono or KIMMTRAK plus anti-PD-1, and we thought, let's do the phase II, and then that will allow us to only choose one arm for the phase III, because then we would have a smaller, shorter, faster phase III. That was the reason to do the phase II to phase III. Because of recent rapid accrual and following discussion and agreement with the FDA, we've decided to do something quite novel, which is to convert the phase II into a phase III, retaining all three arms. There are two benefits that come out of this, actually. The first is we're now going to get more robust evaluation of two KIMMTRAK regimens. Rather than 40 patients per arm, we're now going to have 170 patients per arm. Number two, it gives us two shots on goal: KIMMTRAK monotherapy and KIMMTRAK plus anti-PD-1. But the really incredible thing is because we are able to include all patients randomized to date, we're actually going to have a faster time to completion than in the original design, in fact, up to 12 months faster. So with that in mind, we are very proud to have at Immunocore an incredible melanoma franchise, now with three phase III trials. In addition to KIMMTRAK, which is approved in metastatic uveal, the ATOM registrational trial will start later this year, sponsored by EORTC. PRISM-MEL started in first-line metastatic cutaneous melanoma, and then the TEBE-AM, as I announced, is now a fully fledged phase III trial. With that, I'd like to call up my colleagues, and Bahija, I'll hand it over to you. All right. Thank you very much. Thank you both. That was really great. Now we open it up for your questions. Hi, guys. Jonathan Chang from Leerink Partners. Thanks for taking my questions. Go ahead, please. First question: Can you discuss your thoughts on how you're thinking, enrollment will proceed in the PRISM-MEL-301 study? Are there things in this data set and are learnings from the TEBE-AM study that make you more or less confident in how quickly this study could proceed? Great. Thank you. David, do you want to take that? If I heard you correctly, it was about the confidence and the pace of the phase III PRISM-MEL based on the TEBE-AM? Correct. Or from this data set. Yeah. So I, I would say two. One is, we've been really impressed with the rate of accrual in the TEBE-AM. Actually, more recently, it's exceeded our expectation. And as we have gone out, with the PRISM-MEL trial, it's a first-line setting, and so that's why Mohammed designed a more favorable, prime dosing regimen. We've gotten great enthusiasm from, global sites. So over 150 sites are interested. So I think that's what give us, confidence in the operational aspects of the trial. I think in terms of the data here, what gives us confidence is the monotherapy disease control rate that we see, the internal consistency with the PRAME-positive versus the PRAME-negative, the supporting data of the ctDNA, and then I think, Jonathan, the apples-to-apples comparison in the second-line population of our activity versus relatlimab-nivolumab, ours being a monotherapy and relatlimab-nivolumab being a combination. Got it. Anything you want to add? Second question. As we look ahead to updates on brenetafusp and other tumor types, what are the key learnings from today's presentation as it pertains to potential success in tumor types beyond melanoma? Thank you. Do you want to take that, Mohammed? Yeah, sure. I think, you know, one of the key messages which you heard from both David and from Dr. Davar, is that the endpoint that I think we'll be looking for is disease control, 'cause it goes beyond RECIST response. So that's certainly going to be a continuing theme. But beyond that, of course, ctDNA, which we learned from tebentafusp, we're seeing it with brenetafusp and cutaneous, is another marker that we think is drug specific. Beyond that, I would say that, you know, for the additional tumor types, like ovarian and lung, they are certainly much more heterogeneous than melanoma. So we think that, of course, we need to enroll specific cohorts. Then also, I think we're going to be looking at combinations to allow us to move to earlier lines because we're learning about this T cell fitness signature, which suggests moving to earlier lines, we should see even better activity. So, the really key, I just want to add to—I agree with everything that Mohammed has said. The key for us is not to— is to capture all the patients that are most likely to benefit, and I think that's what we learned from KIMMTRAK, and we see it now validated in the market because we see even better on the duration of treatment. That tells you something. Okay. Come on. Clay? Great. Thank you very much for the presentation, Tyler Van Buren from TD Cowen. So, I really enjoyed David's intro. You guys make a good point that the disease control rate of 56% versus 46% with both of them and the 42% molecular response lines up perfectly, kind of suggesting that maybe you could see a similar 49% survival benefit with brenetafusp like you did with tebentafusp. But I guess the two key differences are the target, right? 