Introduction: Johns Hopkins University

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Year in Review, as today we’re going to focus on the management of melanoma and nonmelanoma skin cancers with Dr Evan Lipson from the Johns Hopkins School of Medicine and the Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

As always, if you have any questions or cases you’d like to run by us, just type them into the chat room. We’ll talk about as many of these as we have time. As always, there’s a 1-minute premeeting and postmeeting survey in the chat room for you to take. If you take that you’ll get a lot more out of this experience, and we’ll learn a little bit about you.

We know a lot of people end up listening to our webinars, particularly on replay. If you’re into podcasts, check out our Oncology Today series, including a recent program looking at nonmelanoma skin cancer, so much going on there.

We do webinars all the time. We’re really looking forward to tomorrow. We’re going to be talking about new agents and strategies in lung cancer. Really interested to see what they say about the anti-CD3 bispecific tarlatamab, now approved in small cell cancer of the lung, how that’s going to play out. Next week, July 17^th, we have a program on antibody-drug conjugates in breast cancer, so much going on there, really looking forward to hearing about that. And then on the 18^th we’ll be talking about the use of ALK-targeted therapy, particularly in the adjuvant setting and the big ALINA trial, what that means in general for lung cancer nowadays.

In August we’ll be back again talking about HER2-targeted treatment of GI cancers. Of course, now we have a pan-tumor approval of T-DXd in IHC 3+. Really curious to see what the GI people are doing with that. We haven’t talked about neuroendocrine tumors, but we’re going to talk about that on August 29^th. I’m looking forward to getting updated on that.

But today we’re here with Dr Lipson to talk about this past year, particularly the ASCO Meeting, in terms of some of the key papers. We will be talking about new agents that are unapproved and new therapies, so keep that in mind and check out the package inserts for everything we’re going to be talking about today.

These are just some of the papers that came out over the past year that we’re going to be alluding to as we go through this today. Obviously, a ton of stuff. We really want to get Dr Lipson’s global take, particularly on what it means clinically, but also to the future of cancer treatment, particularly in these skin cancers.

But Evan, I’ve got to say, I woke up this morning and checked out the Miami Herald, and there’s an article about you guys got another billion dollars from Mr Bloomberg, who I think has built half of Hopkins down there. I’m just kind of curious, I always like to touch base with you about what’s going on. I always view Hopkins as the checkpoint central. You’ve done so much research there. Curious, I know he’s — Mr Bloomberg has given you guys a bunch of money for immunotherapy as well. I’m curious what you’re doing with that. So any Hopkins updates and any Baltimore updates? As you know, I went to Hopkins, I’m a Baltimore native, so I’m curious what’s going on around there anyhow. So what’s up with Hopkins?

DR LIPSON: Yeah. Well, it’s great to be with you. Thanks for having me. Your hometown, Charm City, continues to be an exciting place, as does Hopkins. And you’re right, Mr Bloomberg, his generosity continues to provide philanthropic dollars. His billion-dollar financial gift I think means that most of the medical students who come to Hopkins will now attend tuition free, and there will be support for living expenses. There’s also financial aid for nursing and public health and other graduate programs. So it’s really quite an investment he’s making really in all of us.

In terms of the work that he’s funded for us, we do a lot of the scientific correlative work, and many of our studies through the Bloomberg-Kimmel Institute for Cancer Immunotherapy. So for example we’re working on a study right now looking at the activity of immunotherapy in patients with advanced basal cell carcinoma who have been previously untreated, and we’re using some of the Bloomberg funds to look at some of the science behind what we’re doing to the immune system, modulating it, helping to activate it.

DR LOVE: Yeah. I was curious, when we were preparing this, we were thinking we hear so much stuff about IOs with melanoma and squamous cell that we hadn’t seen much with basal cell. I think they have pretty high TMB, you would maybe expect them to respond. What do we know about that at this point?

DR LIPSON: Yeah, you’re right. Basal cell carcinoma does have a very high TMB. It’s of course a sun-exposed cancer, the ultraviolet damage causing all that DNA damage, so the TMB is quite high, and because of that you’d expect that it would be a great candidate for immunotherapy. Other cancers that look like that, cutaneous squamous cell carcinoma, the non-virus-associated Merkel cell carcinomas, they also have high TMBs, and they have really high response rates to immunotherapies.

So the way that cemiplimab, actually in this case, cemiplimab was tested was in patients with advanced basal cell carcinoma who had already had a hedgehog inhibitor, and in that setting, for those patients, the response rates to anti-PD-1, to cemiplimab, were only about 30%. And that seemed low, and we couldn’t really explain why, and so we thought perhaps it was due to the fact that they had already had the hedgehog inhibitor prior to getting the anti-PD-1.

And so years ago we started a study looking at patients with advanced basal cell carcinoma who had never had a hedgehog inhibitor, so treatment-naïve advanced basal cell carcinoma, and we gave them nivolumab, also an anti-PD-1 therapy. And it’s still small. We’ve only got about 20 patients or so enrolled on the study who are evaluable, but we’re seeing about a 50% response rate so far.

And this is important because if it is in fact true that using anti-PD-1 in the front-line setting is going to be more effective than waiting until somebody has already had a hedgehog inhibitor, this is important information for the basal cell population patients. So we have more investigations to go. The study, as I said, is still small. We have additional patients to accrue and lots of science to investigate, but that is the objective, to understand what is the most effective way to use anti-PD-1 for patients with advanced basal cell carcinoma.

DR LOVE: I can only imagine what patient-reported outcomes would look like if you had a trial comparing a hedgehog inhibitor to PD-1, because I hear bad things about these hedgehog inhibitors.

But I’m curious, like when you give an IO to somebody with basal cell who hasn’t had hedgehog does it like melt away the same way it does with squamous cell?

