2026.09.24 | GP | Pharma | IMCR & IMTX PRAME Agents

Primary:

IMCR

IMTX

Associated:

IOVA

REPL

Viewpoint:

KOL - Physician

Moderator: Delaney Pacitti (DP)

| Sep 23, 2026 | 38 Min Read

Jay Lee (JL), Assistant Professor of Surgery - Duke University

SU MMARY

Overview

The discussion focused on the evolving landscape of treatments for advanced metastatic melanoma, particularly targeting PRAME. The expert, a surgeon oncologist, shared insights on current treatment paradigms, emerging therapies, and the challenges associated with these treatments. The conversation highlighted the potential of new agents like Iovance's AMTAGVI, Replimune's RP1, and PRAME-targeted therapies from companies like Immatics and Immunocore.

Key Insights

The expert emphasized the potential of PRAME as a target in melanoma treatment, noting the promising efficacy of TCR-based therapies like Immatics' IMA203. There is a significant dropout rate for treatments like AMTAGVI due to toxicity and logistical challenges, highlighting the need for more tolerable options. The expert expressed interest in the logistical simplicity and reduced toxicity of bispecific T-cell effectors, despite their lower efficacy compared to cell therapies. The expert is keenly interested in the reduced toxicity potential of new treatments, even if it means a slight compromise on efficacy, to expand treatment options for patients who are currently ineligible for existing therapies.

Competitive Landscape

Company/Product

Positive Aspects

Negative Aspects

Market Positioning

Iovance's AMTAGVI

High efficacy in eligible patients

High toxicity and significant dropout rate

Established but limited by patient eligibility

Replimune's RP1

Recently FDA approved, potential for wide use

Not yet commercially available

Expected to shift treatment paradigms soon

Immatics' IMA203

Promising efficacy in early trials

Limited by HLA restriction

Potentially high efficacy but limited reach

Immunocore's Bispecifics

Logistically simpler, potentially less toxic

Lower efficacy in early trials

Suitable for less fit patients

Quantitative Insights

Metric

Value/Range

Objective Response Rate

30% minimum for interest, 50% promising for IMA203

Progression-Free Survival

12–16 months desired for new therapies

Grade 3/4 Toxicity

10%–20% outside of hematologic issues

Clinical Data

The expert discussed the importance of monitoring cytokine release and immune-related adverse events in new cell therapies. The potential for bone marrow suppression and its recovery is a critical safety concern. The expert highlighted the need for treatments that can reduce IL-2 related toxicity, which is a significant barrier for many patients.

Overall, the discussion underscored the dynamic nature of melanoma treatment development and the ongoing need for therapies that balance efficacy with tolerability to broaden patient access.

DP: Hello, everyone. Good afternoon. Thank you so much for joining in. This is Delaney here with Guidepoint. I have Dr. Jay Lee on the line with me. We're going to be discussing some expectations for a few of the agents targeting PRAME in melanoma, advanced metastatic melanoma.

Audience, if you guys have any questions while we're on the line, you can send them to me or ask@guidepoint.com, and I will ask them on your behalf. And please keep in mind, we're only discussing information that is available in the public domain. Dr. Lee, thank you for being here. Before we start, would you mind telling our audience a little bit about your professional background and recap of your current melanoma practice?

JL: Of course, yes. Thanks for having me, Delaney. Happy to be here. So my name is Jay. I'm one of the surgeon oncologist over at Duke. And so I work at a large academic medical center. My practice is almost exclusively in patients with melanoma. And within that space, I have deep experience in patients who have advanced melanoma that has progressed on first-line therapies like PD-L1 therapy.

So I treat a high volume of patients. I have personal experience treating patients with some of the emerging treatments like Iovance's AMTAGVI as well as trial experience, treating patients with emerging therapies like Replimune's RP1, which is just FDA approved as well. So certainly want to discuss my trial non-public data experience with that, but happy to discuss my general knowledge of that product as well. And as someone who's got a lot of experience in this space, also very aware of these other emerging PRAME-based therapies, which I'm happy to discuss further as well.

DP: Perfect. And maybe just getting a bit of a snapshot of what the treatment paradigm is like now, if you kind of have an idea of what your treatment mix looks like for patients who progress on a PD-1 inhibitor or RP1-containing regimen. So if you've had patients start on RP1 or how many patients you send to AMTAGVI or if you're retreating with checkpoint inhibitors, I guess, overall, what are your — I guess, how would you portion out which patients are eligible and move forward with which options?