'Cause these are very similar T cell engagers, and then the disease, right, with cutaneous versus uveal, as we think about disease control and molecular response translating to overall response. So it'd be helpful to hear you guys elaborate on your confidence that those two differences won't have a negative impact in that translation. Okay. David, you want to take one? Yeah. So I guess one question is our confidence in disease control rate as an endpoint and its ability to translate into PFS. I think, I think what we're seeing is the consistency across whether it's KIMMTRAK in uveal melanoma, KIMMTRAK in cutaneous melanoma, and now brenetafusp in cutaneous melanoma. I think it's Tyler, it's this phenotype of a closed umbrella spider plot, is really the underlying feature that we see across. I think if you look, for example, at the PRAME-negative patients, those tumors are not really under control. Those tumors are going up. So I think what convinces me, Tyler, about this data set here is, once again, the PRAME, the fact that we see the disease control in the PRAME-positive, not the PRAME-negative. Number two, this concept of tumor reduction. The reason we specifically call that out is because we know that tumors don't spontaneously decrease on their own. It is clear evidence of a treatment effect. So with KIMMTRAK in the first-line, we see 25% of patients having that durable tumor reduction. The 30% threshold for PR is, I don't think, relevant for this platform. In brenetafusp, we see 28% of patients having that durable tumor reduction in a very heavily pretreated patient. And then the ctDNA, the fact that the ctDNA reductions, the molecular response for both KIMMTRAK and for brenetafusp, the fact that those correlate with outcome, with PFS and survival, gives us further confidence that it is a real measure of benefit. Yeah. You want to add something? Yeah, I was going to just— because you were asking us to compare tebentafusp versus brenetafusp and if there are any differences. I would just add two more. I agree with everything that David said. The other is, I think it's really important to understand, like, the biology. GP-100 is something that's not critical to driving the tumor. PRAME is a target that's actually critical to driving the tumor. It's associated with poor prognosis. It drives the tumor. So it's a target that the tumor is less likely to lose. The other is that, you know, just like GP-100, PRAME is, like, expressed in more than 90%, you know, close to 90%. It's a highly expressed target, and the number of peptides that are TCR bispecific targets is likely even higher than GP-100. At least preclinically, that's what we see. Those are differences between tebentafusp and PRAME, but actually favor PRAME. Yeah. Actually, I'll just add one other point, sorry, Tyler, which I forgot to add. And that is, you know, with tebentafusp, the benefit is probably half in PD and half in disease control, and that's what gives you the survival benefit. My sense is with brenetafusp, that's shifted more to the disease control side. So there is some PD pseudo- progression that's going to give us survival benefit, but it does appear that brenetafusp is more of a disease control drug even than KIMMTRAK was. Okay, and just, one follow-up on the disease control comment. So I mean, the patients with prior BRAF inhibitor treatment clearly do worse. We could remove them from the waterfall plot and do our math, our own math. But as we think about disease control rate, have you guys looked at how much better, how much more it improves if you remove those patients that were on BRAF inhibitors? Because obviously you're not enrolling those in the frontline trial. Yeah, no, that's a good question. I mean, and you can comment on, prior BRAF and, you know, the challenge of those. What we wanted to do is provide kind of a, "Here's the totality of the data," rather than, you know, "Let's remove these ones because they rapidly progress." So we have the totality of the data, but I think, Tyler, you picked up on something really interesting, which is the prior BRAF patients did tend to be the ones to progress, and in the first-line trial, that obviously won't be relevant. But do you want to comment on prior BRAF and what the impact is and your experience with immunotherapy? So, patients with prior BRAF/MEK inhibitor exposure tend to do quite poorly. You can get this sense from two