DR LIPSON: Well, it’s a little variable. I would say that generally the kinetics of the tumor are slower. I think basal cell typically grows more slowly than squamous and probably responds to therapy more slowly that squamous cell does, at least to immunotherapy, more slowly than squamous cell, certainly more slowly than Merkel cell does. Merkel cell dissolves and explodes quite rapidly.

So it’s a great question. We are trying to get answers to all of those questions. How frequently does it respond? If it does, how durable are those responses? If it does, how quickly does the tumor go from 100% to 50 to 30 to 20 to 0? We shall see.

DR LOVE: Many people don’t know that Baltimore is really the lacrosse center of the United States. … Hopkins lacrosse team. When I was there they won the national championship, like 2,300 people there. But anyhow, how was the team this year?

DR LIPSON: Well, Hopkins lacrosse is always an exciting place to be. Certainly in Maryland, too. I mean Maryland, right, the official —

DR LOVE: Yeah. Maryland for sure. Yeah.

DR LIPSON: The official team sport of Maryland is lacrosse. So yeah, the Hopkins lacrosse team is of course an exciting team to watch. I’d have to look up exactly what their record is, but I think we’re all very proud of their — very proud of their performance this year regardless.

Metastatic Melanoma

DR LOVE: Alright. Well, let’s get down to some papers here. We’re going to start out — we’re going to work our way up to the nonmetastatic setting, which is so confusing to me, just this afternoon I watched the plenary presentation and discussion. I have more questions than I can even begin to answer — ask you. But let’s just start out with metastatic disease. Any comments on this follow-up we saw to KEYNOTE-006? Maybe just kind of review what that was and what your thoughts were about the follow-up that came out here in the JCO.

DR LIPSON: Sure. So this was one of the real early, first trials, and this was one of the studies that solidified for us that anti-PD-1 in first line is superior to ipilimumab in first line. In this case it was pembrolizumab that was being tested, but this moved ipilimumab off of the menu for first-line monotherapies, and — replaced by pembrolizumab.

And so the overall survival curve, which you had up a second ago, separated nicely, and what we saw over time was that even with mature — maturing data the curves continued to separate, and so this is practice affirming that in fact yes, a PD-1-based therapy really is the way to go rather than an ipilimumab monotherapy.

DR LOVE: Any comments about what’s been seen in terms of correlation with response and in long-term outcome?

DR LIPSON: Well, we’ve known for a long time that the deeper the response, the longer patients continued to do well, so the more regression that you see in someone’s tumor the more likely it is that they’re going to continue to survive over time. As you see, in the third line in that curve, this is the stable disease, is that the PD or stable disease there? The green curve at the bottom. I can’t see.

DR LOVE: Stable disease. Stable.

DR LIPSON: Yeah, that’s the stable disease.

DR LOVE: Stable.

DR LIPSON: So the stable disease crowd just really never has done very well, and this was not a surprise to see this bourne out in this study as well. But this isn’t the only one. The stable folks just don’t particularly do well, and then the CRs, up at the top, they of course oftentimes do quite well for long periods of time.

DR LOVE: So at ASCO you were saying that this is one of the biggest years for skin cancers at ASCO that we’ve had for a while. Of course, we had the big NADINA trial in the plenary presentation. There was a bunch of other stuff, including follow up of the RELATIVITY-047 trial.

Actually, before you get into that, could you just in a brief way talk about how you decide upon first-line therapy in metastatic disease?

DR LIPSON: Yeah. I’d be glad to. This is a topic that comes up all the time, and unfortunately we’re still shooting from the hip because we don’t have a solid biomarker that would guide us in one direction or another. But I’ll give you my broad sketch.

So essentially right now we have 3 options for treating a treatment-naïve patient with metastatic melanoma. All right. So let me paint 3 pictures for you.

There’s a 65-year-old woman with brain metastases, maybe a 3 and a 4 and a 5 mm brain metastasis, and a half a dozen lung metastases, perhaps they’re a centimeter across, and a couple — a few liver metastases who’s otherwise healthy, right? That patient gets full-dose ipi plus nivo in our clinic. We have good, solid data for ipi plus nivo in melanoma brain metastases. We have 7 and a half years of overall survival data using ipi plus nivo, and the overall survival rate at 5, 6, 7, 8 years is about 50%. And so when that patient walks in ready to embark upon aggressive therapy and says what’s the likelihood that I’m going to be alive in 6 or 7 years I can point to the 067 data and say it’s about 50/50. So that’s one side of the spectrum, a reasonably healthy person with widely metastatic disease.

Now I want to go to the other side of the spectrum completely, which is somebody with very low-volume disease who has a bad autoimmune condition at baseline, very difficult to control ulcerative colitis for example, or even somebody who’s got a kidney transplant. So there I’m using anti-PD-1 by itself, and I’m being very gentle, and I’m being very cautious, and I’m monitoring them very, very closely just to make sure we’re not getting into all sorts of toxicity trouble, et cetera.

And then there’s everybody in between. There’s the 75-year-old guy who’s got COPD, who’s got a few lung metastases but nothing in the brain, no metastasis in the brain, where you want to give that patient the benefit of an increased progression-free survival, like we saw in RELATIVITY-047. But you realize that a toxicity in this patient is maybe not going to go so well, and so you’re not excited about exposing them to a therapy that’s got a serious tox rate of 50% or 55%, but a toxicity rate, a serious toxicity rate of 20% might be acceptable. That’s a patient where I would use nivo plus rela, just the RELATIVITY-047 regimen.

DR LOVE: So before you go through that paper I’ve got to tell you that I’ve got a feeling Brian in the chat room might be from Michigan, but he says that Johns Hopkins lacrosse 2024 11 and 5, not too bad, but they lost to Michigan, so I think he’s trying to rub that one in your face a little bit.