JL: Yes. Great question. So the first question we have to answer for patients who have progressed on PD-L1 is whether they have a BRAF mutation that can be targeted with BRAF/MEK-targeted therapy. It's about half of our patients who fall in that category who have a targetable BRAF mutation. So if that is the case, which is about half of those patients, then they need to go on BRAF/MEK therapy next. And so that is usually we'll do for about half of our patients. That

treatment, unfortunately, has not a great duration of response.

Patients often respond upfront very nicely. But within a year, most of those patients have recurred. And so we see initial responses that are quite impressive. But again, one of the limitations there is that patients will have a disease recur and they relapse within a year for most patients. And so for the majority of those patients that eventually relapse within a year or for the patients who do not have that mutation, then the first thing we're looking to put those patients on is AMTAGVI from Iovance.

There's a lot of dropout that happens from that because it's a pretty toxic treatment. And so a lot of our patients aren't fit enough to go on that study. It's also true that there are some pretty significant restrictions on who we can use that for. So for example, if they have untreated brain metastases, we cannot treat those patients as well with AMTAGVI or other cell therapies that are being evaluated. There's some significant safety concerns with that with the whole cell therapy line of treatment. So another big dropout we have is from that.

And then the last issue with AMTAGVI and other cell-based therapies like it is, you need to have an appropriate target tumor to either take out with surgery or do a biopsy on. And there are some patients who don't have an appropriate target. And so we see dropout from that. So all said and done of all the patients who could get AMTAGVI, probably maybe half of them or maybe even a little less than half of them are actually able to get it because of dropout from all these reasons.

Now that RP1 has been approved, there's a significant number of patients that I think will be able to get that drug. We don't have it in hand yet. It's, I believe, going to be available commercially for us within the first week of October is when we're told it's supposed to be shipped out to us.

But all these patients I'll talk about who either aren't fit enough to get it primarily being the big dropout, they would all be potentially eligible to get RP1 once it's available. So that I think is going to definitely shift over once we have that drug in hand, which again, hopefully, will be in the first couple of weeks of October here.

DP: That all sounds great. Actually, before we move on to PRAME, I do want to talk just a little bit more about RP1 and planned uptake for that. I guess is your center already kind of good to go? I know I talked to other physicians who have concern about having to work with the interventional radiologist using RP1. Is that something — are you expecting any sort of lag in uptake, something that you guys would have to get used to doing or are you ready to hit the ground running once it becomes available to you?

JL: I think we're more or less ready to hit the ground running with that. A lot of that has to do with the fact that we were already participating in the trial for the IGNYTE-3. And so we're set up to do it at least on a small scale for doing this therapy with interventional radiology. We've given patients treatment through interventional radiology on the trial. I think it becomes a little harder if you want to scale it up and treat all the patients who are eligible with it being commercially available now.

And so I don't think there will be a lag in getting started, at least at my institutions and others like it, where we've already worked with IR, either in a trial setting or in similar oncolytic viruses like T-VEC, which have been around for a lot longer. I do think there will be some lag in scaling it up. And so, you know, if I had, for example, 10 patients in a month who I could give RP1 to potentially, I think it would be a little hard right now. If you ask me if I have a drug right now, could I give it to all 10 of them?

No, I don't think we have the capacity to give it to all 10. I think within a few months, we will. But certainly, we could start with two to three, which honestly speaking, we wouldn't do much more of that at the beginning anyway, just to make sure we had a good understanding of how it was working operationally for us in the commercial setting and that

kind of thing.

DP: All right. Great. So let's move on. Let's talk about PRAME as we have some agents in development that are targeting PRAME. Maybe just kind of overall on how attractive you find that target and whether the HLA restriction is going to be limiting to the patient population that's eligible?

JL: Yes. And so, you know, PRAME is a really interesting target that I think has a lot of potential. I think we're still trying to figure out through some of the trials that are emerging through that about how effective it is really going to be. I think the things it has going forward is that, you know, there is some demonstration of efficacy, particularly in the cell therapy line, so using, you know, TCR-based therapy to modify a PRAME, and HLA-based receptor to go after it kind of like Immatics' IMA203 product. I think that is showing definitely some potential for efficacy that is impressive.