settings, right? So we did phase III trial of PD-1, then PD-1 CTLA-4, and then BRAF/MEK versus the reverse sequence of BRAF/MEK followed by PD-1 CTLA-4. So the ECOG-ACRIN EA6134 DREAMseq trial. Frontline trial, right? What is the proportion of patients in a frontline trial where the drug is paid for by the NCI, who got second-line BRAF/MEK in a trial that is run by the NCI at the academic medical centers? The answer is 90%, which meant that 10% of patients who failed frontline PD-1 CTLA-4 did not receive molecular-targeted therapy. The proportion of patients who failed molecularly targeted therapy, who did not receive PD-1, approximately 20%. So the problem that you have is in a frontline setting, people who fail BRAF/MEK are bad actors. They don't even make the second-line of therapy, let alone, you know, go on to do well. So the point here is when you look at this in the context of the frontline trial, what this suggests is two things: One, the patients tend to get frontline in the adjuvant setting, more targeted, more immune therapy than targeted therapy. This is not likely to change. If anything, it's likely to grow with the neo adjuvant data that you're going to hear on Sunday, as well as the update from the Moderna vaccine data that you heard from Jeffrey Weber yesterday. Even with the COLUMBUS data, the early update, this is not likely to change the landscape so much. So what we really think is probably going to happen is that we're not really going to enroll patients with too much prior BRAF exposure. We think we're going to enroll patients with some amount of prior PD-1 adjuvant exposure, but not too much BRAF. And actually, those patients not being on the trial is actually, if anything, a good thing. Because those patients are going to blow through both arms quite badly. If anything, they're going to blow through the control arm terribly. Great. Hey, Jessica Fye, JP Morgan. I had a couple. So you talked about better T cell fitness in earlier lines of therapy. So I'm curious what proportion of frontline melanoma patients we should think of as having a similar degree of T cell fitness as the fit subset that you showed? Is there, like, a good reference for that? And then a few on your phase III trial. Can you talk about your confidence that you'll be able to preserve efficacy in phase III with the less frequent dosing over time? Can you talk a little bit about the process of the HLA testing and what that means from a practical standpoint as you enroll the phase III? And related to, you know, that trial again, is there any interest in maybe simultaneously testing PRAME-positive population in addition to the overall population? Okay. So, there are multiple questions. I think I'll start with Koustubh on the melanoma and the signature, and then I'll come to David, then Mohammed. Sure. Thanks, Koustubh. Thanks for the question. In the data that you saw, which was in late line, T cell fitness, which is defined by the median. So the point being that we don't have an absolute threshold, and it's empirical. And so again, the expectation is that T cell fitness improves in earlier lines, as Dr. Davar showed as well. And so, at the moment, we don't have that first-line data. We'll generate that, we'll explore it, but the expectation is that should improve and could potentially be more than the median that we saw here. But of course, at the moment, we don't have that data. Yeah. I mean, in the figure, just to add to what Koustubh said, in the figure, you can see half of the patients with 1-2 prior lines are above that threshold. So presumably, as Koustubh said, it's going to be even higher than that in the first-line setting. Okay. Mohammed, do you want to address the- Yeah, I can just address the question about the frequency of dosing as well as the HLA. So with regards to frequency dosing, if you think about the frontline data set, the highest risk for progression is in the first 12 months— the first 12 weeks. So that's why we intentionally picked the weekly dosing through the first 12 weeks, because that's where the risk is greatest. Then we moved to biweekly, which is for the remainder of the year. And then we certainly have data from our 201 study when we did combine with anti-checkpoint, that beyond a year, we moved to monthly, and we did not see tumor escape. So that's sort of at least our thinking and understanding for how we did that sort of graduated dosing frequency. With regards to the HLA testing, what's really interesting, because we're now talking and activating the sites, so they're giving us feedback. A lot of the sites have experience with KIMMTRAK, so they've actually made HLA part of their standard thing for melanoma patients. So they're like: "We're not even