But anyhow, what do we see here with the updated — now we have 3-year survival outcomes here with nivo/rela? And also, what do you see in terms of tolerability when you add rela? Does it add any toxicity?

DR LIPSON: Great questions. So just to back up a sec. So RELATIVITY-047 is a global study, about 700 patients, metastatic melanoma previously untreated. It randomized patients to either get nivo by itself, which is the green box there, or nivo plus rela put together in the same IV bag essentially. The primary endpoint for the study was progression-free survival, and what was presented at ASCO this year was the 3-year update.

So at the very beginning of the study, as we first presented it back in 2021, what we saw was an improvement in progression-free survival with nivo plus rela compared with nivo alone. There was some secondary metrics that we looked at, like overall survival and overall response rate, and they did not meet statistical significance. The trial wasn’t powered in the same way as it was for progression-free survival, but you can see the curve that’s there in front of you, where it separates nicely.

So what we saw in the 3-year follow up was maturing data that demonstrates that the PFS curve continues — curves continue to separate, so we’re more reassured that the durability of the impact is persistent. So what does that mean for us in terms of how we treat patients now that nivo/rela is approved and has been for a couple of years, and we have some longer follow up data? What it means is we can say to these people we knew from the first reporting of the data that we were seeing a difference in progression-free survival, and now that a few years have gone by we can say that that progression-free survival has persisted and that the responses that we’re seeing are durable, the benefit that we’re seeing is durable.

DR LOVE: So also, I’m curious what happens when you add ipi there, which again we saw at ASCO. Would you like to comment on RELATIVITY-048?

DR LIPSON: For sure.

DR LOVE: It seems like a good idea.

DR LIPSON: Yeah. I think it probably is, for which patients we’re not entirely sure.

Alright. So let me go back just a sec. So in all of the nivo and pembro and all of the anti-PD-1 monotherapy studies the risk of a serious toxicity is somewhere in the ballpark of about 10% to 15% approximately. When you add relatlimab to that combination — to that agent, so nivo plus rela together, when you put those 2 together the serious tox rate is something in the ballpark of about 20% or 22%, so there is a slightly uptick when you add relatlimab and compare it to just the nivo or pembro, the anti-PD-1 monotherapies by themselves.

In 048 what was added to nivo plus rela was a low-dose ipilimumab, so 1 mg/kg of ipilimumab. Normally ipi is given 4 doses and that’s it. So you give it — ipi plus nivo is 4 combo doses, and then you go to nivo monotherapy. The 048 regimen was every-8-week low-dose ipi continuous, so it was a little different than what we’re used to.

In any case, this was a small study, 46 patients, and so we have to take all of this with a grain of salt. But the response rates are what you see there on the screen, and the serious toxicity rate was 39%. So yeah, that’s the slide there, so 39%.

Alright. So how does that shake out? Well, nivo plus rela the serious tox rate is say 22%, and ipi plus nivo used at full dose is about 55%. So this is somewhere in the middle, so the efficacy signal was pretty good. It’s a small study. The toxicity signal is just as I described.

I think the real question is what is the appropriate patient population. Who needs all 3 of these checkpoint pathways blocked? It’s hard to know.

DR LOVE: So I’m also curious. Another paper that came out was looking at RP1 with nivo in patients who progress. Any comments on that one?

DR LIPSON: Yeah. This is a really fascinating molecule, RP1. So the first generation of these injectable therapies was brought out several years ago, which is talimogene laherparepvec, which is a mouthful, but that’s sometimes called T-vec. And we used T-vec in patients where we’ve got little, tiny metastases and transits crawling up an arm or crawling up a leg. RP1 is, I think, safely you can call it a second-generation, and it’s used here in patients with anti-PD-1 refractory melanoma.

And so you can see overall response rate there. That’s a pretty impressive overall response rate for this patient population. This is a difficult patient population to treat. And so I think more than anything this study was intriguing because it suggested to all of us that this injectable therapy might actually be a real synergy. The activity here in a very difficult to treat patient population might be real. So we’ll learn more about this in combination in future trials, but I’m cautiously optimistic.

DR LOVE: So can we kind of go back? You said something before that’s kind of been spinning around in my head. I want to bring it back up. I think I heard you say that in patients who have a heavy autoimmune history you still would go ahead — I mean kidney transplant, et cetera, you still would go ahead and give an IO first line, for example somebody who’s BRAF wild type. Like how do you do that?

DR LIPSON: Yeah. That’s a great — that’s a great question. So this came up several years ago. We saw a bunch of kidney transplant patients who clearly needed to get their immune systems turned around, the suppression that these kidney transplant, any transplant really, patient gets is enough to make the immune system sleepy such that it can’t see these new skin cancers forming. And these cancers just explode oftentimes, so they really need our help.

In any case, we treated a few patients back in the day that demonstrated that you could help the immune systems of these patients get activated against cancer, but you had to be really careful because you could also knock out allografts. So we started a study a bunch of years ago that looked at a particular recipe using tacrolimus to try to keep the kidney safe, the allograft safe.

At the same time Dr Glenn Hanna up at Harvard looked at a different combination. He used an mTOR inhibitor for the same reason. And as it turns out, the combination that Dr Hanna investigated, which is essentially anti-PD-1 plus prednisone plus an mTOR inhibitor, that seems to really have good efficacy and reasonable safety in patients with kidney transplants. So we are — by no means do we have the absolute answer for all of these people, but we are ever — we’re slightly closer to understanding how to at least safely do that until we learn more.

So the answer to your question is how do we give patients anti-PD-1 when they’ve had an organ transplant, the answer at the moment is we switch them over to an mTOR inhibitor, and we give them a little low-dose prednisone, and we monitor their allograft function very, very closely.