They're recording objective response rates kind of in the 50% range, which is certainly — even though it's in a small trial setting is encouraging. And so I think there's definitely promise using it in that regard. The other way it's being harnessed or targeted is through use of kind of what we call bispecific T-cell effectors, which aren't cell therapies, but they kind of grab two different targets and try to put them together. The effect, you know, the efficacy from that has been less impressive in the Phase I and Phase II trial data.

We've seen something more like maybe 15% response rates in the early trial data. The thing it has going for it in that regard, even though it may be less effective or less impressive in the efficacy is that the toxicity looks like it's potentially more tolerable than some of the cell therapies. So you don't need lymphodepleted chemotherapy beforehand. And also, it's logistically just easier because these bispecific T-cell effectors from Immunocore, like KIMMTRAK, and the brenetafusp, the IMC-F106C target, they have two different drugs they're developing in that pipeline.

Those drugs are off the shelf. So we don't have to worry about the logistics of cell therapy. So I do think that the restriction of having to use it in a specific HLA haplotype is a big one. I mean it's only 40% of our patients in most studies that have that type. So it's good to have this for those patients. But for the remaining 60% of patients, I need something to give those patients. So, you know, that's a big limitation because you're already cutting your field over in half just to be able to use this drug.

So if the efficacy that we're seeing in the early trials is similar, you know, which, again, is not as impressive as what we're seeing in the cell-based therapies like for Immatics, then I think that these bispecific effectors definitely have some potential to be used because they're, simplicity, they're logistically a little less complicated. There may be some less toxicity, but it does have some severe restrictions just based on not being able to give it to everybody. And the efficacy is not as impressive. So there may be a role for it still, but I'm not as convinced about that being as helpful for us.

DP: Excellent. Maybe we can focus in — we can discuss the Immunocore bispecific and the T-cell therapy from Immatics is anzu-cel or IMA203, however you prefer to call it. We can just dig a little deeper into each of them. If we start with anzu-cel, I guess maybe wondering overall kind of what portion of patients do you think might be eligible and fit enough to undergo a therapy like this?

And then thinking about it comparatively to AMTAGVI as my understanding is that is allowed in the control arm, what would you like to see in terms of AMTAGVI proportion in the control arm, I guess, in order to make your decisions about the two of them or to make them comparable like how many of the patients on the trial would need to have gotten TIL therapy in order to make them comparable?

JL: Yes. It's a really great question about like how many really have to be on there. I do think that, you know, overall,

the kind of patient I'm picturing that could get anzu-cel is very similar to the patient that I would normally put on AMTAGVI. What the limiting factor is for both of these is the need for lymphodepleting chemotherapy and the need for IL-2. Now, you know, anzu-cel does have going for it that they're using a lower dose IL-2 regimen, which has the potential for less toxicity.

So on the whole, you know, the patients that I would be potentially looking at doing AMTAGVI for that I'm a little concerned about if they're a little marginal with their fitness for getting that treatment because of concerns about toxicity from the IL-2, then those patients, I'm going to think more heavily about putting on something like anzu-cel that has lower dose IL-2 and doesn't require surgery because they're using leukapheresis to get the T cells in this case.

So again, I think even though the overall pool is similar, there are certainly more patients that could potentially get anzu-cel because of this reduced toxicity or theoretically reduced toxicity compared to Iovance. Without it being a true randomized controlled trial comparing anzu-cel directly to AMTAGVI, it's hard to say exactly how much I would anticipate that proportion needing to be in the control arm.

I would say because it's designed as kind of an investigator's choice control arm for that particular trial, I think it should reflect closely what we typically use in that population in the commercial practice in our experience with it. So something around 20% or maybe 30% of that investigator's choice might want to see at a minimum that be used patients having AMTAGVI in that control arm because I think that pretty closely mirrors what we actually see in the commercial setting for those patients.

DP: Excellent. Maybe looking ahead to — I think to get an update next year from the SUPRAME trial based on the data we've seen in the past, if we're thinking about just quantifying some things with endpoints, what sort of median PFS, we might not have a mature OS at that point, but maybe just PFS would be meaningful to you and kind of a ceiling, like what would it need to be the threshold to be interesting to you? And then what do you think would be like best case scenario?

JL: Yes. I think, you know, what we have to compare to easily right now is, you know, we have the Phase Ib trial results already from this product. And so we have that to kind of look at. We also have kind of benchmarks to look at Iovance for as well as some from RP1, which all kind of compete, I think, in the same patients here. And what we're looking for is the minimum want the objective response — the overall response rate, excuse me, to be at least as good as AMTAGVI and RP1 but that puts at, you know, 30% is what we're looking for.

