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Emerging Therapies for Metastatic Melanoma
Bently Doonan, MD, examines emerging therapies for metastatic melanoma. He identifies LAG3 inhibition and its role in melanoma. He helps to familiarize physicians with TIL therapy and he discusses outpatient systemic cytokine therapy for relapsed metastatic melanoma
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Learn more about Bently Doonan, MD
Bently Doonan, MD
Bently Doonan, MD, MS is an assistant professor in the Division of Hematology & Oncology at the University of Florida College of Medicine. Dr. Doonan earned his undergraduate degree in biology, cum laude, from Coastal Carolina University.Learn more about Bently Doonan, MD
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preroll: The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And I invite you to listen as we discuss emerging therapies for metastatic melanoma. Joining me is Dr. Bently Doonan. He's an Assistant Professor in the Division of Hematology Oncology at the University of Florida College of Medicine, and he practices at UF Health Shands Hospital in Gainesville, Florida.
Dr. Doonan, it's a pleasure to have you with us today. We have a lot of exciting emerging therapies to talk about. Before we get into some of those, tell us a little bit about metastatic melanoma, its prevalence, and what you've been seeing in the trends.
Dr Bently Doonan: Yeah. Well, thank you so much for having me first and foremost. It's great get to talk about this field, talk about something that I'm sort of very passionate in in patients that I see every week in my clinic. So I primarily treat patients with advanced cutaneous melanoma and other cutaneous malignancies at UF Health Shands Hospital. So it's really at the forefront of what I do.
And really the other part of it is that I'm also a clinician scientist. So I do research in the field and in the area and have been doing that since dating back to 2008. And so, to give sort of a big picture focus on the field, really going back to when my career first started looking at research in melanoma, we had nothing. We had some experimental therapies, we had some promise for immunotherapy and nothing had really cracked through the ceiling to give us much benefit.
And the world really changed in 2011 with the advent of ipilimumab or ipi, that really sort of changed the game and changed the landscape and followed three years later by nivolumab and pembrolizumab or nivo and pembro, to make it easier, really changed the world. So we went from completely having no beneficial therapeutics available to then having three or four different drugs and targeted therapies soon followed after that, that really changed the landscape and brought this completely uniformly fatal disease to having patients that are long-term survivors, patients that achieved durable remission and some long-term cures.
And so really when we look at the landscape for the first 50 years of modern oncology, there is nothing for melanoma. And then in the last decade, we were given these three to five new therapies, three of them being immunotherapies, and then the advent of the targeted therapies. And we won't speak today about T-VEC, but that's another sort of immune-based therapy in the space that have really, really changed the game.
Looking at the next 10 years going forward, we're really sitting on the cusp of another major leap forward. There are some therapies that are likely to come out within the next really 12 to 24 months. Some of that being delayed by just the effects of COVID on the research development on clinical trials is really going to change the field that much further. So it seems that 10 years in melanoma really is game-changing.
Melanie Cole (Host): Wow. That is fascinating. What an exciting time to be in your field. And thank you for telling us how it's evolved in recent decades and why alternative pathways and these novel strategies were so desperately needed. So identify LAG-3 inhibition and its role in melanoma for us.
Dr Bently Doonan: Yeah. So most practicing physicians realize that the real breakthrough in immunotherapy has been checkpoint inhibition. And when we speak about checkpoint inhibition, what we're really talking about is that there are natural mechanisms that exist in the immune environment that limit how activated your immune system gets against itself. And this is a protective mechanism that then gets abused by cancer cells. We're having this unchecked inflammation that really can drive T cells to actually not function appropriately. And this is sort of a hallmark of many cancers, is the up-regulation of these immune checkpoints. And the ones that people are most familiar with are CTLA-4 and then PD-1 and those are the targets of the drugs that we've spoken about so far, ipi and nivo. These have been really well-validated among many cancer types. But unfortunately, really we still see about 20% of the total cancer population, higher in melanoma than other cancers, but about 20% sort of globally and probably closer to 40% of our melanoma patients that really derive benefit from this, that really we don't know is what happens when patients don't respond to this or what happens after that.
There's lots of mechanisms at play for why these therapies fail or why they don't work or why they become sort of obsolete over time. And one of that is because the whole process of checkpoint inhibition is actually much more complicated than just having two or three different receptors or logins on the surface of these cells that silence the environment. There's multiple other checkpoint inhibitors like LAG-3, which is the one we'll talk about today, but there's multiple other ones that are downstream of this that function similarly to what we're talking about.
Now, LAG-3 is important to discuss here because this is really the next one up at bat. This is the one that's in the batter's box. This is the one that's the furthest along in clinical development. And it's the one that's got the most promise to get into the clinic the soonest. So LAG-3 or lymphocyte activation gene 3, you can think of it as just being another step on the cascade of immune checkpoint pathways.