DR LOVE: And of course an informed patient, if they lose the graft, it’s not life threatening. They can go back on dialysis. But have you ever done it in anybody who’s had transplant — heart transplant?

DR LIPSON: Yeah. We have. I think —

DR LOVE: Really?

DR LIPSON: Well, yeah.

DR LOVE: Wow.

DR LIPSON: When the nonkidney transplant patients, the hearts and the livers and the lungs, and they basically say to me this disease is going to take my life, and I am not going to go down looking. I’m going to go down swinging. And so I totally accept the risks that we might knock out this allograft, but I’m not going to let this cancer take my life.

And so we do the same thing. We get them over to an mTOR inhibitor. We get them on some low-dose prednisone. We make sure that after making that switch their allograft is healthy, and then we give them anti-PD-1.

DR LOVE: Have you had anybody lose — die because of that?

DR LIPSON: We haven’t had anybody — let’s see. Have we had anybody die? We’ve definitely had some allograft loss, for sure. We’ve published this, as have others.

We’ve definitely had some patients who have died, and it’s been difficult to tell what was the — what was the more important contributor, the cancer itself or the failing graft. But I think in the setting where the cancer is going to take someone’s life anyway, as I said, I think patients are pretty enthusiastic about trying everything they possibly can, even if it means that they’re going to take their — take the allograft that’s so far been healthy and make it reject.

DR LOVE: It’s such a difficult situation and decision to make.

Getting back to autoimmune disease. You didn’t mention multiple sclerosis. I mean if you had somebody who had active multiple sclerosis would you offer a PD-1 to them?

DR LIPSON: We certainly see these patients, and just like the organ transplant folks it’s always a conversation about what the likelihood is that we’re going to see exacerbation of these conditions and what that’s going to mean for somebody. Oftentimes patients who have a more mild form of autoimmunity, so psoriasis for example, that’s an easier conversation, right?

DR LOVE: Sure.

DR LIPSON: Well, we can say well your psoriasis might flare, and this is going to cause X, Y, Z complications, but the likelihood it’s going to be fatal or seriously harm you is pretty low. When somebody’s got multiple sclerosis or something that’s really going to potentially cause some significant harm it’s a much more difficult conversation.

I think, again, it gets down to the discussion about what’s going to happen if we don’t use one of the more powerful immunotherapies. And some patients say, “You know what, I’m just not into that. I’m not going to do anything to potentially worsen this autoimmune condition. Let’s try other things to treat the cancer.” And other folks say, “I respect the data on how powerful these immune modulators can be. I’m willing to give it a try.”

DR LOVE: So I remember at the beginning of the pandemic we were starting to do cases of people presenting by video, and we had a patient with lung cancer who had multiple sclerosis, and the patient very well informed, got several opinions, went ahead, got PD-1 therapy, had a great response, and they turned out — the PD-1 level was 0, which you don’t see too many responses with that, but it worked in that situation.

DR LIPSON: Yeah.

DR LOVE: One more kind of classic immune question just to catch up with you, correlation between immune toxicity and treatment benefit. Where are we with that? I’ve heard some people say skin toxicity is more tolerated with benefit. What do you all at Hopkins think about it? When you see somebody with IREs do you say oh, hey, this may be good?

DR LIPSON: Yeah. So generally the literature does support that in patients that develop particularly Grade 3 and 4 serious toxicities there is a correlation between that and the development of a tumor response for sure.

There was just a paper published not too long ago that looked at well, what specifically are the toxicities that correlate with the response. And this is not the first group to look at this, but patients with arthritis, that might correlate more with tumor response in patients who have, for example, liver toxicity. That doesn’t seem to match up as well. So I don’t think all toxicities are created equal, but in general that’s true, that patients that have bad toxicity that correlates with tumor response.

DR LOVE: Incidentally, I never told you that you’re on our short list as RTP narrator for the future because we like your voice.

DR LIPSON: Oh, well, thank you.

DR LOVE: But anyhow, let’s go on and get into — let’s get into TILs here, the hot topic, a new approval. Let’s first of all talk about what they are and how it works.

DR LIPSON: Sure. TIL. This is really exciting. So tumor-infiltrating lymphocyte therapy. So TIL is exactly what it sounds like. They are the lymphocytes that have infiltrated into the tumors, and at the moment they are being excised either surgically or by biopsy, which we’ll get into in just a second, but they are being excised and then taken into the laboratory. They are activated in the lab, this takes a few weeks, and then the patient is then admitted, given some myeloablative chemotherapy, and then the activated T cells that were removed from their body, followed by some interleukin-2 to provide some just general immunoactivation. So that is the cycle that you’ve got on the screen there.

DR LOVE: Alright. Well, let’s talk about what we know. As I mentioned, it was just approved in February. What do we know about the activity and tolerability of this, and what’s your experience with it?

DR LIPSON: Yeah. Lifileucel. So this is the first therapy that’s been — first TIL therapy that’s been FDA approved for patients with melanoma. This is an exciting moment, I think, for all of us really, but this goes back decades. Dr Steve Rosenberg at the NCI had started testing this back in the 1980s. Dr Suzanne Topalian, who is head of the melanoma program here at Hopkins, was involved in these studies as well.

Anyhow, it’s been known for long periods of time that if you tweak these tumor infiltrating lymphocytes in just the right way you can give them back to a patient, and you can see these durable antitumor responses, sometimes over decades. It did take decades for it to become commercialized, but now we are there. It’s FDA approved earlier this year.

