Immunocore Holdings plc (IMCR) Earnings Call Transcript & Summary

All right. We can get started. Good evening, everyone, and thank you for taking the time to be here. We're happy to be with you today. And here, especially at ASCO, it's always a great time to see the progress that everybody, as a community, is making against cancer. So today, it's my pleasure, really, to introduce Dr. Davar, who's going to -- and David, actually, who you know, who's going to talk to you about PRAME, look at the data again and frame in the context of the platform. So we will be making some forward-looking statements. And without further ado, I'm going to actually pass it on 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 I'm actually even more excited today to be part of a really talented team pioneering T-cell receptor checkpoints -- sorry, T-cell receptor therapeutics. I'm going to give you some insights from what we've learned from KIMMTRAK, because that's going to 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. And 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 going to 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 15 or longer years. However, for checkpoints, we know this is really anecdotal. And in large 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 our 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 minus 1% to minus 29%. Now there are 2 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 RECIST partial response. But the even more amazing fact is that the median duration of tumor reduction, calculated the same way you calculate needed 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 that, 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 1 or 2 years. And 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 the 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 2 really important translational insights that our superb translational medicine team has made. The first is ctDNA, which we showed for uveal melanoma and 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, triple and ctDNA molecular response. Now the question is why. Why is it higher? And we think there's probably 2 reasons. The first, of course, is the tumor. The tumor has undergone less immune editing in the first line compared to 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. And 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 2 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 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 we'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 is 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 a onco presentation. These are my disclosures. So essentially, brenetafusp, or brene for short, is an ImmTAC bispecific T cell engager that's targeting the A2-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 A2 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's melanoma or not is actually looking 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 today represent the continuation of the data from an earlier -- an update of the earlier data that was presented by Omid at ESMO 2022. The primary endpoints were essentially MTD and efficacy. And as is typical with the ImmTAC platform, essentially, patients receive a step-up dose, 1 to 2 step-up doses before receiving the cohort-defined target dose. And all these patients are obviously A2 (0201) 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 there are patients were 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 1, but 2. 80% of patients had prior CTLA-4 therapy. Almost all of whom had received this in combination with OPDIVO. 40% of patients additionally had another prior checkpoint inhibitor in addition to PD-1 or CTLA-4. The combination pembro arm had heavily pretreated patients as well who are even more heavily pretreated with a high number of patients with BRAF prior exposure and primary resistance to checkpoint inhibitor therapy. And primary resistance is important because primary resistance represents a proportion of patients who have no prior response. These are patients who received a checkpoint and whose next scan shows tumor growth, so no prior response or what is termed primary progression to checkpoint inhibitor agent. 90% of these patients in the monotherapy cohort were PRAME-positive and the 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. Brene monotherapy resulted in -- the most frequent adverse event observed was 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 bind -- when you give somebody a T cell bi-engager, you're going to 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 have to report it as an adverse event, but it's not truly a clinically significant adverse event. So it's a -- that's beyond that clinically insignificant treatment-related grade 3 event, which is transient. We do not see significant other treatment-related adverse events outside of that. Couple of instances of patients with grade 3 rashes and fevers that were easily managed. This is the swimmers plot that essentially talks about the extended durable disease control in the monotherapy patient population. There were 36 patients that were evaluable, and the vast majority at 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 the checkpoint inhibitor swimmers plot. So in the checkpoint inhibitor swimmers plot, you see early rapid regressions in tumor. You can see about 10% to 15% of patients with delayed responses over time, but that's not what you see here. What you're seeing 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, the patient down there with a minus 30 at 22 months, who converts from having durable SD to a PR after not 1, not 2, not 3, not 4 CAT scans, but at 2 -- almost 2 years. Multiple patients at SD without tumor reduction, but also many patients at SD with tumor reduction that did not hit the 30% threshold required for RECIST response. And 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 a common -- with the proportion of patients with PR and confirmed tumor reduction, meaning PR or SD with confirmed tumor reduction has been 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 tebe, 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 are only 5, 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 in PRAME-positive patients. Tumor reductions were observed, as mentioned, in primarily 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 burden, such as shown here. These are patients with tumor burdens that are greater than 10 -- 100 millimeters. That's 10 centimeters of tumor. So that basically is tumor that is greater than 2 grapefruits inside your body. So 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 half log reduction in the baseline ctDNA, as you've seen on the slide. And these molecular responses also tended to have a more longer, more greater, more durable progression-free survival as well as overall survival. And 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 4 patients had almost near complete ctDNA clearance. Additionally, molecular response was also seen in patients with primary PD-1 resistance. And that's another very important point because that indicates a nonoverlapping MOA for this agent, which is kind of what you would expect. The exciting survival data shown on this slide, again, in the survival evaluable patient population of 47, we saw a median PFS of all patients of 3.3 months. But in the PRAME-positive patient population, this was 4.2 months and again, a 6-month OS rate of 95% in the 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 exciting internal -- represent 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 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 3 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 patient 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 pembro is very favorable. The addition of pembro did not appear alter the safety profile in a significant fashion. Brene can safely be combined, and the safety profile suggests that this is something that is likely to be very well tolerable in 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 phenotype, 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 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 illicit 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 priori, looking at the data for the first time is the stemness phenotypes. 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. It's a whole blood RNA seq using PAXgene stored blood, looking at a couple of key subsets. And what they observed was that when you look at the molecular benefit looking in 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. So 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, brene 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 brene 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 BDR and confirm SD with tumor reduction of 32%, molecular response at 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 brene benefit best and they also platform sort of contiguous with the efficacy of the platform. The T cell fitness signature developed internally appears to be associated with brene benefit and is clearly present in earlier lines of therapy, and 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 an idea of combining this drug with checkpoint inhibitor in an earlier line of therapy. So this is the design of the Phase III trial that will be evaluating brene. Just a couple of 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 brene -- the combination of brene plus nivo against the control arm of either nivo or nivo-rela administered every 4 weeks. The inclusion criteria include patients who are PD-1 previously untreated advanced melanoma who have to be A2 restricted. There is 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 typical that you would allow. And there's a very important -- we have to 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 at this current landscape. And this is also supported by the fact that you're seeing efficacy in this end-line setting in patients with 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 nonoverlapping MOA of this drug relative to other agents, which certainly gives you confidence in this trial design. The primary end point is BICR defined PFS with key secondary endpoints being overall survival and an objective response rate and then the ctDNA being exploratory endpoint. So we thank all our colleagues. This trial is actually a global Phase III trial. I think we are happy to note that the first patient on this trial was actually randomized today, actually, at the University of Pittsburgh. We have been -- 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, high disease control rate, which, as we've talked about, is what we believe the appropriate metric for this platform of 56%. This is in -- this is higher and superior to rela plus nivo from the RELATIVITY-020 trial, which is a combination rela plus nivo, 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 rela plus nivo, 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 brene plus nivo, 2 agents, each with different mechanism of action, each with known monotherapy activity. This duo, 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 brene monotherapy to RELATIVITY-020, we -- this gives us confidence in the first line, brene plus nivo will be superior to rela plus nivo. 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 2 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 3 arms. And there are 2 benefits that come out of this actually. The first is we're now going to get more robust evaluation of 2 KIMMTRAK regimens. Rather than 40 patients per arm, we're now going to have 170 patients per arm. Number two, it gives us 2 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 3 Phase III trials. In addition to KIMMTRAK, which is approved in metastatic uveal, the ADAM registrational trial will start later this year, as sponsored by [ EU ITC ]. 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. So 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 a really great. And now we open it up for your questions.

