Hi, everybody.
I am Dr Allison Betoff Warner.
I am the director of the Advanced Melanoma Program at Stanford Cancer Institute, and I’m thrilled to be joined by two colleagues today to talk about advancements in PD-1 refractory melanoma.
So I’ll turn it first to Dr Mehmi to introduce himself.
Good morning, everybody.
I’m Inderjit Mehmi at the Angeles Clinic with Cedars. I’m a medical oncologist interested primarily in melanoma care of all stages. Happy to be here to talk about some of these important topics.
Hi, and I’m Omid Hamid. I’m the chief of research and immuno-oncology here at the Angeles Clinic and Research Institute, a Cedars-Sinai affiliate in Los Angeles.
My interests are in drug development, particularly in the immunotherapeutic field.
Great. I think the main focus of our discussion today is going to be on resistance to PD-1-based therapy. There have been lots of ways to think about this and define it. More recently, we have seen formal Society for Immunotherapy of Cancer (SITC) definitions for how to define PD-1 resistance. Dr Hamid, if you can just start us off by discussing briefly how we think about formal definitions of PD-1 resistance, and then we can get into some of the primary and secondary definitions.
This is a great place to start because when we’re going to develop drugs, we all need to have the same language and contribute to the conversation on the same footing. The SITC has sent out a consensus guideline, which most of us agree to. Primary resistance to immune checkpoint inhibitors is defined as a minimum of two cycles of drug exposure, with the best response being either progressive disease or stable disease lasting less than six months. These have to be confirmed, meaning you have one assessment that must be confirmed at least four weeks after progressive disease.
Why is that? Because when we get into single-agent checkpoint inhibitors or combinations, there is this idea that, as was brought forth initially and published by Jed Wolchok, Steve O’Day, Steve Hodi, myself, and others, about the kinetics of response. You can initially see what is deemed as progression, but then the immune system kicks in, and after two to three months, you can see a response. So four to six weeks after a confirmatory scan, that’s become a standard in the multitude of clinical trials that we have.
As we’ve moved forward, we’ve understood that primary resistance is where checkpoint inhibitors are not a viable second-line or further option, or may not be. We’ve now developed further therapeutics there.
Great. That was super helpful. I think making sure, as you said, that we’re all speaking the same language and thinking about this as we select treatments for our patients. And then also thinking about how we use these guidelines to define populations for clinical trials to ensure we’re all starting from the same baseline.
To talk next about what we do when our patients are PD-1 refractory, with PD-1 refractory melanoma, most patients now in the frontline, if newly diagnosed metastatic melanoma, are getting combinations of PD-1 plus something. But many of our patients will start with adjuvant or neoadjuvant therapy, receiving single-agent PD-1. Doctor Mehmi, could you start us off by talking briefly about how to approach these patients with single-agent PD-1 and refractory melanoma? Where do we go from there, and what are the options with combinations of checkpoint blockade strategies?
Thank you, Allison. Treating these patients is becoming more challenging. When looking at the current set of patients, as you said, they’ve been exposed to single-agent PD-1 in adjuvant or neoadjuvant settings. Sometimes, in neoadjuvant settings, most of these patients are getting combination therapy. Adena studies show everyone is transitioning to two doses of ipilimumab, trying to get the deepest pathological complete responses (pCR) and eliminate the adjuvant portion.
This creates a group of patients who, when they don’t respond, are very challenging. You hope some are BRAF-mutated—40 to 45% are—which makes it easier to salvage with targeted therapy for a short term. The remaining patients are very challenging. For single-agent PD-1 refractory cases, ipilimumab and nivolumab combinations, supported by the SWOG study led by Avandi, show around 30% response with some durability. It’s a reasonable option.
For PD-1 refractory patients, LAG-3 combinations seem less effective. Trials by Regeneron and BMS show about 10–12% response rates with little durability. So PD-1/LAG-3 combinations might be considered when nothing else is left. Tumor-infiltrating lymphocytes (TIL) therapy may be more relevant, which we can discuss later.
Certainly, the topic of 2024 was TILs in melanoma. But I want to flesh out details around combination checkpoint strategies. The SWOG 1616 study from Ari Vanderbilt and others, and smaller studies by Dan Olson and others, showed about 25% response rates with ipilimumab plus pembrolizumab. While not high, these patients may achieve durable responses.
For refractory patients, toxicity risks of combination strategies, especially ipilimumab and nivolumab, are worth taking. These strategies have been around for a decade, and we are adept at managing checkpoint toxicity. We weigh risks differently for refractory patients compared to newly diagnosed ones.
Novel LAG-3 agents with different dosing strategies may show promise, but current options aren’t sufficient as second-line therapies.