And the waterfall plot that you’ve got there on the screen is a pretty good illustration of what we’re seeing. And so the population that was being tested there is the PD-1-refractory population, and in fact that is how lifileucel is approved. Patients with advanced melanoma who have had an anti-PD-1-based therapy, and if they have a BRAF mutation in their melanoma then they’ve had a BRAF mutation — BRAF-mutant-based therapy, as well, so BRAF/MEK inhibitors for example.

And what you’re seeing there is an approximately 30% response rate in that patient population, and that’s a difficult patient population to treat. So the response rate itself is encouraging, and also the durability of response. So the duration there you’re seeing is that’s a flat plateau right there. That is a flat curve.

And so for the patients for whom this works it really is quite a success, so I think we’re all intrigued by the data. I think we’re all feeling our way out how it’s going to work in the commercial setting. Will the number of patients that require this therapy be able to be enrolled and harvested and then processed and then retreated in enough time?

We’re all very cognizant that this is a — this is not a small deal therapy. This comes with a boxed warning for a reason. There are prolonged cytopenias on this treatment regimen, mostly because of the chemotherapy that’s involved. We see occasional severe infections. We see impairments of organs. And I think the question for a lot of us is could the regimen that goes along with this therapy, the chemotherapy, the high-dose IL-2, could any of these pieces be modulated to make this therapy more easily tolerated, to make it safer.

So right now this is the next-line standard therapy for patients that have progressed through anti-PD-1-based regimens and for patients with BRAF mutations, BRAF/MEK-based regimens. I think a lot of patients in our clinic are being referred to the big centers around for consideration of TIL.

DR LOVE: Who actually is giving it?

DR LIPSON: Well, there are a bunch of approved centers around the country, and that number continues to increase. Over time I think it’s going to look a lot like it used to look in the high-dose IL-2 days when there were, I don’t know, a hundred or so centers around the United States that were centers that gave a lot of high-dose IL-2. They’re going to be big academic centers or big community cancer centers that are going to give a lot of lifileucel therapy.

One of the studies that’s being done right now, which you’ve got there, is looking at pembrolizumab in combination with lifileucel to see if the combination could be synergistic or at least additive, so lots of questions there.

DR LOVE: Any thoughts about whether or not an IO is going to be synergistic? I mean theoretically would you expect it to be?

DR LIPSON: Well, there’s some early evidence that perhaps it could be. I think if you give somebody activated T cells and hope that it could mount an antitumor response you might expect that you could further activate those T cells by giving it a little bit of anti-PD-1. So sure, I could think of a reason why there might be synergy between pembro, for example, and lifileucel.

I think some of the other medications that are given and some of the other interventions that are required as part of lifileucel therapy are also, I wouldn’t call them sticking points, but they are elements that give us pause with regard to whether a patient is a candidate for TIL. So for example, if a patient does not have an easily resectable tumor at this point really lifileucel therapy is not on the table. You need to be able to remove a tumor surgically in order to get those cells to be able to grow them and give them back to the patient.

The reason that’s important here in this OBX-115 trial that was presented by Dr Amaria at ASCO is because this trial did not use a harvest, a surgical harvest, rather it used a needle biopsy to get tumor tissue. So right there you’re expanding the number of patients in that population because you don’t need to have somebody who has a surgically harvestable tumor, you just need somebody who has a biopsiable tumor for a core needle biopsy or a couple of core needle biopsies.

So this is a very small study, and so this is all of course with a grain of salt. But what we saw were encouraging results. We see some responses with this OBX-115 regimen.

The other thing that’s important to note, if you go back 1 slide, the other thing that’s important to note is that this regimen was given without IL-2, and so high-dose interleukin-2 is not an easy drug to tolerate in some people. So there, again, if you could give a TIL therapy without having to give somebody high-dose IL-2 you expand the population of patients for whom it might be tolerable.

Nonmetastatic Melanoma and Other Skin Cancers

DR LOVE: So I want to move on and get into nonmetastatic also. We’ve got so many questions about that, not only what was — what’s been presented, but also what’s been going on in the last couple years in general and what you all are doing. And of course we’ve got to start out with the NADINA trial, the plenary presentation. Can you talk a little bit about the background of it, and then we’ll go through what they saw, and then what you’ve been doing since ASCO or even what you were doing before ASCO in these patients?

DR LIPSON: Yeah. This is exciting stuff. I think this is probably the biggest splash at ASCO this year.

So the NADINA trial tested neoadjuvant nivo plus ipi in patients with resectable Stage III melanoma. So the background on this is that several Phase I and II trials have suggested to us over the past several years that in patients with resectable what they call macroscopic Stage III melanoma neoadjuvant immunotherapy seems to be more efficacious than adjuvant immunotherapy. One of those was the SWOG 1801 study presented by Sapna Patel last year that looked at pembrolizumab used perioperatively, so before and after surgery, compared to just adjuvant, and the event-free survival was improved in patients that got it before and then after.

So leading up to the NADINA study were some smaller trials demonstrating that the neoadjuvant approach was going to be more effective. In addition to that, Christian Blank, who was the lead PI on the NADINA trial, had some laboratory evidence showing that if you give somebody immunotherapy while the tumor is still in place the population of T cells that you get out of that patient is more robust, more diverse, than if you do it after that tumor has already been removed.

Anyway, so on the heels of all of that evidence, preclinical and scientific, this was a Phase III study where patients were randomly assigned to get 2 cycles of neoadjuvant ipi at low dose plus nivolumab followed by surgery or to get surgery and then follow that by adjuvant nivolumab, and that’s just the standard of care. So right now patients with resectable melanoma get the melanoma resected and then they get adjuvant nivo or adjuvant pembro. So this was neoadjuvant nivo plus ipi compared against the standard of care.

