Transforming Melanoma Care with Neoadjuvant Immunotherapy

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today I'm happy to be joined by Dr. Joseph Skitzki, Director of Melanoma and Cutaneous Oncology Surgery here at Cleveland Clinic. He's here today to talk about neoadjuvant therapy for treatment of melanoma. So welcome.

Joseph Skitzki, MD: Thank you.

Dale Shepard, MD, PhD: Give us a little bit of idea of what you do here at Cleveland Clinic.

Joseph Skitzki, MD: So I am one of the surgeons who deals with cutaneous malignancies, mostly melanoma but also non-melanoma cutaneous malignancies. Typically, I'll see patients after they're seen by their dermatologist where they'll have a biopsy, and if it's something that requires further surgery, I'll be seeing them. Particular for melanoma, if it spreads to lymph nodes or other parts of the body, then I'm usually the surgeon who will see them. And so it's been great to be here and there's been a lot of advancements in melanoma, so I'm excited about the era that we're living in.

Dale Shepard, MD, PhD: Perfect. Now before we talk about the era we're living in, maybe we take a step back and say, well, how have we historically surgically treated melanoma?

Joseph Skitzki, MD: Yeah, so I've been in the melanoma business for about 20 years, and so literally about 15 years ago, surgery was the end all answer for all stages of melanoma. If you had an early melanoma, it was easy enough to remove it. It was curative for the most part. As melanomas became more aggressive and if they spread to the lymph nodes, we would still do surgery, but again, the outcomes were not as great. And so when it spreads to other parts of the body, the survival can drop off significantly.

And to give you an example, about 15 years ago, if I would've seen a patient that their melanoma either spread to their lymph node or came back in their lymph nodes, we couldn't do a surgery. It's a pretty big surgery, removing all the lymph nodes in that area. And those patients, we didn't really have good additional treatment. We had chemotherapy, but it really didn't work. The last chemotherapy that was approved for melanoma was in 1976. It was dacarbazine. And so really didn't work very well, and we didn't have any adjuvants or treatments after surgery that were effective.

We used to use things like interferon, but really not very effective and pretty toxic. And so we would take a patient if they had lymph node disease, remove all the lymph nodes in that area and potentially give them radiation to the area. It was pretty morbid. The surgery and the radiation could really increase the risk of lymphedema or swelling of their extremity, and the outcomes were not great. About 25% of those patients, the disease would not come back or cause a problem. But about 75% of the time, the disease came back and melanoma was the cause of their mortality usually within five years.

And so that was horrible. 25% of patients can survive just with surgery alone and some of the extra things that we would add in. But that all changed. 2011, 2012, we had the introduction of small molecule inhibitors and immunotherapy. And so immunotherapy has been a game-changer. It's basically blocking antibodies that allow your immune system to go wild. And so it has very little side effects, was shown to be very effective for melanoma when it's metastatic or spread to other parts of the body.

And we were actually able to start using that in clinical trials as a preventative measure. So if somebody presented, say in 2016 or so and they had lymph nodes that had to be removed, we would remove them and then they would get adjuvant immunotherapy. And adjuvant immunotherapy reduced the chance of the melanoma coming back down to about 50%, so 75 to 50%. So 50% of patients were alive and were doing well at five years.

Now in the last four or five years, we know that the immunotherapy works incredibly well. It works well for metastatic melanoma, works well as an adjuvant and basically using the same medications, we can give it maybe a dose or two before the lymph nodes are all removed. And those patients can do phenomenally well. Two-thirds of those patients can have what we call a major pathologic response where there's less than 10% of viable tumor. So the immunotherapy by itself, your own immune system took care of 90% of that tumor.

Two-thirds of patients have a major pathologic response, so the majority of patients respond to it. It's not very toxic either. And when we take those patients to surgery, sometimes the surgery can be even less. We don't necessarily need to remove all the lymph nodes, maybe just the one or two involved lymph nodes. So surgeries become less morbid and the patients do extremely well. Two-thirds have a major path response, and if you have a major path response, 95% survival rate at five years.

Dale Shepard, MD, PhD: Impressive.

Joseph Skitzki, MD: Yeah. So the data is very, very impressive. So we went from 15 years ago, 25% survival rate, roughly, all comers to 50% using it as a after surgery add-on to about a good 75 to anywhere to 95% survival rate. So it's very, very different. Surgery used to be the be-all for melanoma, but now with immunotherapy, it's been a game-changer.

Dale Shepard, MD, PhD: And so you mentioned maybe less extensive surgery for lymph nodes. What about the primary tumor itself? Is that something where even if you get a response, you still kind of have the same pre-treatment surgical margins for safety, or has that been minimized as well?

Joseph Skitzki, MD: So that's a good question. Right now we're using the immunotherapy in a neoadjuvant setting. In other words, using it before you have surgery. It's usually used for nodal disease, so when the melanoma presents in the lymph node or has recurred in a lymph node. For the primary sites, we still haven't been too aggressive with using neoadjuvant immunotherapy because surgery by itself for the primary is curative. It's high, high chance for cure rate.