So it to be interesting to me to be useful, it have to at least meet that minimum response. I would hope that overall survival mean will be above 12 months, so something in the, you know, 12–16-month range as they've already reported in their Phase Ib trial results. And then progression-free survival, similarly, I would hope that it would be at least kind of in the 12–16-month range as well. And those are kind of — that's kind of the floor for what we're looking at for this being kind of interesting to us. I think we're also going to be looking closely at Grade 3, 4 toxicity.

It's a little hard to judge that for these cell therapies that involve lymphodepleted chemotherapy as both Iovance's AMTAGVI and anzu-cel involves because basically, almost 100% of people are going to have Grade 3, 4 toxicity from hematologic issues because we're intentionally depleting their immune system with the chemotherapy.

But if you subtract that away, you know, something around like a 10%–20% Grade 3, 4 toxicity outside of that would be important to know about for safety parameters, especially since one of the theoretical advantages of using anzu-cel is this lower dose IL-2, which is where a lot of the toxicity of this treatment is coming from. I really can't emphasize enough how much that concerns physicians who treat patients in this space about the IL-2. And a lot of patients, we don't even put on treatment because we're so worried about them, you know, having issues with the IL-2.

And so anything that reduces that is important to us, and we want to see that borne out in the toxicity as well. You may know if you've looked at data from Iovance's AMTAGVI trial that there's a measurable risk of mortality after treatment, not for the cancer, but, you know, if we go to the treatment, the 7%–10% range. And so that's something that we definitely be on the lookout for. And so if something like anzu-cel can show us that it's as effective and less toxic, that will really make us want to adopt that pretty quickly if that can be shown in the trial.

DP: These kind of efficacy benchmarks, are these going to be different for what you're looking for with the Immunocore bispecific brenetafusp given the logistical challenge of a cell therapy or I guess, how are you planning to compare these two? Although brene is going to be first-line, they're hoping, but— JL: Yes. It's a good question. So I would say, you know, the threshold of the benchmarks are going to be set a little bit lower for the bispecific effectors coming from Immunocore. And that is because there is less toxicity. And so there's patients who probably can't even get the cell therapies because they're too frail. And so that helps that benchmark be a little lower because we wouldn't be able to give them anything anyway. And the same goes for the objective response rate or some of the overall response rate being lower.

We even though a 13% response rate, let's say, is not all that impressive. If I can't give anything else to that patient anyway, I'll take that over anything else. If we are going to expect these products, these bispecifics from Immunocore to really make a dent into what we're already doing for Iovance or in these kind of fit patients who can get that, it would have to be higher. It have to be in the 20% range or the 30% range. And then we'd have a discussion about whether a less toxicity in something is worth a decrease in efficacy.

Let's say, it was a 20% response rate as opposed to a 30% response rate, which is what the benchmark is for AMTAGVI and RP1, then it becomes more of a discussion in that case. And certainly, if it's similar, if it's 30% or even higher, then it would be much more likely that we would give this product over the cell therapies. Especially for patients who have this haplotype and that the 60% of patients who don't have haplotype, we can give the cell therapies to so they can get it.

So the threshold for us using these therapies at all is a little lower. So we'd accept lower kind of response rates because less toxicity, simplistically easier and then the patients who can't get the cell therapies can get these treatments. But if it really wants to compete in the same space as AMTAGVI, RP1, and anzu-cel, it really has to show us that it does as well in those categories. And if it won't, it's going to be really relegated to the less fit patients.

DP: What else or what sort of things are you going to be looking for in the next readout or in the readout for the SUPRAME trial? Is there specific toxicities that you're keeping your eye on? Is there anything else that you're really going to be looking for?

JL: Yes. I mean there's two things that come to mind for me. One is just making sure that things like cytokine release and immune-related adverse events that those are not somehow significantly worse than what we're seeing for Iovance in their AMTAGVI line. Cell therapy is still a really new field in terms of its commercial use. And even with AMTAGVI, we're seeing some unexpected things or things that are requiring with us to really think a lot harder about how to recover and how to make sure patients kind of recover from these toxicities.