And so what the study looked at was called event-free survival. So event-free survival was all the metrics that you would expect; did the disease come back and things like that. And so the whole study looked at about 420 patients. They were randomized, and what Christian Blank presented was the event-free survival over the course of the last — I forget what the total follow-up was. But the 12-month event-free survival was 83% or 84% or so in the neoadjuvant group, and it was only 52% — sorry, 57% in the adjuvant group. So there was a very large space between those 2 curves, the neoadjuvant and the adjuvant group. So this was a wildly positive trial and very encouraging.

The patients that had the neoadjuvant therapy actually went on to do a bunch of different things. And this was based on the pathologic response. So when you take the tissue out of a patient that has had neoadjuvant therapy it’s assessed by the pathologist to look for a path response. And so that’s a complete path response, no tumor left behind; a major path response, less than 10% of tumor, et cetera, et cetera, partial, nonresponse, et cetera.

And so what they did was that the patients that had the pathologic complete response did not get anymore immunotherapy, and this made some sense. In other tumor types, Merkel cell, cutaneous squamous cell, this is a pattern that we’ve seen emerge in the last several years, where if the patient’s really had a fantastic pathologic complete response the thought is that you’ve done all the work that you need to do, and you don’t need to give them any further therapy. And that’s the way that these patients here on NADINA were treated.

Anyway, so your question about what are we doing here and what were we doing before, I think generally in the melanoma community we are moving toward neoadjuvant therapy for patients with resectable disease. And the question about what therapy regimen each particular patient needs I think it still unanswered. But I think that when you ask — if you ask 10 melanoma oncologists for a patient with resectable melanoma if you had the option to give them adjuvant versus neoadjuvant and then adjuvant therapy, I think most of us would say yeah. The time is now, the time is — we are ready for neoadjuvant therapy now.

DR LOVE: Well, there’s a whole lot of details to talk about there, beginning with the fact that they, after 2 — 6 weeks and 2 doses of ipi/nivo, if they did have a major path response that was it. They didn’t get any more treatment.

DR LIPSON: Yup.

DR LOVE: Is that what you’re going to do? And if so, how come?

DR LIPSON: Yeah. I think that’s probably our approach for patients that really have a path CR. As I said, I think more and more we’re seeing in tumor types like Merkel cell and cutaneous squamous cell that the patients that have had the path CR are probably done, and I think we’ll probably adopt that here.

DR LOVE: So nobody in the chat room has asked about cell-free DNA yet, so I guess I’ll ask about it. Do you see a future in melanoma, and do you think — do you envision a scenario where maybe you’d look at that after the 2 doses, and maybe if it was positive think twice about stopping it?

DR LIPSON: Yeah. We absolutely do think there is a future in cell-free DNA or circulating tumor DNA as it’s called. We’ve done a couple of studies, and I’m not sure that it’s ready for primetime just yet, but I will say that your question about the positivity is a great one, and that is to say that when we have seen ctDNA positive it does mean that there is some disease activity there, and if you wait long enough it’s going to show up on a scan. So yes, I think that in the setting of a patient with ctDNA-positive disease I would probably think twice about stopping therapy, at least until the ctDNA became negative.

DR LOVE: So I’m curious also about — this is a longstanding question in oncology, and as far as I know we have not seen survival benefit to adjuvant therapy in melanoma, yet we use it all the time. We used to say you needed to see survival benefit to do that. What’s the thinking about why we’re doing this anyhow?

DR LIPSON: Yeah. It’s a great question. You’re right. Survival benefit, overall survival benefit has been really hard to come by in the adjuvant studies for melanoma.

I think generally the benefit for the adjuvant has been disease-free survival. We have recurrence-free survival, distant metastasis-free survival. And I think that’s not for nothing. I mean, I think the benefit of delaying the disease return is real. And I think patients are living longer event-free lives with the addition of effective adjuvant therapies, and I think we can even improve on that further by giving somebody neoadjuvant therapy, which is the curve that you just put up on the screen there. So adjuvant pembro has been shown to be beneficial with regard to relapse-free survival, and the neoadjuvant/adjuvant approach that Dr Patel talked about, that even improves the curve more.

DR LOVE: So yeah. I mean it’s kind of a recapitulation of what you were just talking about, but are there situations where you’re concerned about giving the ipi where you might use neoadjuvant pembro?

DR LIPSON: Yeah, for sure. I think the decision making now for patients with neoadjuvant on the table, resectable disease where we’re thinking neoadjuvant, I think the decision making is much like it is in the metastatic setting, where we don’t really have a good biomarker to figure out who needs which pathways blocked, PD-1, CTLA4, LAG3. So we’re shooting from the hip based on toxicity profiles and who we think can tolerate what and how big is the disease burden and how many opportunities we have to treat or how many shots on goal, as I like to say.

So yeah, I mean there are certainly patients where we’re erring on the side of caution and giving what we think is the least toxic of all of the options. And the opposite is also true. We see patients where we think we have a single opportunity to treat this patient, let’s be as aggressive as we think we need to be, and if the toxicity happens, it happens, but at least we’ll have given this patient a reasonable shot at beating back this cancer.

DR LOVE: So I said that usually the chat room asks about cell-free DNA. It turns out that they actually had asked before I had asked you the question, so yeah.

DR LIPSON: I see.

DR LOVE: They’re on top of it as well.

I was so fascinated by this mRNA vaccine thing. I think the first time I saw it was last year at ASCO, and then Jeff Weber presented it, so more data. This is just super wild. This is from Moderna, right?

DR LIPSON: That’s right.

DR LOVE: The same company that did the vaccine. So mRNA vaccines with pembro. So can you explain what this is, what we know about it and where you think it’s heading?

DR LIPSON: Yeah. This is exciting. This is intriguing on many levels. So this is an individualized neoantigen therapy, so this is an mRNA molecule that is bespoke. It’s made from each patient’s individual tumor. So the tumor is removed from the patient, it is sequenced so we understand what the genetic makeup of the tumor is, and then an mRNA molecule is made that mimics — that reflects those genetic results.