It doesn't have the same breadth or depth of knowledge that we have about CTLA-4 or about PD-1, because it doesn't have as simple of a lock and key mechanism with its login that other agents do. But what we do know is that when we inhibit this, both in preclinical studies and what we have now from some early first-in-human phase I, phase II, and even up to phase III data now is that in humans it can be quite effective in diseases where T-cell exhaustion is a problem. And melanoma's really the hallmark disease for having a T-cell based immune effect to be effective, that's where ipi and nivo and pembro have really shown the biggest benefit.
Melanie Cole (Host): So then familiarize other physicians with TIL therapy. Speak about tumor-infiltrating lymphocytes. I found this fascinating in my research.
Dr Bently Doonan: Yeah. So TIL therapy, again, this is another aspect of immunotherapy that's sort of was pioneered and started in melanoma and then is a technique that's the hopeful ability to span across multiple tumor types. So this is really pioneered in the '80s by Steve Rosenberg's group at the surgical branch of the NIH. And he had a seminal paper in mice back in 1986, where they were showing the potential of actually taking a tumor and then you remove it from a host and ex-vivo expand it. There's T-cells that are embedded within the tumor that are effective at killing that. And by expanding those T-cells and reintroducing them into a new host or into the same host, you could actually show an immune response.
Now, they quickly followed this in first-in-human studies in the late '80s. And this is some hallmark pictures that are in pretty much every immunology textbook in the country, showing that patients with large aggressive metastatic melanomas, when this therapy worked, it was profound. We were talking about a 34% overall response rate, which was better than high dose IL-2, which is really the only game in town at that point. And within that, there was about 6% to 7% that had complete responses that are very durable responses even up to four or five years later.
But it didn't really change the landscape. And part of this was because it's difficult to do the handling of cells and expansion and really coordinating this in the early '90s was very difficult. It really wasn't until advent of CAR T-cell therapy and some of these other cellular therapies like dendritic cell vaccines and our ability to improve the way that we can handle, process, deliver and treat patients with cellular therapy, the TIL therapy really started to come back into the forefront and really into the forefront for melanoma.
There was a company that sort of partnered with Dr. Rosenberg's group and sort of took his ideas and collaborated with the NIH called Iovance, and they've created a product called lifileucel. And lifileucel is likely to be the first commercially available TIL-based therapy in the next 12 to 24 months. Their goals was actually to have this approved or sent to the FDA last year, but they ran into some roadblocks with some internal testing and some analysis they needed to do on followup and also the COVID slog that's happened to the NIH.
But what they're showing in some of their data that they presented at ASCO last summer, was that in heavily pretreated patients, so these are patients with advanced metastatic melanoma and on average had received three or more than three lines of prior therapy. So this is either having targeted therapy, receiving both ipi and nivo or other cellular-based vaccines. And what they saw was an overall response rate of about 35%, which is good. But really the big thing that they saw is there was a disease control rate of 80%.
Now, a disease control rate means you're not going to likely die from your disease. Now, it might not make your disease go away, but if it holds your disease at bay, it's really effectively doing the same thing for the patient and really turning it into more of a chronic medical condition. Almost everyone who saw a response or reduction in their primary tumor size, and these responses were very durable, so they were really durable and they actually deepened over time. And adding to this, it was really generally well-tolerated. The side effects that we're seeing with it is that the cellular therapies actually followed by a period of high dose IL-2, which is really where all of the toxicity comes from.
And so my suspicion is, is that when they get these things ironed out with the FDA and they submit their application next year, that this is going to be a therapy that's viable and approved by the FDA likely in 2022, if not by 2023. And so what we've done seeing this sort of potential for this in the future here at UF Health Shands Hospital, is that we've actually in discussions with Iovance at becoming one of the treatment centers for lifileucel when it inevitably gets that approval.
Melanie Cole (Host): Dr. Doonan, TIL therapy sounds absolutely fascinating. As you said, it's progressing to FDA approval likely in the next year. Tell us a little bit more about how it's even done.
Dr Bently Doonan: Absolutely. So cell therapy is really interesting. It's very viable and what we've learned a lot from the CAR T-cell-derived products is that we actually need to do more than just give cellular product. So how it works is a patient's identified as meeting the criteria. So this is people that have progressed on previous lines of therapy. And we actually would bring them in and do a surgical removal of one of their tumors. That gets sent off to the company for the actual expansion of the TILs and they develop the product that's then going to go back into the patient. That process takes about three to four weeks, depending on the turnaround time for it.
While that's happening, the patient is going to be admitted to the hospital and they actually have to receive something called lymphodepleting chemotherapy. Now, lymphodepleting chemotherapy is non-myeloablative, so it does not reduce your bone marrow down to the part of, say, receiving a transplant, but it does condition the immune environment to remove some of those cells that are going to inhibit the function of the TIL therapy.
After you've received the lymphodepleting chemotherapy, you then receive the TIL product. And what we know is that patients generally have no negative response to that. It's your own T-cells, there's very limited risk of having a reaction to it. And it's even probably less than that of getting an autologous transplant for a disease like multiple myeloma or lymphoma. After you receive the product, then the only issue that really we're seeing with the toxicity is that following the TIL administration is that we give a drug in the adjutant setting to expand the function of that TIL product, and that's IL-2. IL-2 is tried and true long-term therapy that's been given in melanoma, and this is sort of what we call moderate dose IL-2. It's still a high dose, but you're only going to have to receive five or six doses of it every 12 hours or so. So it's in typical fashion with high-dose IL-2, it's given multiple sessions as the patient can tolerate over many weeks, many return visits to the hospital with lots of toxicity.