And so, you know, one, I think, in particular, that we're watching for, for things there in the cell therapy line of products is, you know, we're messing around with the immune system so much that some of our patients to kind of just kill their bone marrow. And so, you know, we've seen that happen to our patients where they just can't recover. They can become transfusion dependent and then we really can't — really give them a lot of therapy at all moving forward. So that is something that we're going to be watching for is to see what that looks like.

The early readout in the Phase Ib trial would suggest that most of these patients who have cytopenias, where their

bone marrow kind of gets suppressed intentionally by the treatment, have it recovered within a couple of weeks. So that's encouraging. But it's a small study.

And so in the Phase III trial, which has, you know, I think, 400 or 500 patients, we'd really be looking to see if there's any signal emerging for patients having more persistent issues with bone marrow failure, which is really, you know, not a great problem to have for anyone, let alone someone's got cancer. So that will be really important for us to keep track of as well.

DP: I'm thinking about eligibility, let me see if this makes sense in my brain, and I can get it out loud. Perhaps patients that might be eligible for both AMTAGVI and anzu-cel or one or the other. And you said earlier about with Immatics' lower dose IL-2 regimen, perhaps it would be easier for some patients to receive anzu-cel, but then they have the restriction of needing to have express the HLA-A*02:01 positive. How do you see that portioning out?

Like what portion of patients do you think would be better suited for anzu-cel because of the lower dose IL-2? And then what portion do you think are restricted and cannot have that because of the HLA restriction. And I guess then if they are not HLA positive and they cannot undergo the lymphodepletion for AMTAGVI, then what do you do?

JL: Yes. It's a really good question because we're trying to play all these different scenarios out. But I think the most important thing we have to sort out first is whether they can even get anzu-cel or not. So the first big cut is going to be whether they're HLA positive or not. So right upfront, probably 60% of our patients can't even get anzu-cel because it's dependent on having the right haplotype here. So immediately, 60% of patients are going to go off and get something else, whether that's AMTAGVI or RP1 or going on to trial or something else.

Of the remaining 40% of patients, I would say there's probably, you know, a third of them or so that I'm confident enough about their fitness that they could get either. And in those patients, because we have more experience with AMTAGVI and how it behaves in the commercial setting, and we know that it appears to behaving the same as the trial, we would preferentially put those more fit patients on AMTAGVI because we know they can handle it, and we know what the experience has been with it, and we're confident in that.

For a newer product like anzu-cel, we would usually first start using it for these more marginal patients. So the two- thirds of patients where I'm not as confident they can tolerate AMTAGVI or who I just really don't think they can tolerate AMTAGVI at all. The remaining kind of two-thirds of patients in this 40% category of HLA type would go on anzu-cel in that regard.

DP: Great. Ok. So now looking toward Immunocore and brenetafusp. So now we're looking at the first-line. I guess maybe just overall with the trial design, how challenging is a first-line trial for this population? And what kind of — again, what kind of PFS benefit is going to be meaningful to this patient population?

JL: Yes. A first-line trial is good and bad in some ways. I mean most of the data we have in this space about treatments in this regard, you know, immunotherapy-based treatments like this is, would suggest that the earlier you treat patients with these newer therapies or just, you know, with more effective therapies in general, the more likely you are to see a significant signal. And so for example, for AMTAGVI, it is very well established that if, you know, they've gotten two, three, four lines of therapy with AMTAGVI, the more lines of treatment they get, the less effective it tends to be.

And we see that in a lot of cancers and a lot of therapies in general. So getting it in the first-line setting is going to help them in some ways because they have, you know, greater potential for efficacy in that regard. It's going to hurt them because all other things they're comparing it to, in this case, you know, PD-L1-based therapies, they're also going to do very well.

And so showing that you can really significantly improve that in the Phase III trial can hamstring you some because, you know, you're expecting a pretty good response in an untreated population for people who are getting PD-L1- based therapies to begin with. So showing you can do better than that it can be an uphill climb, especially since they're including combination nivo-rela in their control arm as well. So it may be challenging in that setting to kind of show a significant difference compared to that standard of care.

This is why patients who get treated with these newer therapies in the pre-treated setting, so patients who are already on their second or third-line therapy, even though the response rates are less impressive, it is easier to show in many conditions that you're going to have improvement over whatever the standard you're comparing it to is because they don't respond very well to being retreated with these other therapies. So, you know, it remains to be seen, I think, in the first-line setting, how successful they will be showing that their therapy is definitively better than the standard of care. We'll just have to see.