And so this trial is — which is, as you say, Jeff Weber presented at ASCO this year, KEYNOTE-942, this is patients with resected melanoma who received pembrolizumab plus or minus the individualized neoantigen therapy, the mRNA. And if you go to the next slide you’ll see the — yeah, the RFS.

So this is the initial presentation of the results, and then if you click 1 more it’ll go — expand the — there you go.

So this was a more mature version of what was presented previously, and this just shows the continued separation of these curves. And I will say the statistics here, not to get too bogged down in the details, but the statistics here look a little bit better than they did when the data were initially presented. But beyond that, if you take all of this together, what it did for I think a lot of us in the community is this is a really intriguing result, and I think the benefit with regard to relapse-free survival of giving somebody pembrolizumab or nivolumab is real.

And the question is when you add an mRNA, a bespoke mRNA, individualized neoantigen therapy, do you even improve those odds further. And the separation of these 2 curves suggests that maybe in fact that is happening. So based on these results there is a Phase III study going on right now that Hopkins is actually participating in that will help us to answer this question.

DR LOVE: Any tolerability issues with this vaccine? Or I’m not sure. Do you call it a vaccine?

DR LIPSON: We don’t. We call it an individualized neoantigen therapy. But because it’s an mRNA molecule everybody calls it a vaccine because that’s kind of how that began. But anyway, yeah, the tolerability has actually been pretty good. So I think because we’re used to seeing the addition of something to the checkpoint agents, like when we added ipi and nivo together the toxicity really kind of escalated. I think a lot of us expected to see this additional therapy result in worse toxicity. That really didn’t take place, as far as we can tell. As I say, doing this Phase III study, so it’ll be a much larger trial, we’ll get a better picture of it. But as far as we know it was pretty well tolerated.

I think the question that’s going to come out of this, in the setting of all of this neoadjuvant talk, is — what we’re developing is an adjuvant regimen, right? This is for patients that have had their disease resected. So where does that fit in a world where a lot of these patients are moving toward the neoadjuvant approach? So that’s not entirely clear as things stand at the moment.

DR LOVE: So let’s get back to clinical decision making. Actually, Hasan in the chat room asked a question relevant to something I was going to ask you about next, which is, as you mentioned, Georgina Long presented a follow up from the COMBI-AD study, but Hasan wants to know, before we even get into this data, how do you choose between IO and targeted therapy in the adjuvant setting, and does the NADINA trial effect the way you approach that?

DR LIPSON: Great question. Okay. So let’s just talk about the adjuvant setting by itself for a second, and then we’ll talk about NADINA, which was neoadjuvant. But in the adjuvant setting — so we have a pretty detailed conversation with all of the patients where adjuvant therapy is on the table, and that includes a lot of stages now. So the Stage IIB and IIC patients now have an anti-PD-1 option, and then the Stage III and IV patients of course sometimes have a targeted option and oftentimes have an immunotherapy option. So it’s a lot of patients and a lot of regimens.

Anyhow, with regard to choosing between BRAF/MEK therapy and immunotherapy, in particular anti-PD-1 therapy, in a resected patient with BRAF-mutant melanoma, which I think is what the question is, that is a complex conversation. So what we talk about involves the risk of a long-term toxicity, which is going to be higher in a patient who’s getting anti-PD-1 than in a patient who’s getting dabrafenib plus trametinib, for example.

We talk about logistics. We talk about taking a pill twice a day. We talk — versus coming in every 6 weeks, for example, for adjuvant pembrolizumab. We talk about impacts on fertility in patients who are thinking about having kids or women of childbearing potential, et cetera. We talk about what comes next after somebody has had any one of these therapies and if their disease were to grow after that. So there is a lot to wrap your hands around.

I think generally patients fall into 2 categories. There are the patients that can’t sleep at night unless they know they’re doing absolutely everything they can to beat this thing back, and those are the folks who really are excited about doing adjuvant therapy. There are the folks that are pretty satisfied that they’ve had their surgery, and they want to go live their lives and not worry about toxicity, and if the disease comes back, they’ll deal with it then. And we support patients in whatever camp they fall into.

There are definitely patients that say I want nothing to do with the possibility of having long-term arthritis or having long-term hypophysitis or needing to take replacement hydrocortisone for the rest of my life. I want targeted therapy that’s much less likely to have a long-term side effect.

Anyway. So all of these are possibilities, and all of these are considerations.

DR LOVE: So “Doctor, immunotherapy sounds so exciting, do you think maybe it’s going to be more effective in the long run if I do that rather than this targeted treatment?”

DR LIPSON: That’s a great question. So because they have not been compared head to head we really cannot say either way.

DR LOVE: “Doctor, if it were you or somebody in your family what do you think you would do?”

DR LIPSON: Yeah, we get that a lot. Right. So I think the recommendations that we make oftentimes are not based on our own leanings, but they’re really based on what the patient is telling me. And patients make it pretty clear. They say I’m really afraid of this disease, and I really just want to do something right now, and I want to be as aggressive as I can be, but I don’t want to wind up with the possibility of being a 45-year-old guy that has to take replacement hormones for the rest of my life. And I think for those patients I say look, what sounds like is right for you is probably targeted therapy for a year, dabrafenib and trametinib or enco/bini or whatever for a year. And that seems like a comfortable decision for you.

So I think it’s really based on what the patient expresses to me. It really is a conversation.

DR LOVE: The other thing is with BRAF you can stop it.

DR LIPSON: Right.

DR LOVE: Once you’ve got the IO in there, you’re in the game.

DR LIPSON: Yup.