This therapy has a much briefer window of giving the IL-2 as an adjuvant. And once that's complete, there's no further therapy that's needed. So after recovery from that period, the person's discharged from the hospital and then does the remainder of their care in the outpatient setting.
Melanie Cole (Host): Can you discuss briefly for us outpatient systemic cytokine therapy for relapsed metastatic melanoma, because we have a lot to get through. Wow, this is such an interesting podcast, but briefly go over this outpatient cytokine therapy for us.
Dr Bently Doonan: Yeah, absolutely. So what we were talking about with the lifileucel and the big side effects or the toxicity that it has on the tail end of that therapy is because it requires administration of high-dose IL-2. Now, high-dose IL-2 has been used since the early '80s for melanoma. It's effective. It's also been used in renal cell carcinoma before. But it has to be administered really in an intensive care setting. Some of the side effects can be severe or life-threatening, renal failure, pulmonary edema, and some other really high risks syndromes.
So though we know it's always been effective in melanoma, the ability to deliver this to patients has really been really focused at some high volume centers with expertise in it with also some high risk. And it really has been supplanted by checkpoint inhibition in terms of its value. Now, company or a group of investigators, what they did is they sort of found a novel way of addressing this ability to expand IL-2 through the advent of a drug called bempegaldesleukin, or we can call it bempeg. It's much easier to say Bempeg. But it's the first in its class, immunostimulatory IL-2 cytokines pro-drug, which means when it's engineered, it can be given in a controlled and sustained release instead of as a high dose sort of cytokine surge. Most cytokines when given actually have an incredibly short half-life on the matter of seconds to minutes. And that's by design because if these were to stay on and turned on at a very high level, the side effects are incredibly high.
So in the formulation that they've made, it's able to deliver a similar effect to what high-dose IL-2 can do, but in a much safer, slower, controlled, and most importantly, outpatient environment. And so what they've shown so far, and they've only reached sort of phase I, phase II data, there was a trial called PIVOT-02, which was giving this drug in addition to nivolumab every three weeks. And it was really remarkable, the level of response that they were seeing, is that they were seeing a 52% response rate to treatment.
Now, this is a small sample size, and this is really feeding into a much larger phase III clinical trial, called PIVOT IO 001 that's currently enrolling. But what this would potentially do is it really keeps the treatment of melanoma in the clinic. And it really gives some therapies that we know have been effective for the last 20 or 30 years a much better toxicity profile and a much better and easier delivery mechanism. So the ability to deliver this to patients in the outpatient setting is really going to be revolutionary for what we can do.
Melanie Cole (Host): As we continue this, talking about efficacy and trials for metastatic melanoma, has the combination of nivolumab and RELA shown efficacy? Tell us through which mechanism this works.
Dr Bently Doonan: Oh, absolutely. So that's really what we've seen with all checkpoints, is that each checkpoint is likely to have some degree of individual drug-specific effect. So as a monotherapy, each of the previous checkpoints have some effect and, for a select group of patients, it's probably the only thing they need, even in the early ipi studies. There's probably about 8% to 10% of patients with melanoma that a dose of ipi or multiple doses of ipi is probably the only thing they would need to actually have their disease response. And we see that similarly in both nivolumab and pembrolizumab. We also see that with relatlimab, having some single agent benefit, especially in patients that were previously treated. But when we add it to nivolumab, we see that the combined benefit from these two therapies at the same time really outpaces the individual therapy. So it's really a situation where one plus one doesn't equal two. It's that one plus one really equals three or four.
Now, we see that similarly with the ipi-nivo combination, but the big issue there is that when we're compounding the effect, we're also really compounding the toxicity. So, if you look at the individual toxicities of a drug like nivolumab or pembrolizumab are severe side effects, really only happen in 10 to 15% of patients. And in clinical practice, it's probably even a little bit less than that. When we do ipi, we're really looking at 30% of patients, if not more, are going to get a serious one. And when we combine those two, it doesn't go, "Well, 30 plus 10 should be 40. It's 30 plus 10 really turns into 75." So it really becomes almost everyone is going to get a more significant side effect from the combination.
Now, when we do relatlimab plus nivolumab and what they've shown in some of the clinical trials is that you do get that same compounded effect in terms of improving the effect of the drug. So, if you look at the efficacy of nivolumab alone, in terms of progression-free survival in this trial that they did, you saw about four and a half months of progression-free survival with nivolumab, which similar to what we see in the community. Now, with the addition of relatlimab to nivolumab, it was significantly increased. That went up to 10 months, so more than double the actual progression-free survival effect by adding the two drugs together.