waiting for your protocol. We're testing HLA as part of standard care, and we know which ones are HLA- positive." Other ones who have access to HLA testing, they said: "Oh, our testing takes, you know, a week or more, whereas our central testing, they can sign the consent at any point, the pre-screening consent, and they can get it tested basically within a week." So it's barely even faster than their own. Essentially, most sites are able to do it as standard of care on their own, and if not, they're leveraging our pre-screening consent to screen patients while they're still being sort of evaluated for their metastatic setting. I think you had one question on the PRAME-positive versus negative and a powering or primary endpoint. Is that, is that the question? Yeah. Yeah. Yeah, so, yeah. So I mean, that's an interesting idea. When we designed the trial, Jess, we actually designed it assuming a 90%. We, we assumed 10% wouldn't get benefit, so we already took that into account when we designed the trial. I think we'd have to consider whether we would have PRAME-positive co-primary endpoint or something, as some companies have done. But I think the fact that 90% are positive, if you're not positive in the ITT, then probably 90% is, you know, not gonna make a difference. Yeah. And also, you don't know what the negatives are gonna do in the combo, right? Yeah. Because of the— Yeah, the fact is that, as Bahija just said, the idea was that the negatives are still getting nivolumab. So it's not like— Exactly. T hey're getting no active therapy. Hi, this is Naureen Quibria from Capital One. Actually, I'd just like to piggyback on what Tyler asked, which is, you know, in terms of patient baseline patient characteristics, where you would expect clinical benefit or responses with brenetafusp. Is it just PRAME-positive, or those that haven't had BRAF or MEK inhibitor or prior exposure, or do you expect to see other, yeah, other types of patients where, you know, you might see benefit? And then I have a second follow-up. Okay, David, you want— Yeah. So, one of the metric I sometimes use, as we said, is tumor reduction, as is a patient benefiting or not. You can also use ctDNA reduction. These are early measures of whether a patient's benefiting. Obviously, longer term is PFS and survival. And when you look at those two metrics, we see benefit in patients with high tumor burden and low tumor burden. We see benefit in patients with brain mets, liver mets, or both. I think the place we don't really see tumor reduction at least, or ctDNA, is in the PRAME-negatives. I think that's the clearest one. I think the BRAF prior therapy is one that we've talked about here, where most of the patients had either PD or tumor growth. In the first-line setting, of course, as you heard, that's not gonna be an issue. Okay, great. But we haven't seen anything, any other baseline characteristics, except for T cell fitness would be the other one. Maybe I missed it, but, you know, in the abstract, there was a sort of broad range of doses that were tested. Yeah. What's the dose that you're expanding with? Yeah, Mohammed, do you want to take that one? Mm-hmm. Yeah. We have two doses going into from the Optimus project. Right. So from our phase I, f rom our phase I, what we saw was that we started seeing both consistent biologic activity and clinical activity starting at 20. We went as high as 320, but we selected 160 as sort of the — based on modeling the t he best dose. So in the PRISM-MEL, we have 160 and 40, which is above the lowest dose and doesn't require steroids. Is it, you know, Mark, you might wanna explain that? So that's part of the Optimus, the Project Optimus. So we'll do 40 patients, I think, you know, going in, and then we drop one, and we continue. Great. Thank you. Oh, go ahead, please. Can't hear you. Thank you. Sorry. Alex from Barclays, for Peter Lawson. Just a bit of a hypothetical question, but what do you think will be the, the benefit of adding, of combining with nivolumab in the frontline setting versus, just doing monotherapy? I think it's before I give it to the expert, it's just if you want really to enroll the trial. I don't think, you know, with the standards of care being nivolumab to go head-to-head without having the data in that setting, I don't think you will enroll that trial. But you wanna— Yeah. So I would expect at least additive activity because there are different mechanisms, and we're adding them together. You know, they work in different ways. Now, the small dataset that we did show here, you know, with the 7 and 9 patients, you know, that wasn't a dataset for safety because those patients would never have responded to PD-1. They were already, for the most