Overall, salvage therapy depth and benefit may be realized with aggressive checkpoint inhibitor combinations. We need to focus on novel therapeutics and design strategies for primary refractory patients. Novel approaches must spur drug design and therapy improvements.
Finally, TIL therapy, FDA-approved in 2024, deserves its place in our next discussion.
This is not a new strategy, right?
This was pioneered in the late 1980s by Dr Rosenberg at the National Cancer Institute.
But over the last five years or so, we’ve seen real ability to centrally manufacture, ship these products, and develop this as a real commercial product that now has proven efficacy for PD-1 refractory melanoma. You know, so we saw the publication of the C1 44 01 trial, which is the registration trial that led to the accelerated approval of lifeluo or Antagthe. And you know, just to sort of highlight the process, right, this is a different approach. It’s still an immunotherapy approach. But the idea is that for many patients, we will be able to activate T-cells with checkpoint blockade, but it’s not the right cells, right? Patients get all the toxicity sometimes and none of the efficacy. And one of the main reasons that may happen is that the cells we activate aren’t recognizing the tumor or making it into the tumor for many different reasons. So TILs come at this a different way and essentially says, if I take out a piece of a patient’s tumor, I am able to find T-cells that have the ability to treat and kill tumors within that patient’s tumor. And so let’s go after those tumor-specific T-cells, take those out of a patient via surgery, expand them into many, many billions of cells. And then we give the patient a brief period of lymphodepleting chemotherapy that gets rid of the competition. As I always tell my patients, we’re trying to stack the deck to favor these TIL lymphocytes, infuse the cells.
And then the patients do get up to six doses of high-dose IL-2 to try to further stimulate those TILs once they are back within the patient.
And as we all know, this has about a 30% response rate, 31% in PD-1 refractory melanoma.
But we saw a second study from the Netherlands Cancer Institute, the M14 TIL trial, with a very, very similar approach. Cells were made on site and not frozen, but otherwise, the process looks nearly identical. And that had up to a 49% response rate, with 20% of patients having complete responses. And nearly all of those patients were also PD-1 refractory. So one of the key differences here was getting patients truly in the second line from that Netherlands Cancer Institute study. And I think one of the things that we really need to be thinking about as a field, exactly as you were mentioning, is not putting patients through, OK, let’s go through this line, then let’s try this line, then let’s try this line, and waiting to get to TILs until they’re either too sick or their tumors and their T-cells are really beat up and aren’t going to work anymore. And so, you know, we’ve really had a strategy here at Stanford of, you know, patients get combination checkpoint blockade in the front line, and as soon as we have evidence that they are PD-1 refractory, we are taking them to TIL therapy. And I think, you know, with the FDA approval in 2024, this really becomes one of our first thoughts for fit patients who are young, you know, physiologically young, good performance status, good organ function, and who can and are willing to go through this therapy. I think this needs to be one of our first thoughts.
And it’s just the whole idea of this is not just the patient benefit, it’s that we have had decades of understanding about early TIL being better. We know that in any type of T-cell therapy, less exposure to therapy gives you more vibrant cells. We all believe that TILs have a benefit over CAR-T in that it’s multi-antigen specific and tumor-specific tumor antigen-specific, but even greater than that is, if we do not support the growth in this field, we can’t move on to things that will make TILs easier for us.
What is that? Not needing a surgeon, just doing biopsies, decreasing the amount of lymphodepletion. So that decreases the toxicity, that cost, the hospitalization. And we’re moving on to finding different ways of finding those T-cells, whether it’s, you know, bracing for them or going out of the circulation in different ways, obviating surgery. And that’s a very early part of what we’re doing.
But also, the TIL approval has led to the belief that we don’t need to 100% invest in just checkpoint, that we have other areas we need to be looking at.
TILs have opened the idea of NK cell development in our field, TILs have opened the idea of something that has been around but has always been put on the back burner, microenvironment macrophage therapeutics, et cetera. So there’s a lot going on here, and a lot of benefit that you yourself and our patients are getting.
Yeah, and I would just add also, you know, this idea of engineered T-cells and not necessarily just CARs, right? But, you know, we certainly are seeing engineered TILs now in clinical trials that potentially eliminate the need to give the cytokine, which is the hardest part for many of our patients. And that makes this potentially more accessible to patients who have cardiovascular disease or pulmonary disease where we worry that, you know, the IL-2 might be really tough. But also, we’ve seen beautiful data, and this moves us into some of the experimental approaches that are coming in active clinical trials. But we’ve seen beautiful early data for an engineered TCR-T cell that targets brain. That’s the I A 203 or I MA 203, and PRAME is a target that is expressed greater than 90% in nearly all melanomas, cutaneous, non-cutaneous, uveal, et cetera. So it’s a really good target.