And the best thing that we see with the combination is that we're really not seeing a huge increase in the treatment-related adverse effects. And so this is the potential to then give us the benefits of doing combination immunotherapy, similar to ipi and nivo without having to take on the increased risks that ipi and nivo had in terms of side effects. So instead of going up to a side effect profile of say greater than 50% of patients having a grade 3 or 4 adverse effect with ipi-nivo, it's really more like 18% of patients. And so it's less than half the degree of toxicity that ipi-nivo carries and probably a very similar efficacy to it.
The other benefit is that since this is not a competing mechanism, is that you still allow ipi to be used in the future. I really feel, and I think probably most people in the field would say that if the rest of the survival data that's sort of being worked on in these larger trials bears fruit that shows that not only progression-free survival we're seeing, but if we're also seeing overall survival, the combination of relatlimab and nivolumab is really going to supplant the use of ipilimumab or ipi in the first-line metastatic melanoma.
Melanie Cole (Host): Along those lines then, what was the overall response percentage rates seen in the potential application of bempeg in combination with nivolumab?
Dr Bently Doonan: So looking at bempeg, the overall response rate with bempeg plus nivo was 50%. And so that 50%, it's important to say is in a much smaller cohort of people. So the nivo+RELA trial was up to, I think, 750 people that were stratified against the two arms versus this being both a signal-seeking, toxicity-seeking, and then early expansion cohort, the bempeg PIVOT-02 trial, I think was only in a matter of, say, like 50 or 60 patients.
So with that though, 34% of the patients in that trial had a complete response. Now complete response is something that we achieved for in all trials and in all therapies, because those are patients that are the most likely to remain cured. But chasing a complete response really overlooks that if you can just have stable disease or prevent progression of disease, you have an overall response rate that's really clinically meaningful to your patients.
Now, the other interesting things about the bempeg is that the duration of response in this trial has not been reached. So this is in those patients who respond, they tend to respond for a very long time. And so those that reached some degree of disease control by modified iRECIST criteria maintained that control rate for more than 30 months. And the progression-free survival in this intent to treat population was almost three years long.
That's really probably stronger and more robust than what we're seeing with some of the other combinatorial data. But if you think about it, it's because this is actually putting something into the mix that's got some cytotoxic effect against the melanoma cells, but also stimulates wider T-cell expansion. So IL-2's mechanism of action is slightly different than the mechanism of action with the relatlimab. And because of that, I would probably say that the bempeg probably does carry a slightly higher side effect profile risk than does the relatlimab.
Melanie Cole (Host): What an informative podcast this is and you're an excellent educator. Dr. Doonan, as we wrap up, discuss any ongoing research studies, research that you're doing at UF Health Shands Hospital. Any game-changers that you see? What would you like other physicians to take away from this podcast today?
Dr Bently Doonan: Absolutely. So I think as a practicing clinical oncologist, I think we're all going to see the benefit of a lot of these sort of multinational and these bigger projects and this work that we talked about in the next 12 to 24 months. And it will really be practice-changing. What I do here at UF Health Shands Hospital, as part of both a practicing physician and also as a physician scientist, is I really focus on strategies to overcome this resistance to immunotherapy and to overcome the tumor microenvironment and how it inhibits the ability to deliver immunotherapy.
And with that, I focus specifically on the most advanced and the highest risk melanoma lesions, which are melanoma brain metastasis. And so my research focus really is looking at new novel mechanisms of therapy and ways of targeting brain metastasis in patients with metastatic melanoma. And it's important because all of the trials we talked about today and all these therapies, they're going to make these patients live longer if they are going to be effective and we're going to be seeing patients with melanoma live longer and live better. And the double-edged sword to that is that whenever we have therapies that make cancer patients live longer, as long as the disease is still present, what we're really doing is also increasing the likelihood that they'll develop a distant metastasis at some point or develop brain metastasis.
Now, in some studies we're already looking at about 40% to 60% of patients with advanced melanoma, having melanoma brain metastasis at some point during the course of their treatment. And when they get those lesions, it's really tough sort of decide how we treat them. The treatment paradigm has not fully been established, but it follows the similar course of how we treat systemic disease, where we look at double agent immunotherapy to treat it.
Unfortunately, because the brain is a little bit more complicated than the rest of the body in terms of the tumor microenvironment, the therapies are less effective in the brain. So single agent immunotherapy has very poor response rate. The addition of double agent immunotherapy improves that slightly, but in these patients, the risk of relapse is really high.
So one of the first and foremost programs that I'm sort of to develop here with my research and with my clinical aspect is to really come up with trials that are directly targeted for these patients with melanoma brain metastasis. We have some drugs that we're testing in collaboration with some of our industry partners that we think are going to have a very high likelihood of success in this space and we've got some promising preclinical data and some promising preclinical work. And so I do this research at UF Health Shands Hospital as part of also our University of Florida Brain Tumor Immunotherapy Program under the guidance of Dr. Duane Mitchell. And so our goal is to really create a clinic and a landing point for patients of all types with brain metastasis, sort of starting with patients with melanoma brain metastasis, where we're going to have the science, the scientists, the preclinical acumen, and then the ability to deliver our therapy to patients with advanced disease. And so that's something that we're really, really excited about here at the University of Florida Health Shands Hospital and what we're going to have in the future.