Jonathan Chang from Leerink Partners. 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/or 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?

So if I heard you correctly, it was about the confidence in the pace of the Phase III PRISM-MEL based on the TEBE-AM.

Correct.

Or from this data set.

Yes. So I would say 2. 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 PRAME dosing regimen. We've gotten great enthusiasm from global sites. So over 150 sites are interested. So I think that's what gives 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 rela-nivo, ours being a monotherapy and rela-nivo being a combination.

Got it. Second question. And as we look ahead to updates on brene and other tumor types, what are the key learnings from today's presentation as it pertains to potential success in tumor types beyond melanoma?

Do you want to take that, Mohammed?

Yes, sure. I think 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 because 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 tebe, we're seeing it with brene in cutaneous is another marker that we think is drug specific. Beyond that, I would say that for the additional tumor types like ovarian and lung, they're certainly much more heterogeneous than melanoma. So we think that, of course, we need to enroll specific cohorts. And then also, I think we're going to be looking at combinations to allow us to move to earlier lines because we were learning about this T cell fitness signature, which suggests moving to earlier lines, we should see even better activity.

So really, the 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.

Great. Tyler Van Buren from TD Cowen. So I really enjoyed David's intro. You guys make a good point. That disease control rate of 56% versus 46% with both of them in the 42% molecular response lines up perfectly, kind of suggesting that maybe you could see a similar 49% survival benefit with breneta like you did with tebe. But I guess the 2 key differences are the target, right, because 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 2 differences won't have a negative impact on that translation.

David, do you want to take this one?

Yes. So I guess one question is our confidence in disease control rate as an endpoint and its ability to translate into PFS. I think what we're seeing is the consistency across whether it's KIMMTRAK in uveal melanoma, KIMMTRAK in cutaneous melanoma and now brene 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 and the PRAME-positive, not the PRAME-negative. Number two, this concept of tumor reduction. The reason we specifically called 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 brene, 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 brene, the fact that those correlate with outcome with PFS and survival gives us further confidence that it is a real measure of benefit.

Yes, you want to add something to that?

I was going to just -- because you were asking us to compare tebe versus brene and if there are any differences. I would just add 2 more. I agree with everything that David said. The other -- I think it's really important to understand, like, the biology. gp100 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 just like gp100, PRAME is, like, expressed in more than 90% -- close to 90% -- it's a highly expressed target and the number of peptides that are TCR bispecific targets is likely even higher than gp100. At least preclinically, that's what we see. So those are differences between tebe and PRAME but actually favor PRAME.