part, refractory. So that was not asking, "Do you get additive activity?" It's asking: Can you safely combine them? Interestingly, there was one confirmed PR there, and then, you know, three out of four ctDNA molecular responses. So promising, but the best way to do it is in a—m y belief always is in a randomized trial, is the only way you can really tease apart, combining two active therapies. Justin Zelin, BTIG. So the T cell fitness data looks really interesting, and it makes a lot of sense. David, just curious if you looked at PRAME H-score and correlation to efficacy here, if you saw any interesting trends there? Yeah. No, that's a really important question, Justin, because we did talk about it a couple of years ago. If you remember, we talked about, we saw an enrichment of responses for gp100 at the higher H-score, but we saw survival benefit at high and low, and that wasn't something I think we could ever, you know. So that led us to think maybe the same would be true for PRAME. I think what we now realize actually is it's less about high and low. It's does the patient have any PRAME or not? So it's about PRAME zero versus PRAME-positive, rather than PRAME high or low. I think the initial data we had last year was, tended to be more high PRAME patients anyway because they were cutaneous melanoma, but that's our latest thinking. Got it. Maybe another question from back then was the combinability of multiple ImmTACs and just how you're thinking about that in the future. Uh, yeah. Mohammed, you want to talk about that? Go ahead. Yeah. So I think, it's we're learning. Obviously, combining two ImmTACs, we're gonna have clearly overlapping toxicity. Both will cause CRS. What we're seeing with tebentafusp and PRAME is that we can combine. We just need to sort of separate them out a little bit, right? Because you don't want to give the two together because there's additive toxicity. But we're still learning, we're still enrolling, so stay tuned. So it's the same thing. Mohammed has the experience with the PD-1, PD-L1, and CTLA-4, and so you have, with that overlapping toxicity, you really have to go, you know, more careful, and that's exactly, he's finding himself doing that again, with PRAME and tebentafusp. Hi! Oh, sorry. Go ahead. Hi, Avantika from Mizuho. I had two questions. One was, assuming that phase III study for cutaneous melanoma is positive and gets approval, how would brenetafusp and nivolumab be positioned versus some of the other first-line agents? And then my second question was, can you remind us what the combination agents you're using for the other tumor cohorts, and what's the reasoning behind those? Okay, there are two, two long questions. One for David and one for, Yeah. You, Mohamed. So number one is we're hoping this will be the next immune mechanism to be approved in first-line after LAG-3, the next novel mechanism. We think, first of all, the safety is going to be really well-tolerated, based on what you heard from Dr. Davar, so even better tolerated than all other immune therapy combinations there. The study is designed, of course, to show superiority over nivolumab alone, and it's also—t he intent is to show superiority over LAG-3 plus nivolumab as well. So the intent is in HLA-A*02- positive to be the best combination partner in patients who would receive nivolumab or nivolumab LAG-3. I think that the upside for us is, can the activity actually be better than in a cross trial than nivolumab plus ipi? That, I think, would be the upside for us, but I think even the base case would be a really good outcome for us. Mohamed? Yeah. With regards to your question about combination, so the thought behind the combination partners were basically standard of care agents that are used across the tumor types that we were interested in from a PRAME high expression, so basically lung, ovarian, endometrial. So most of the combination partners are single-agent chemotherapy. We have amended the study, so we're adding additional combination partners informed by this whole T cell fitness picture of how can you move to earlier. So besides the fact that many of the combination partners are standard of care, they also now allow us to move to earlier lines of therapy. So some of the new combination partners will allow us to move to even earlier. And then in addition, as you know, for lung, there's targeted, and for melanoma, the targeted therapy. Some of the new combination cohorts will include targeted therapy. Hi, everyone. Gil Blum, Needham & Company. I want to spend a second here on this T cell fitness part of the picture. And just help us understand better, what does it mean that, you know, all these patients have experienced sometimes multiple checkpoints in the