Melanie Cole (Host): Dr Doonan, that was outstanding. Thank you so much for joining us today and telling us about all the exciting emerging therapies for metastatic melanoma and the game-changers. I hope that you'll join us again and fill us in as things progress. And thank you again for being with us today.
To refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.
preroll: The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And I invite you to listen as we discuss emerging therapies for metastatic melanoma. Joining me is Dr. Bently Doonan. He's an Assistant Professor in the Division of Hematology Oncology at the University of Florida College of Medicine, and he practices at UF Health Shands Hospital in Gainesville, Florida.
Dr. Doonan, it's a pleasure to have you with us today. We have a lot of exciting emerging therapies to talk about. Before we get into some of those, tell us a little bit about metastatic melanoma, its prevalence, and what you've been seeing in the trends.
Dr Bently Doonan: Yeah. Well, thank you so much for having me first and foremost. It's great get to talk about this field, talk about something that I'm sort of very passionate in in patients that I see every week in my clinic. So I primarily treat patients with advanced cutaneous melanoma and other cutaneous malignancies at UF Health Shands Hospital. So it's really at the forefront of what I do.
And really the other part of it is that I'm also a clinician scientist. So I do research in the field and in the area and have been doing that since dating back to 2008. And so, to give sort of a big picture focus on the field, really going back to when my career first started looking at research in melanoma, we had nothing. We had some experimental therapies, we had some promise for immunotherapy and nothing had really cracked through the ceiling to give us much benefit.
And the world really changed in 2011 with the advent of ipilimumab or ipi, that really sort of changed the game and changed the landscape and followed three years later by nivolumab and pembrolizumab or nivo and pembro, to make it easier, really changed the world. So we went from completely having no beneficial therapeutics available to then having three or four different drugs and targeted therapies soon followed after that, that really changed the landscape and brought this completely uniformly fatal disease to having patients that are long-term survivors, patients that achieved durable remission and some long-term cures.
And so really when we look at the landscape for the first 50 years of modern oncology, there is nothing for melanoma. And then in the last decade, we were given these three to five new therapies, three of them being immunotherapies, and then the advent of the targeted therapies. And we won't speak today about T-VEC, but that's another sort of immune-based therapy in the space that have really, really changed the game.
Looking at the next 10 years going forward, we're really sitting on the cusp of another major leap forward. There are some therapies that are likely to come out within the next really 12 to 24 months. Some of that being delayed by just the effects of COVID on the research development on clinical trials is really going to change the field that much further. So it seems that 10 years in melanoma really is game-changing.
Melanie Cole (Host): Wow. That is fascinating. What an exciting time to be in your field. And thank you for telling us how it's evolved in recent decades and why alternative pathways and these novel strategies were so desperately needed. So identify LAG-3 inhibition and its role in melanoma for us.
Dr Bently Doonan: Yeah. So most practicing physicians realize that the real breakthrough in immunotherapy has been checkpoint inhibition. And when we speak about checkpoint inhibition, what we're really talking about is that there are natural mechanisms that exist in the immune environment that limit how activated your immune system gets against itself. And this is a protective mechanism that then gets abused by cancer cells. We're having this unchecked inflammation that really can drive T cells to actually not function appropriately. And this is sort of a hallmark of many cancers, is the up-regulation of these immune checkpoints. And the ones that people are most familiar with are CTLA-4 and then PD-1 and those are the targets of the drugs that we've spoken about so far, ipi and nivo. These have been really well-validated among many cancer types. But unfortunately, really we still see about 20% of the total cancer population, higher in melanoma than other cancers, but about 20% sort of globally and probably closer to 40% of our melanoma patients that really derive benefit from this, that really we don't know is what happens when patients don't respond to this or what happens after that.
There's lots of mechanisms at play for why these therapies fail or why they don't work or why they become sort of obsolete over time. And one of that is because the whole process of checkpoint inhibition is actually much more complicated than just having two or three different receptors or logins on the surface of these cells that silence the environment. There's multiple other checkpoint inhibitors like LAG-3, which is the one we'll talk about today, but there's multiple other ones that are downstream of this that function similarly to what we're talking about.
Now, LAG-3 is important to discuss here because this is really the next one up at bat. This is the one that's in the batter's box. This is the one that's the furthest along in clinical development. And it's the one that's got the most promise to get into the clinic the soonest. So LAG-3 or lymphocyte activation gene 3, you can think of it as just being another step on the cascade of immune checkpoint pathways.
It doesn't have the same breadth or depth of knowledge that we have about CTLA-4 or about PD-1, because it doesn't have as simple of a lock and key mechanism with its login that other agents do. But what we do know is that when we inhibit this, both in preclinical studies and what we have now from some early first-in-human phase I, phase II, and even up to phase III data now is that in humans it can be quite effective in diseases where T-cell exhaustion is a problem. And melanoma's really the hallmark disease for having a T-cell based immune effect to be effective, that's where ipi and nivo and pembro have really shown the biggest benefit.