DP: Do you think you need to see a drastic difference in the control arm to see brene enter as a first-line like a default treatment, I guess, brene and nivo as a default treatment or do you think it might just become another option for first- line therapy?

JL: It may become another option, especially if it shows that it's similar in efficacy and either similar in toxicity. And, you know, I think the best position you can be in for sure, for getting the drug to market is to get us to use it is to show us that it works in the second and third-line setting because we've got great options already in the first-line setting. I mean the PD-L1 therapies that we use currently as the backbone, they work really well. And they don't work for everybody, but they work really well.

And so, you know, it's going to be — it's a little hard to displace the standard of care as it is without showing that it's, you know, gosh, if it were like 60%–70% of patients, like something like double what we're getting right now for response that we're responding to, you know, these newer therapies that we can talk about, but that's a hard thing to achieve. And it's just really hard to find a therapy that effective, right? So I'm not going to rule that out being possible.

And if it's — if these newer therapies for Immunocore with the bispecifics, if they are really, you know, if they're similar in efficacy and either better in toxicity or similar, then surely they can enter the conversation about, you know, about need to use them. But we have so much experience using PD-L1 and so many patients do really well with it. It's going to be very hard to take that from a well-established therapy if there isn't a clear advantage to using this other therapy.

DP: What sort of magnitude of benefit do you think you'd need to see to have brene-nivo as the default front line therapy? Maybe what hazard ratio from the trial?

JL: I would say we'd want to see, you know, probably at least a 20% reduction. So like something like 0.8 or, you know, 0.75, that would have to be a pretty significant reduction. Something like a 10% thing, maybe we talk about it, but it would have to be pretty significant for us to want to jump ship.

DP: If it's not, I guess, as high as you're hoping, but still enough to have an effect and receive an approval for front line therapy, if it's not used as a default, how often do you think you'd be reaching for it? I guess that might compare — might change based on what sort of data we see. So I guess my question is, if you're not using it as a front line therapy, what happens to this combination? What happens to brene? Would you still consider in second line? Is that an option to then rechallenge with nivo? What are the options here if you're not using it upfront?

JL: I mean, if you're not using it upfront, and that's what it was approved for and the FDA label, there really isn't another way for us to use that drug. And so if it isn't — if it's approved for first-line therapy, and, you know, we're not going to use it as first-line therapy, there isn't going to be much use for it at that point. And I think the other challenge

of it is that it already includes PD-L1 therapy as part of the treatment arms.

And so, you know, we're going to move on to something else at that point if we're not using it in the first-line setting. So if it doesn't get used in the first-line setting, you know, whether it's impressively better or just a little bit better, if we don't use it in the first-line setting, we're probably not — we're not going to use it at all if it doesn't — if we don't decide to use it in the first-line setting for a particular patient.

DP: Are there things — I mean, ahead of seeing established data, are there things about the combination that you think would make a patient better suited for the combination rather than a PD-1 therapy or monotherapy alone, I guess, to make — if it was just one of your options, if it wasn't your default, you know, what do you think would have you reaching for that more often?

JL: Yes, that's a good question. I think the — some of the things that we can kind of talk about doing are, you know, someone who would truly be getting a single-agent PD-L1 if we're trying to decide to give a single agent or dual agent like nivo-rela, Opdualag, in most cases, we will go for giving them the dual checkpoint inhibitor therapy Opdualag or ipi-nivo as long as they're fit enough to get it. The problem with those dual therapies like nivo-rela or ipi- nivo is that they have significant toxicity. They work well, but they have a lot of toxicity.

And so if the trial shows that, you know, the combination of brene plus nivo is as effective as the other combinations and is still more effective than single-agent nivo but has less toxicity, there could be a role for using it in that way as long as the toxicity really is significantly reduced compared to the combinations, either nivo-rela or ipi-nivo. That is a relatively low bar for it to meet because the toxicity is so high with the combination checkpoint inhibitors like nivo-rela and ipi-nivo.

So if it can show us that, then again, for a more frail patient where we still want the additional efficacy, of combination treatment, but aren't willing to kind of gamble on the increased toxicity, those patients could benefit. And these are often patients who are more frail or maybe they have further issues with autoimmune disease like Crohn's disease, you know, really bad ulcerative colitis or really bad rheumatoid arthritis. That's where we currently have limitations with PD-L1-based therapy, particularly if we add on another checkpoint inhibitor on top of that.