second-line? What does it mean for T cell exhaustion and kind of the markers that you would look on a T cell, like things like PD-1 expression, for example, right? So I'm just trying to understand how that translates into the front line, even though you spoke of the adjuvant setting as well. Yeah, Koustubh can take that because it's really work from us and also from others in the literature. But go ahead, Koustubh. Sure. So the way to conceptualize, excuse me, T cell fitness is to think about it in terms of the ability of T cells to self-renew, to proliferate, to differentiate into effective T cells that then actually kill the tumor cell. What's been observed is that T cells, when they're repeatedly exposed to antigens, tumor antigens, for instance, then they get exhausted, but over time, they not only get exhausted, but they also senesce. So it's, and then they can't proliferate and self-renew, et cetera. So what was observed in the CAR T and the adoptive cell therapy was that patients who responded actually had in the cells that were infused, more of these naive and stem cell memory T cells, so that could self-renew and proliferate and then go on to become killers. That was the interesting finding in the analysis that Dr. Davar presented, where we see a signature of these naive and stem cell memory T cells that are associated with better outcomes, and even more importantly, in the context of PRISM-MEL-301, that the level of the signature is higher in earlier lines of therapy, which, given what I just said, makes good sense because in early lines of therapy, particularly in untreated patients, these, they've not been exposed to as many tumor antigens over a prolonged period, and so they have more of these naive and stem cell memory T cells. And so that's how we are thinking about it. Over here. Maybe a few questions on the TEBE-AM study, the pivotal trial. Sorry, Eric Schmidt from Cantor Fitzgerald. First, did you take a look at the phase II data? I know it was an open-label study, so anything you want to share or can share with us prior to your FDA interactions. Two, I assume we're not going to see anything from the phase II later this year as originally planned. And three, can you give us a sense, David, of that timeline that you said was accelerated? When will we, in fact, potentially see the phase III? Thank you. Yeah, great set of questions. Number one is we did not look at the data, and that was part of going to the FDA to get their agreement that we can include those patients. That's what has allowed us to accelerate. And Eric, we didn't feel we needed to because we had confidence already. Remember, the phase II was really to select a dose. It wasn't to give us confidence. So as a consequence, we obviously won't be sharing any data 'cause we won't be looking at it anyway. In terms of the acceleration, and this is where we're counting on Mohammed's superb team here, but, we are hoping to complete the phase III enrollment by first quarter of 2026, although we're trying to push that into 2025, obviously, if we can. Jeffrey Hung, Morgan Stanley. In your study, did PRAME expression levels differ based on number of prior lines of therapy? And then you have one PR that's ongoing in the combination and four PRs from the monotherapy. I know it's small numbers, but can you just talk about any differences in monotherapy versus combination in terms of time to PR or any other distinguishing characteristics of their clinical benefit? Thanks. Great. Koustubh, you want to talk about the expression of PRAME, and then David or Mohammed? Yeah, in terms of PRAME expression by lines of therapy, we haven't seen that much heterogeneity. As you saw, 90% or thereabouts of cutaneous melanoma already have high PRAME expression, so there's not that much heterogeneity in PRAME expression. In terms of PRs, it's interesting because we had one patient who was actually stable disease till month 22, and actually was at like - 28, - 29. This, you know, fell under what we called stable disease with minor response, but of course, most people would say that's not a response. And then they converted to PR at month 22. So—but then that PR is still - 32, -33%. So we have a lot of PRs. Well, we have PRs that are hovering at the - 30 to minus, you know— Twenty-nine. Minus forty percent, and then we have stable disease that are hovering at the, you know, -10% to -29%. That's what we saw in KIMMTRAK too. So I bundle those all together. I don't just talk about RECIST responses. I talk about, you know, tumor reduction, durable tumor reduction responses. And there, what we see is we do see very frequently rapid tumor reduction very early. This is not something where you have to wait a long time, but sometimes we see