Melanie Cole (Host): So then familiarize other physicians with TIL therapy. Speak about tumor-infiltrating lymphocytes. I found this fascinating in my research.
Dr Bently Doonan: Yeah. So TIL therapy, again, this is another aspect of immunotherapy that's sort of was pioneered and started in melanoma and then is a technique that's the hopeful ability to span across multiple tumor types. So this is really pioneered in the '80s by Steve Rosenberg's group at the surgical branch of the NIH. And he had a seminal paper in mice back in 1986, where they were showing the potential of actually taking a tumor and then you remove it from a host and ex-vivo expand it. There's T-cells that are embedded within the tumor that are effective at killing that. And by expanding those T-cells and reintroducing them into a new host or into the same host, you could actually show an immune response.
Now, they quickly followed this in first-in-human studies in the late '80s. And this is some hallmark pictures that are in pretty much every immunology textbook in the country, showing that patients with large aggressive metastatic melanomas, when this therapy worked, it was profound. We were talking about a 34% overall response rate, which was better than high dose IL-2, which is really the only game in town at that point. And within that, there was about 6% to 7% that had complete responses that are very durable responses even up to four or five years later.
But it didn't really change the landscape. And part of this was because it's difficult to do the handling of cells and expansion and really coordinating this in the early '90s was very difficult. It really wasn't until advent of CAR T-cell therapy and some of these other cellular therapies like dendritic cell vaccines and our ability to improve the way that we can handle, process, deliver and treat patients with cellular therapy, the TIL therapy really started to come back into the forefront and really into the forefront for melanoma.
There was a company that sort of partnered with Dr. Rosenberg's group and sort of took his ideas and collaborated with the NIH called Iovance, and they've created a product called lifileucel. And lifileucel is likely to be the first commercially available TIL-based therapy in the next 12 to 24 months. Their goals was actually to have this approved or sent to the FDA last year, but they ran into some roadblocks with some internal testing and some analysis they needed to do on followup and also the COVID slog that's happened to the NIH.
But what they're showing in some of their data that they presented at ASCO last summer, was that in heavily pretreated patients, so these are patients with advanced metastatic melanoma and on average had received three or more than three lines of prior therapy. So this is either having targeted therapy, receiving both ipi and nivo or other cellular-based vaccines. And what they saw was an overall response rate of about 35%, which is good. But really the big thing that they saw is there was a disease control rate of 80%.
Now, a disease control rate means you're not going to likely die from your disease. Now, it might not make your disease go away, but if it holds your disease at bay, it's really effectively doing the same thing for the patient and really turning it into more of a chronic medical condition. Almost everyone who saw a response or reduction in their primary tumor size, and these responses were very durable, so they were really durable and they actually deepened over time. And adding to this, it was really generally well-tolerated. The side effects that we're seeing with it is that the cellular therapies actually followed by a period of high dose IL-2, which is really where all of the toxicity comes from.
And so my suspicion is, is that when they get these things ironed out with the FDA and they submit their application next year, that this is going to be a therapy that's viable and approved by the FDA likely in 2022, if not by 2023. And so what we've done seeing this sort of potential for this in the future here at UF Health Shands Hospital, is that we've actually in discussions with Iovance at becoming one of the treatment centers for lifileucel when it inevitably gets that approval.
Melanie Cole (Host): Dr. Doonan, TIL therapy sounds absolutely fascinating. As you said, it's progressing to FDA approval likely in the next year. Tell us a little bit more about how it's even done.
Dr Bently Doonan: Absolutely. So cell therapy is really interesting. It's very viable and what we've learned a lot from the CAR T-cell-derived products is that we actually need to do more than just give cellular product. So how it works is a patient's identified as meeting the criteria. So this is people that have progressed on previous lines of therapy. And we actually would bring them in and do a surgical removal of one of their tumors. That gets sent off to the company for the actual expansion of the TILs and they develop the product that's then going to go back into the patient. That process takes about three to four weeks, depending on the turnaround time for it.
While that's happening, the patient is going to be admitted to the hospital and they actually have to receive something called lymphodepleting chemotherapy. Now, lymphodepleting chemotherapy is non-myeloablative, so it does not reduce your bone marrow down to the part of, say, receiving a transplant, but it does condition the immune environment to remove some of those cells that are going to inhibit the function of the TIL therapy.
After you've received the lymphodepleting chemotherapy, you then receive the TIL product. And what we know is that patients generally have no negative response to that. It's your own T-cells, there's very limited risk of having a reaction to it. And it's even probably less than that of getting an autologous transplant for a disease like multiple myeloma or lymphoma. After you receive the product, then the only issue that really we're seeing with the toxicity is that following the TIL administration is that we give a drug in the adjutant setting to expand the function of that TIL product, and that's IL-2. IL-2 is tried and true long-term therapy that's been given in melanoma, and this is sort of what we call moderate dose IL-2. It's still a high dose, but you're only going to have to receive five or six doses of it every 12 hours or so. So it's in typical fashion with high-dose IL-2, it's given multiple sessions as the patient can tolerate over many weeks, many return visits to the hospital with lots of toxicity.