Yes. Actually, I'll just add one other point. Sorry, Tyler, which I forgot to add. And that is with tebe, 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 shifted more to the disease control side. So there is some PD pseudo progression that's going to give a survival benefit, but it does appear that brene 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 frontline trial.

Yes. No, that's a good question. I mean -- and you can comment on prior BRAF and the challenge of those. There -- what we didn't -- what we wanted to do is provide kind of here's the totality of the data rather than 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 on your experience with immunotherapies.

So patients with prior BRAF MEK inhibitor exposure tend to do quite poorly. You can get this sense from 2 settings, right? So we did this 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 6134/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 and the academic medical centers? The answer is 90%, which meant that 10% of patients who fail frontline PD-1 CTLA4 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 isn't a front-line setting. People who fail BRAF MEK are bad actors. They don't even make the second line of therapy, let alone go and do it. So the point here is when you look at this in the context of the frontline trial, what this suggests is 2 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 neoadjuvant data that you're going to hear on Sunday as well as the update from the Moderna vaccine data that you heard from Jeff 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.

Jess Fye, JPMorgan. 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 that trial again, is there any interest in maybe simultaneously testing the PRAME-positive population in addition to the overall population?

Okay. So multiple questions. I think I'll start with Koustubh on the melanoma and the signature. And then I'll come to David and Mohammed. Go ahead, Koustubh.

Sure. Thanks for the question. In the data that you saw, which was in late line, T cell fitness was just 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, 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.

Yes. In the figure, just to add to what Koustubh said, in the figure, you can see half of the patients with 1 to 2 prior lines are above that threshold. So presumably, as Koustubh said, it's going to be even higher than that from the first-line setting. Mohammed, do you want to address the...

Yes. I can, Jess, address the question about the frequency of dosing as well as the HLA. So with regards to frequency of dosing, if you think about the frontline data set, the highest risk for progression is in the first 12 months -- sorry, 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 move 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 Astra's checkpoints that beyond the 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 of care, and we know which ones are HLA positive." Other ones who have access to HLA testing, they said, "Oh, our testing takes 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. So, essentially, most sites are able to do it as standard of care on their own. And if not, they're leveraging our prescreening 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 powering our primary endpoint. Is that the question?

Yes.

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Yes. So, I mean that's an interesting idea. When we designed the trial, Jess, we actually designed it assuming 90% -- 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 a PRAME-positive co-primary end point 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 not going to make a difference.

And also, you don't know what the negatives are going to do in the combo right?

Yes, the fact is that, as Bahija said, the idea was that the negatives still getting nivo. So it's not like they're getting no active therapy.

This is Naureen Quibria from Capital One. Actually, I'd just like to piggyback on what Tyler asked, which is in terms of patient -- baseline patient characteristics where you would expect clinical benefit or responses with brene, is it just PRAME-positive? Or those that haven't had BRAF or MEK inhibitor prior exposure? Or do you expect to see other types of patients where you might see benefit? And then I have a second follow-up.

Okay. David, do you want to...

Yes. So one of the -- the metrics I sometimes use, as we said, is tumor reduction as -- is the patient benefiting or not. You can also use ctDNA reduction. These are early measures of whether patients are benefiting. Obviously longer term is PFS and survival. And when you look at those 2 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. But in the first-line setting, of course, as you heard, that's not going to be an issue. But we haven't seen anything, any other baseline characteristics, except for T cell fitness would be the other one.

And maybe I missed it, but in the abstract, there was a sort of broad range of doses that were tested. So what's the dose that you're expanding with?

Mohammed, do you want to take that one? We have 2 doses going into -- from the Optimus project.

So from 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 -- sort of -- based on modeling the best dose. In the PRISM-MEL, we have 160 and 40, which is above the lowest dose and doesn't require steroids.

[ Mark ], you might want to explain that. So that's part of the Optimus, the project Optimus, where we'll do 40 patients, I think, going in. And then we dropped 1 and we continue.

[ Alex ] from Barclays for Peter Lawson. Just a bit of a hypothetical question, but what do you think will be the benefit of adding -- of combining with nivo in the frontline setting versus just doing monotherapy?

I think it's the -- before I give it to the expert, it's just -- if you want really to enroll the trial, I don't think, with the standards of care being nivo to go head to head without having the data in that setting, I don't think you will enroll that trial. But you want to...

Yes. So I would expect at least additive activity because there are different mechanisms, and we're adding them together. They work in different ways. Now the small data set that we did show here with the 7 and 9 patients, that wasn't -- that was a data set 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 3 out of 4 ctDNA molecular responses, so promising. But the best way to do it is -- my belief is in a randomized trial is the only way you can really tease apart combining 2 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 in correlation to efficacy here, if you saw any interesting trends there.