So if this — if the study results support it, which I think is a big if. But again, what I'd be looking for is it would have to be equally effective as combination checkpoint inhibitor therapy, either nivo-rela or ipi-nivo and have significantly less toxicity. You have to do both those things for it to really, you know, have a role for these patients who are I'm worried about getting the combination therapy too.

DP: So let's say brene-nivo is positive and becomes a front line option for you. Let's say you have anzu-cel available to you in second line. How are you thinking about or would you consider sequencing the two PRAME-targeted treatments? Do you think you have one shot? Can you use it either with brene or anzu-cel or can we use them back to back? Would you put something else in between? How are you thinking about sequencing the two PRAME agents?

JL: Yes. It's hard to tell because none of them are going to be tested directly and they're all kind of emerging at the same time. I think what we're all trying to do usually is if in general, for melanoma, if there is an opportunity to lead with a higher efficacy treatment that has more toxicity, but where we think it's going to have higher efficacy or just that's what the data shows, we'll lead with the higher efficacy treatment first.

So in this case, based on the data we have from earlier trial data, we would start with the IMA203 with anzu-cel because if they were to have some toxicity from a less effective thing that would prevent them from getting kind of a hard-to-tolerate treatment that we would have missed a window to do that.

On the other hand, if I start with the more efficacious but kind of more toxic treatment first and they get effectiveness from it that they don't need to go on anything else. And if they do progress, then they still may have enough reserve to get one of these less toxic and potentially less effective treatments like the bispecifics from Immunocore.

So, you know, most of the times, that's the sequencing that we'll do for these newer oncologic therapies is, we'll still lead with a more effective treatment first because we're trying to lead with the best possible option first. And there may be a more limited window to have these things work, especially if patients have bad toxicities from a less effective treatment that prevents us from doing it. So we talk about windows like having a window to treat a patient a lot in melanoma, especially. And so if there's a window, we want to make sure we lead with our best option first.

DP: And then a bit further behind, Immatics also has their PRAME bispecific in development as well. Maybe do you have hopes and thoughts for this agent as a monotherapy. Now they're also looking into combining with checkpoint inhibitor too. But I guess what are going to be things that you're looking out for in the early data for IMA402 to differentiate it from brenetafusp?

JL: You know we're really looking for the same kind of measures here. One is the overall response rate. What does the toxicity look like? And do they have any data yet from this early readout for duration of response. Those are the things we're going to be looking at I think kind of top of mind in the beginning because if it's starting to look like the other bispecifics and it's kind of fall in the same role.

So that would mean it's, you know, lower overall efficacy, but lower toxicity at the same time. But that's what we're looking for is it going to perform like these other bispecifics that we already have out there or is there something different about it with regard to the efficacy or the toxicity?

DP: Very helpful. All right. These are kind of my specific things. Kind of just summarizing to everything that we've been talking about. So bringing us back to now the SUPRAME trial, talking about second-line therapies. Again, kind of as the trial progresses, if we see more data, like what do you think is going to be the single most important thing, I guess, that informs how and when you would give this therapy.

Is it going to be more so efficacy, durability, logistics, tolerability? I guess what are the kind of the main points that you're going to be looking for and introducing to the landscape if you — now that we also have RP1 available and relative to AMTAGVI, all of that?

JL: Yes. I think the far and away, the two things that have to be established for these emerging treatments in the current space that we have is we have to know if the efficacy is comparable and we have to know where the toxicity is on this. So those are the two most important things that are going to determine how these newer things are positioned in the current market. So, you know, as I said before, if we can show that a product is as effective as our standard right now and is less toxic, we will start using that very quickly, if that's what the trial data says.

If it meets those benchmarks, then a third criteria is what the duration of response is because one of the main issues with one of our current treatments, BRAF/MEK-targeted therapy is that it has great upfront response, but almost everyone has their cancer come back after starting that treatment. That tends not to be as much of an issue for immunotherapy-based treatments, which are — what we're talking about right now.

But, you know, these are newer treatments and the bispecifics, especially, we don't have as good understanding of how that's working in, in a broader population. So that would be important as well. I don't anticipate that a cell therapy like anzu-cel is going to have an issue with that just based on how we know this thing works biologically and what it looks like AMTAGVI is doing.

But again, it's a newer therapy, so we have to make sure that works as well in terms of duration of response. But that's only important if it meets the bare minimum of being as effective with kind of the overall response rate upfront.