This therapy has a much briefer window of giving the IL-2 as an adjuvant. And once that's complete, there's no further therapy that's needed. So after recovery from that period, the person's discharged from the hospital and then does the remainder of their care in the outpatient setting.
Melanie Cole (Host): Can you discuss briefly for us outpatient systemic cytokine therapy for relapsed metastatic melanoma, because we have a lot to get through. Wow, this is such an interesting podcast, but briefly go over this outpatient cytokine therapy for us.
Dr Bently Doonan: Yeah, absolutely. So what we were talking about with the lifileucel and the big side effects or the toxicity that it has on the tail end of that therapy is because it requires administration of high-dose IL-2. Now, high-dose IL-2 has been used since the early '80s for melanoma. It's effective. It's also been used in renal cell carcinoma before. But it has to be administered really in an intensive care setting. Some of the side effects can be severe or life-threatening, renal failure, pulmonary edema, and some other really high risks syndromes.
So though we know it's always been effective in melanoma, the ability to deliver this to patients has really been really focused at some high volume centers with expertise in it with also some high risk. And it really has been supplanted by checkpoint inhibition in terms of its value. Now, company or a group of investigators, what they did is they sort of found a novel way of addressing this ability to expand IL-2 through the advent of a drug called bempegaldesleukin, or we can call it bempeg. It's much easier to say Bempeg. But it's the first in its class, immunostimulatory IL-2 cytokines pro-drug, which means when it's engineered, it can be given in a controlled and sustained release instead of as a high dose sort of cytokine surge. Most cytokines when given actually have an incredibly short half-life on the matter of seconds to minutes. And that's by design because if these were to stay on and turned on at a very high level, the side effects are incredibly high.
So in the formulation that they've made, it's able to deliver a similar effect to what high-dose IL-2 can do, but in a much safer, slower, controlled, and most importantly, outpatient environment. And so what they've shown so far, and they've only reached sort of phase I, phase II data, there was a trial called PIVOT-02, which was giving this drug in addition to nivolumab every three weeks. And it was really remarkable, the level of response that they were seeing, is that they were seeing a 52% response rate to treatment.
Now, this is a small sample size, and this is really feeding into a much larger phase III clinical trial, called PIVOT IO 001 that's currently enrolling. But what this would potentially do is it really keeps the treatment of melanoma in the clinic. And it really gives some therapies that we know have been effective for the last 20 or 30 years a much better toxicity profile and a much better and easier delivery mechanism. So the ability to deliver this to patients in the outpatient setting is really going to be revolutionary for what we can do.
Melanie Cole (Host): As we continue this, talking about efficacy and trials for metastatic melanoma, has the combination of nivolumab and RELA shown efficacy? Tell us through which mechanism this works.
Dr Bently Doonan: Oh, absolutely. So that's really what we've seen with all checkpoints, is that each checkpoint is likely to have some degree of individual drug-specific effect. So as a monotherapy, each of the previous checkpoints have some effect and, for a select group of patients, it's probably the only thing they need, even in the early ipi studies. There's probably about 8% to 10% of patients with melanoma that a dose of ipi or multiple doses of ipi is probably the only thing they would need to actually have their disease response. And we see that similarly in both nivolumab and pembrolizumab. We also see that with relatlimab, having some single agent benefit, especially in patients that were previously treated. But when we add it to nivolumab, we see that the combined benefit from these two therapies at the same time really outpaces the individual therapy. So it's really a situation where one plus one doesn't equal two. It's that one plus one really equals three or four.
Now, we see that similarly with the ipi-nivo combination, but the big issue there is that when we're compounding the effect, we're also really compounding the toxicity. So, if you look at the individual toxicities of a drug like nivolumab or pembrolizumab are severe side effects, really only happen in 10 to 15% of patients. And in clinical practice, it's probably even a little bit less than that. When we do ipi, we're really looking at 30% of patients, if not more, are going to get a serious one. And when we combine those two, it doesn't go, "Well, 30 plus 10 should be 40. It's 30 plus 10 really turns into 75." So it really becomes almost everyone is going to get a more significant side effect from the combination.
Now, when we do relatlimab plus nivolumab and what they've shown in some of the clinical trials is that you do get that same compounded effect in terms of improving the effect of the drug. So, if you look at the efficacy of nivolumab alone, in terms of progression-free survival in this trial that they did, you saw about four and a half months of progression-free survival with nivolumab, which similar to what we see in the community. Now, with the addition of relatlimab to nivolumab, it was significantly increased. That went up to 10 months, so more than double the actual progression-free survival effect by adding the two drugs together.
And the best thing that we see with the combination is that we're really not seeing a huge increase in the treatment-related adverse effects. And so this is the potential to then give us the benefits of doing combination immunotherapy, similar to ipi and nivo without having to take on the increased risks that ipi and nivo had in terms of side effects. So instead of going up to a side effect profile of say greater than 50% of patients having a grade 3 or 4 adverse effect with ipi-nivo, it's really more like 18% of patients. And so it's less than half the degree of toxicity that ipi-nivo carries and probably a very similar efficacy to it.