further deepening as the patient who converted from a PR to from an SD to a PR. But clearly, that patient was benefiting, you know, for the first 22 months of the therapy. Great. Hey, it's Michael Schmidt with Guggenheim. As we think about other opportunities for the PRAME program outside melanoma, and I know you have cohorts ongoing in ovarian cancer and lung cancer, et cetera. What are some of the gating factors to move ahead in additional phase III trials? Is it just purely seeing the disease control rate in those tumor types, or are there other factors that are, you know, driving your consideration set? I would say each, each tumor is really different, and you have to look at, you know, what's the standards of care and how you compare and which line of therapy and everything. I think that's, you know, and which combinations you're going to. I would say it's, you know, we are still— the work is still ongoing, but it really depends on the, on the tumor, I would say. But there is something that's— ou know, when you look at the melanoma, to go back to the melanoma, you know, this, closed umbrella is really becoming a thing for the platform. 'Cause you, you see these, these patients hovering at 29%, and the PR is at 30. So I can— or you see some at 31 or something like that. So it's really interesting. The other thing that we have seen, we didn't talk about it, but in the ESMO data, if you look at the DCR in the ESMO data and the DCR that we have now with these patients, is almost exactly the same. It's 56-57, I think that's what it is. So they're very consistent with, you know, some differences in how many PRs we have. Hi, Jack Allen from Baird. Just wanted to ask a quick one on your expectations as it relates to durability of treatment in the PRISM study. I believe from the KIMMTRAK experience in uveal, you had really durable treatment durations, even some progressive disease being treated through progression, and that ended up benefiting overall survival. How do you see that kind of dynamic playing out as you move into the first-line in cutaneous melanoma? And how quickly do you think people will look for other options after they progress in the PRISM study, and how that will impact maybe overall survival? Yeah, good question. David, you want to talk about one thing we don't talk about as much, actually, is the OS of the PRAME-positive in this late line? Yeah. So we obviously focus on PFS and disease control because that's the primary endpoint of the phase III trial, and we do believe that brenetafusp can deliver that PFS. But what's equally intriguing is it looks like we're repeating the same phenomenon with overall survival. And it's actually quite interesting, and it's something that we're seeing in the brenetafusp program. Can you say the numbers? Yeah. So the— Ninety-five percent. Yes, six months is 95%. I think historically, if you look— Positive. Six months is about 75%. So it's early, but it's actually quite intriguing. And once again, that difference between the PRAME-positive and PRAME-negative provides a reason to believe. I think in cutaneous melanoma, we're a little bit more fortunate than, let's say, in ovarian cancer, where the doctors are very familiar with treating beyond progression, especially they're very familiar with our uveal data. The primary endpoint, of course, is PFS, so once there's a progression event, that's the primary endpoint. But I am hopeful that doctors will continue to treat if they feel the patient is getting benefit. I guess to that end, when you think about continuing, so having more second-line options available— Yeah. Wasn't 30 years, kind of more of the last— Yeah. It wasn't the primary second-line. Do you want to—m aybe, Dr. Davar, maybe you can comment on, from your clinical experience, when would you continue treating with something like this versus switching to a second-line melanoma therapy? So, I guess one important thing to keep in mind about second-line therapies, you know, so again, I sit at a large academic medical center. Patients come to us with second-line therapies all the time. And the first thing we try to do is we try to figure out if the patient actually did progress in the first place or not. Because the key thing to understand about second-line therapies is, you know, it's not a slam dunk, right? So TIL sounds great, but TIL there's a 30% response rate, and it makes you pretty sick. You know, everybody is getting, staying in the hospital for three weeks, and not everybody is guaranteed to get a response. So you can harvest a tumor from 100 patients, 70% of those patients are going to progress. So you've undergone a surgery, and you've wasted 4 weeks for nothing. So the first thing to keep in mind is that