DP: Any kind of other maybe unanswered questions that you have that you're hoping to see from the data set that we'll eventually see?

JL: We talked about this already, but I think looking at how much some of these newer therapies like Iovance's AMTAGVI are being folded into the investigator's choice arm is going to be really important for — particularly for Immatics because it's going to be competing against that in the real world. And so having that therapy in the investigator's choice arm in a pretty measurable way is going to be important for us to see how this may stack up against, you know, what we currently do for these patients.

DP: Excellent. And then kind of same thing, wrapping us up with the brenetafusp conversation, again, kind of main points that you'll be looking for and need to see to make that your default front line therapy?

JL: Yes. So again, this particular treatment because it's being used without having to look at cell therapy directly because it's a bispecific, it will have somewhat lower benchmarks to have to shoot for. So what I really need to see for that one is how is that — how is its efficacy compared to single-agent PD-L1 and combination PD-L1 with, you know, nivo-rela. That's the most important kind of benchmark there for it to position itself because if it's not adding a lot in the first-line setting, it's going to really struggle to be used in a significant way in the real world.

The other thing that we'll be watching for, like I mentioned before, for the other — for anzu-cel, we have to know where the toxicity is for those. That's a moot point if it doesn't work. But if it does work, then we need to make sure that it's — toxicity is comparable. And the hope would be that we have as good toxicity or — sorry, as good efficacy as the, you know, combination checkpoint inhibitors, the nivo-rela, but having less toxicity.

That would be the hope. And if it can do that, it will position itself really well, you know, for the 40% of patients who actually have the right haplotype. We would definitely steer toward using that for anyone with that haplotype and, you know, certainly for those who have maybe more concerns about toxicity for using combination therapy.

DP: And with the brene study with PRISM-MEL-301, just kind of — what would your expectations be for the control arm for nivo and nivo-rela? I guess what would be an idea in your mind for a PFS with the control arm population, just given what you've seen in practice?

JL: Yes. I mean progression-free survival for — in a first-line setting, I would say we would hope it would be at least kind of 12 months or even longer, 12–18 months is what I would hope to see in the first-line setting. Obviously, we would go a lot lower if it were in the pre-treated setting, more like six to twelve months, but I'd be hoping for, you know, 12–18 months as a minimum just based on what we already know about how the baseline treatments work in that setting.

DP: All right, well, thank you so much. Any final thoughts for us or anything to leave us with before we wrap up?

JL: Yes. Certainly, I think that as maybe some of you on the call can tell this space within healthcare is moving and changing rapidly. And I think a lot of what we have right now has to do with making sure that, you know, we actually have a real meaningful change in either how effective a treatment is or how toxic it is. I think we are seeing a lot of treatments emerge that are adding value for how effective they are.

We're not seeing, I think, maybe as much progress in how toxic these things are. And so if any of these emerging products can even match the efficacy, we even take a little less efficacy if they can reduce the toxicity significantly. That is far and away, I think what all of us are looking for in this space is to have less toxicity.

DP: Interesting. How much do you think you'd be willing to sacrifice on the efficacy side to have a more, less or less toxic treatment?

JL: Yes. I mean we would accept maybe a 10% or 20% decrease in efficacy if we can open it up to more patients who otherwise really can't get some of these therapies. So, you know, we're — it's definitely an ongoing discussion in all of us. I think some of the things we struggle with the most is there are some patients just can't get any of these treatments.

And so we really need something to help those patients. And so any new product that can position itself in a way to still have efficacy, even it's not as good and have less toxicity definitely opens things up for us because we're really looking for how to treat these patients who can't even get the newest therapies.

DP: I see. With the front line brene-nivo trial, is that something that you're considering? Is the tolerability profile going to be a main player there to decide what your front line therapy might be?

JL: Yes. I think for that study, especially, there's, I think, significant potential there just because it's a different modality of treatment. It's not cell therapy. So it already has less toxicity. And it has the potential to also be less toxic than combination, you know, nivo-rela or ipi-nivo. So I think there's definitely — all of us are looking with a lot of interest in that specific side of those products.

DP: Excellent. Well, again, thank you so much. Thank you, our audience, for listening. I appreciate it. And everyone, have a wonderful rest of your day. Thank you again, Dr. Lee, and take care, everyone. Bye-bye.

JL: Thanks, Delaney. Bye.

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