DR LOVE: What about the long-term follow up that we’re seeing here and really the question of is there a curve — is there a tail on the curve?

DR LIPSON: Yeah. Is there a separation there? So I think Georgina did a great — Georgina Long did a great job presenting these results. This study is now a decade old, and I think some of the overall survival stats were interesting. This part about the overall survival benefit for patients with V600E but not V600K is intriguing. The curves definitely separate for sure. You can see that on the graphs. I don’t know. When you get down to it, though, there’s a lot of complexity. A lot has happened over the last 10 years, new therapies have been developed. So I don’t know that overall survival is necessary — a benefit, I mean, of overall survival is necessary for me to recommend a therapy like this to a patient.

I really do think it gets back down to recurrence-free survival, distant metastasis-free survival. Could I prevent this patient from popping up a new brain metastasis if I treat them in the adjuvant setting? Could I delay that? Maybe. So I think that’s really where it’s at.

DR LOVE: So we talked mainly about — or completely about melanoma up to now, but let’s talk a little bit about other skin cancers, mainly squamous cell. We talked a little bit about basal cell in the beginning. Any comment on this study looking at, here we go again, neoadjuvant, now IO for squamous cell, something that makes a whole lot — ultimate sense?

It’s funny, we were doing a program, I forget what it was, on MSI high, and we were looking at TMB levels, and like melanoma’s got higher TMB than MSI high, right? Major sensitivity.

DR LIPSON: Yeah. Some of the cutaneous tumors, squamous cell is one of them.

DR LOVE: The squamous cell, same thing. Squamous cell is right up there too.

DR LIPSON: Yeah.

DR LOVE: So anyhow, what about neoadjuvant IO here?

DR LIPSON: Right. So this is another exciting neoadjuvant approach, so similar to the NADINA trial. So this study looked at whether you could use neoadjuvant cemiplimab, also an anti-PD-1, in patients with resectable cutaneous squamous cell carcinoma. And it looked at a few different things. So one is so what is the outcome from a pathologic response rate for this patient population. And the answer there appears to be about half of patients. It was 51% of 80 patients, or 79 patients. And so in about half of cases we saw that we gave 12 weeks of cemiplimab, and they had a pathologic complete response, which means no tumor seen under the microscope. So that’s pretty impressive.

What I think was more impressive was that if you went on in time — and these results were presented in Lancet Oncology. If you went on in time it looked at the depth of response, which is the graph you’ve got there. What you see is the patient — patients that essentially had any response, partial response, major path response, complete response, the curves there look pretty good going out quite a good ways, and there were no recurrences seen in the 40 patients that had the pathologic complete responses.

So a lot of those path CR patients went on to receive no further therapy, no radiation therapy, no further cemiplimab, just plain old observation. So this gets back to what we were talking about before, where if you have a patient that’s had a really remarkable response to therapy, had a pathologic complete response, and they’ve done well with their 12 weeks or whatever it is of neoadjuvant, you can probably stop therapy in a lot of these patients and just monitor them closely, and they’re going to do really well.

DR LOVE: When you think about disparities and think about the difference between getting an IO and then stopping versus disfiguring surgery, radiation therapy, it’s just really amazing. Hopefully patients are receiving that, and obviously the NCCN is keeping it as well.

DR LIPSON: Yeah.

DR LOVE: What about, again, getting back to ASCO 2024, I like this title too, DESQUAMATE study.

DR LIPSON: Yeah. If I could just make 1 comment about something you said a second ago. So the issue about equality and being able to get therapy out to the patients that need it equitably, et cetera, keep in mind that in patients who get just a very brief bit of therapy, in the NADINA study it was just 6 weeks, 2 doses of ipi/nivo, and in the study that you just had pulled up a second ago, the cemiplimab in the cutaneous squams, it was just 12 weeks of therapy, it really shortens the duration that someone needs therapy dramatically, right? I mean, we’re talking about patients who were previously getting a year or 2 years of therapy, and now you’ve shortened that therapy down to 6 weeks or 12 weeks of therapy, right? I mean this is — this is a game changer. Financially it’s a game changer. How much patients need to come back into clinic and see you. It’s a total improvement, right?

DR LOVE: Absolutely.

DR LIPSON: Yeah.

DR LOVE: How about DESQUAMATE?

DR LIPSON: Oh, yeah, DESQUAMATE. This is an interesting study. So this is for Stage II through IV locally-advanced cutaneous squamous cell carcinoma, and the idea here is can you see a histopathological response after 4 cycles of neoadjuvant therapy. So again, this is like can we decrease the amount of therapy that somebody’s going to need, and if they’ve had a nice pathologic complete response do we — can we say we’ve completed the therapy we need to give to this patient.

DR LOVE: One final question from Dr Kumar in the chat room. He’s going to be starting a patient on cemiplimab in that situation with squamous cell. What’s your approach if they don’t respond?

DR LIPSON: Cutaneous squamous cell to cemiplimab, a nonresponder. Yeah, that’s a good one. We’re typically switching to cetuximab, which is unfortunately only effective in probably a third of patients. Oftentimes in patients where PD-1 by — anti-PD-1 by itself has not done the trick we’re looking for a clinical trial for patients with cutaneous squam. We don’t have a lot of great options there.

DR LOVE: Alright, Evan. Well, thank you so much for working with us today. Audience, thank you for attending. Come on back tomorrow night. Really curious to see what these 3 docs have to say about some of the new advances in lung cancer, particularly small cell, tarlatamab. I’m really curious to see how that’s going to play out with cytokine release syndrome with patients with small cell and a lot of tumor are often symptomatic.

Be safe, stay well, and have a great night. Thanks so much, Evan. Have a good one.

DR LIPSON: Thanks very much. Good to be with you.

DR LOVE: Take care.