The other benefit is that since this is not a competing mechanism, is that you still allow ipi to be used in the future. I really feel, and I think probably most people in the field would say that if the rest of the survival data that's sort of being worked on in these larger trials bears fruit that shows that not only progression-free survival we're seeing, but if we're also seeing overall survival, the combination of relatlimab and nivolumab is really going to supplant the use of ipilimumab or ipi in the first-line metastatic melanoma.
Melanie Cole (Host): Along those lines then, what was the overall response percentage rates seen in the potential application of bempeg in combination with nivolumab?
Dr Bently Doonan: So looking at bempeg, the overall response rate with bempeg plus nivo was 50%. And so that 50%, it's important to say is in a much smaller cohort of people. So the nivo+RELA trial was up to, I think, 750 people that were stratified against the two arms versus this being both a signal-seeking, toxicity-seeking, and then early expansion cohort, the bempeg PIVOT-02 trial, I think was only in a matter of, say, like 50 or 60 patients.
So with that though, 34% of the patients in that trial had a complete response. Now complete response is something that we achieved for in all trials and in all therapies, because those are patients that are the most likely to remain cured. But chasing a complete response really overlooks that if you can just have stable disease or prevent progression of disease, you have an overall response rate that's really clinically meaningful to your patients.
Now, the other interesting things about the bempeg is that the duration of response in this trial has not been reached. So this is in those patients who respond, they tend to respond for a very long time. And so those that reached some degree of disease control by modified iRECIST criteria maintained that control rate for more than 30 months. And the progression-free survival in this intent to treat population was almost three years long.
That's really probably stronger and more robust than what we're seeing with some of the other combinatorial data. But if you think about it, it's because this is actually putting something into the mix that's got some cytotoxic effect against the melanoma cells, but also stimulates wider T-cell expansion. So IL-2's mechanism of action is slightly different than the mechanism of action with the relatlimab. And because of that, I would probably say that the bempeg probably does carry a slightly higher side effect profile risk than does the relatlimab.
Melanie Cole (Host): What an informative podcast this is and you're an excellent educator. Dr. Doonan, as we wrap up, discuss any ongoing research studies, research that you're doing at UF Health Shands Hospital. Any game-changers that you see? What would you like other physicians to take away from this podcast today?
Dr Bently Doonan: Absolutely. So I think as a practicing clinical oncologist, I think we're all going to see the benefit of a lot of these sort of multinational and these bigger projects and this work that we talked about in the next 12 to 24 months. And it will really be practice-changing. What I do here at UF Health Shands Hospital, as part of both a practicing physician and also as a physician scientist, is I really focus on strategies to overcome this resistance to immunotherapy and to overcome the tumor microenvironment and how it inhibits the ability to deliver immunotherapy.
And with that, I focus specifically on the most advanced and the highest risk melanoma lesions, which are melanoma brain metastasis. And so my research focus really is looking at new novel mechanisms of therapy and ways of targeting brain metastasis in patients with metastatic melanoma. And it's important because all of the trials we talked about today and all these therapies, they're going to make these patients live longer if they are going to be effective and we're going to be seeing patients with melanoma live longer and live better. And the double-edged sword to that is that whenever we have therapies that make cancer patients live longer, as long as the disease is still present, what we're really doing is also increasing the likelihood that they'll develop a distant metastasis at some point or develop brain metastasis.
Now, in some studies we're already looking at about 40% to 60% of patients with advanced melanoma, having melanoma brain metastasis at some point during the course of their treatment. And when they get those lesions, it's really tough sort of decide how we treat them. The treatment paradigm has not fully been established, but it follows the similar course of how we treat systemic disease, where we look at double agent immunotherapy to treat it.
Unfortunately, because the brain is a little bit more complicated than the rest of the body in terms of the tumor microenvironment, the therapies are less effective in the brain. So single agent immunotherapy has very poor response rate. The addition of double agent immunotherapy improves that slightly, but in these patients, the risk of relapse is really high.
So one of the first and foremost programs that I'm sort of to develop here with my research and with my clinical aspect is to really come up with trials that are directly targeted for these patients with melanoma brain metastasis. We have some drugs that we're testing in collaboration with some of our industry partners that we think are going to have a very high likelihood of success in this space and we've got some promising preclinical data and some promising preclinical work. And so I do this research at UF Health Shands Hospital as part of also our University of Florida Brain Tumor Immunotherapy Program under the guidance of Dr. Duane Mitchell. And so our goal is to really create a clinic and a landing point for patients of all types with brain metastasis, sort of starting with patients with melanoma brain metastasis, where we're going to have the science, the scientists, the preclinical acumen, and then the ability to deliver our therapy to patients with advanced disease. And so that's something that we're really, really excited about here at the University of Florida Health Shands Hospital and what we're going to have in the future.
Melanie Cole (Host): Dr Doonan, that was outstanding. Thank you so much for joining us today and telling us about all the exciting emerging therapies for metastatic melanoma and the game-changers. I hope that you'll join us again and fill us in as things progress. And thank you again for being with us today.
To refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.