You know, we’ve seen data now for this engineered TCR-T cell for both really impressive response rates from a very early study, but, you know, response rates confirmed upwards of 50% and durability of those responses. And that registration trial is now open and ongoing. And so I think, to your point, this opens up a whole new world of T-cell therapy cells beyond T-cells.
And as you mentioned, other strategies as well. And so, one of the things that we’ve also seen have some really nice data this year was oncolytic viruses as an approach. And so, Doctor Man, I don’t know if you want to talk briefly about some of the oncolytic virus data and where we’re going with that, right? So, you know, we’ve known about oncolytic viruses since TV days and even earlier, and there’s been a number of other studies with a virus, with pox virus and vaccinia viruses that, you know, kind of moved the field a little bit up.
Unfortunately, with T-VAC, when it was combined with checkpoint inhibition, the Mask study didn’t really show a full advantage over pembrolizumab.
But I think the exciting data that’s coming from Replimune’s RP1, you know, first as a single agent showing responses in the injected lesion and beyond.And now they’re going to a phase three study, that’s a registration study that’s open and accruing at multiple sites, looking at RP1 with PD-1 and comparing it to a number of different options that are possible.I think that data, early data, looks very good, response rates are high.
I believe in the 40% or even more, and mid-thirties, and there is a durability, and I think a lot of the times, when we discuss these options with intralesional therapies, our mindset is, is it just effective for that injected lesion?
But RP1 data shows that that’s not true. Actually, you can have responses, and they’ve shown it, that responses are possible in noninjected lesions as well.
So I think that is a really good option that’s going to be coming up and hopefully it stands the test of phase three study.
Because in the past, when we had these inter-regional therapies, they’ve fallen flat.
And some of these were the TLR9 or TLR7/8 agonists, and they haven’t really done well in combination.
So my hope is that this is better, because at the end of the day, when we’re looking at tumor infiltrating lymphocytes, regardless they are native or engineered, they do have lymphodepletion as a component of it, and sometimes that eliminates a certain group of patients.
So, and I feel like that having additional options, let it be inter-regional or additional checkpoint inhibition, we’ll be able to capture a more patient population that are primary refractory.
I think even when we were talking about TILs and I think a lot of the time, the referring oncologists that I talk to, you know, their concerns are, hey, my patients aren’t that young, a lot of comorbidities, you know, are they going to be good for TIL or not?
And I think those are the patients that we need to consider for these RP and inter- or NKL therapies or, you know, additional checkpoint. For example, you know, from GP20.
I think those are some good options that are coming up, and I’m excited about that.
Yeah, I think we’re all excited to see, you know, the RP1 study and now, you know, the registration of phase three, which is the Ignite 3 study, which is a randomized trial for PD-1 refractory melanoma using RP1 plus nivolumab, and I think we’re all excited to see that.
But important to note that that has gotten breakthrough designation by the FDA and potentially, you know, biologic license application now submitted for potential approval, accelerated approval in 2025.
And so I do think that this becomes a strategy that absolutely we should be thinking about for our patients.
And you know, what you mentioned of course, is you know that there are the right treatment for the right patient, right?
Some patients, TILs may be the right treatment, some patients, you know, an inter-lesion may be the right treatment, some patients, it may be, you know, this brain TCR or another approach.
And I think it is important that we recognize that one strategy isn’t going to be the end-all-be-all as a second-line strategy for every patient.
But also, as Dr Jedd has pointed out in many meetings over the last year that he and I have been in together, we should also be thinking about how to potentially combine some of these approaches to maximize them, right?
You know, amazing point.
Amazing point.
Yeah. When you look at even the Replimune’s drug RP1, the point should be made that in predecessors, there was a huge delay in getting into visceral injection, and they’ve come in early.
The good thing is, it may not just be one drug, but this Rep immune alkalic capsule as it were, is now going to carry more and is looking at other solid tumors including ocular melanoma. Let’s not forget that the results seen in ocular melanoma with repetitive injection into viscera, which others haven’t done, have shown injectable lesions regressing and also visceral lesions in the liver regressing.
Why is that important?
Because we found that patients who have liver mets do worse?
That’s an area of resistance.
And why also is this important?
Because oncolytic were initially devices for other solid tumors, not melanoma.
So this can go into all of the 40 indications for PD-1 that we have.
But in the midst of that, and the hopeful success of this drug, is that there’s also an RP3 and that carries not one, not two, but three constructs allowing us to go directly into tumors, allowing us to have less toxicity and allowing us to then build backbones.
And I think for early disease or to overcome these resistance mechanisms.
Yeah, I mean, I think this is an exciting time, you know, just to think about how these therapies can evolve, how they can be used in combination, and how we can find new approaches to bring more patients into that fold of benefiting from immune therapies.
Absolutely.