patients, particularly at large academic medical centers, people are very, very, very cognizant about whether or not somebody should come off a frontline trial and be treated as a progressor before you switch therapies. Because it's not like the second, what, what's coming after that is a slam dunk. We don't have effective, truly effective second-line therapies that are going to cause, like, tremendous responses. You know, we've got targeted therapy, and targeted therapy is often something people want to save. So one thing is, I do, I do certainly believe that in the context of a clinical trial where PFS is BICR- dependent, there'll be a certain hesitation on the part of investigators to take patients off until progression is firstly, a, confirmed, confirmed by central review, one. Two, the aspect of second-line therapies is a very important thing to keep in mind, but in—y ou have to keep in mind that in the context of melanoma, the most effective things, the most exciting things, the plenaries that you've heard about, they're all happening in the adjuvant and the neoadjuvant settings. There are very few truly exciting, you know, novel modalities that are being really talked about in the second or third- line plus settings. So I think for those two reasons, people will be, will be very reticent to take patients off what is potentially a very effective therapy, just because there's this hypothetical belief that some end-line treatment that is an unproven MOA is going to work, and we'll try to give this drug a chance. And until we know for sure, you know, patients have recent confirmed progression and confirmed by central review, then, of course, it's appropriate to take them off, but I don't think it's going to be done inappropriately. Great. The last two questions. We are conscious that we are between you and dinner. I'll be very quick. Thanks for taking the question. This is Tina from Jefferies, on behalf of Mikey. Just thinking about the disease control rate, which looks, I mean, if I'm understanding correctly, your second-line disease control rate of 58% looks similar to what Opdualag shows in first-line. So how much added benefit can you get, or can you assume you get in the phase III, when you add PRAME on top of PD-1? And how would that sort of, you know, increase your confidence in how the control arm would do versus, you know, the drug arm, being that the control arm has around, presumably, 30% of the patients will be enrolled in the U.S., and predominantly most of them would get Opdualag, and the bar there is sort of high with, you know, a 10-month PFS. Just how much more confidence do you think that you'd be able to increase that disease continuation rate and therefore sort of marginally increase PFS and then be able to hit on the, on the primary endpoint of the study? Thank you. Yeah. Good question. I, I will, I'll let you choose who wants to take this one. Yeah. I mean, I'll, I'll take a stab. It's a good question, but, you know, Mohammed, you can add to that. So I think it, it's helpful to remember in the second-line setting, the disease control rate for relatlimab plus nivolumab, 40%, the median PFS, 3.2 months, and then you've heard our disease control rate is 56%, and, you know, in the— As monotherapy. As monotherapy, the median PFS was 3.3 months. So that was our monotherapy data compared to their combination data. Now, you're right, relatlimab plus nivolumab went to 10 months in the first-line setting. We fully expect our therapy, just by itself, to also have greater activity, except now we're adding it on to nivolumab. So now it's essentially nivolumab plus brenetafusp versus nivolumab plus LAG-3. They both get nivolumab, so that cancels out. So now you're left with brenetafusp versus LAG-3. LAG-3 monotherapy, you know, it's hard to find that published data. Now you've seen the brenetafusp monotherapy data. So that's the reason to believe that we expect to have better activity combining these two active agents in first-line than relatlimab plus nivolumab in first-line. That's really what we're going to be testing. So we'll have at least an additive effect, and then we'll see if we have a synergistic effect, since the two mechanisms are a little bit different. That's helpful. Do you have sort of an idea of how LAG does on its own? I don't, I don't think I've ever seen the published data. Nobody has seen the data— Oh. But I think, I don't think it's working. Yeah. Thank you. All right. All right. I want to thank you again for being here. Brian, you want to say something? No, I was just going to say that's—t hanks for your time, and enjoy the weekend of presentations, and we'll look forward to talking to you as the weekend goes on. Great. Thank you very much.