There are some clinical trials looking at it in terms of stage 2B and 2C, thick melanomas that have other concerning features of using immunotherapy to see if you can affect long-term outcomes. The interesting thing about the immunotherapy, not only for the primary or the nodal disease, is that when you remove the nodes or the primary site, the pathologist can look at that and actually tell if there's been a good response or not. So it actually tells you if your treatment's working and it tells you if it's worthwhile to continue.

Dale Shepard, MD, PhD: If you think about, immunotherapy, of course has a good track record here. How about our targeted therapies like BRAF F therapies and things like that?

Joseph Skitzki, MD: Yeah, so BRAF MEK inhibitors are impressive, but I think the data's coming out, and it's taken some time, but it's showing that immunotherapy, usually immunotherapy up front is going to be superior in terms of the chance for cure, chance for long-term survival. The use of BRAF MEK inhibitors as a neoadjuvant or as an adjuvant, they are still used. The excitement as a neoadjuvant really is in the immunotherapy side.

Sometimes patients will present in kind of a dire situation where their disease is extensive and you can use BRAF MEK inhibitors to kind of knock down the disease fairly quickly. But the duration of the responses are not long-lived like they are with immunotherapy. And so most of the clinical trials for neoadjuvant have been with immunotherapy.

Dale Shepard, MD, PhD: Yeah. You talked about certainly this being an approach for nodal disease. Are there other factors that play into deciding which patients might benefit from neoadjuvant therapy? Is it things like biomarkers or anything else that might be in play here?

Joseph Skitzki, MD: Yeah. So for melanoma, we actually don't have any great biomarkers. For lung cancer, they'll measure PL-1, which is one of the targets for the immune system to kind of say if you block that interaction, that you may have a better outcome. We actually don't do that for melanoma. We treat all comers because the response rates are pretty high. More than half the people will respond to immunotherapy. And so with immunotherapy, patients will get treatment.

Dale Shepard, MD, PhD: So I guess the question is from a, are there factors that go into patient selection for neoadjuvant therapy?

Joseph Skitzki, MD: That's a good question because sometimes these immunotherapies, they're very well tolerated, but if you're older, you may have frailty, other comorbidities, cardiac, lung comorbidities, and if you have a low likelihood for a reaction, but if you had a reaction, it could be life altering. And so those are some considerations. When we start talking about combination of immunotherapies, they could have more toxicity so that that's something that you want to be aware of.

That's really the only true contraindication to a neoadjuvant approach. Or if you had other, say, autoimmune issues or areas. For example, if you had a patient that had a solid organ transplant, you may not be interested in using immunotherapy to stimulate an immune response because you can reject your transplanted organ, and that can be very serious. If it's a kidney, patients can go on dialysis, but if it's a lung or the heart, you can't. You have to be judicious with it.

Dale Shepard, MD, PhD: Sure. What do we know at this point about duration of neoadjuvant therapy? It's great response rates. They can be durable, so how do you balance, I've already kind of treated this disease really, really well and then still add in surgery? So what's that interplay in terms of balance?

Joseph Skitzki, MD: Yeah, so right now, typically it was almost like a frame shift. So patients would get a year-long worth of treatment for adjuvant treatment. So they would have their surgery, get one year's worth of adjuvant immunotherapy. It was kind of a frame shift where they just moved it up like two doses or maybe three doses before surgery, and then you have your surgery, then you completed the rest of your immunotherapy. With combination immunotherapy, and that's using something that targets PD-1 and also CTLA-4, those are two of what we call checkpoint inhibitors.

You can use combination medications to target both of those. And there was a very nice, very large study from Europe showing that if you use combination immunotherapy, you can just get away with giving two doses and then base your further treatment on the path response. So if the patient has a major pathologic response, they may not need any other treatment, they may not need any further immunotherapy, they may not need anything else, and they would do very well.

Dale Shepard, MD, PhD: So maybe de-intensify therapy as a result?

Joseph Skitzki, MD: Yes, it's de-intensified and it's definitely for surgery, deescalated. I would say the majority of surgeries I used to do 15 years ago, we just don't have to do anymore for melanoma, which is a great thing. And all those side effects I talked about with lymphedema, other issues with going through a big surgery and recovery, patients can avoid those.

Dale Shepard, MD, PhD: And then even the treatment itself, less likely to get pneumonitis or things like that from the treatment.

Joseph Skitzki, MD: Much less likely.

Dale Shepard, MD, PhD: Yeah?

Joseph Skitzki, MD: Yeah.

Dale Shepard, MD, PhD: Interesting. This is something certainly that seems like it's practice-changing. Is it practice-changing? So sometimes these things happen and is this happening in a community settings? In the sarcoma world, I see way too often where somebody just kind of goes in and takes out something before they should. Is melanoma kind of a similar landscape or are people really adopting the neoadjuvant approach?

Joseph Skitzki, MD: So that's a great question because in the sarcoma world, yeah, we have actually pathways for the "oops" surgeries. And so same thing in melanoma. If somebody presents with a history of melanoma and they have an enlarged lymph node, the teaching really should be, and we've kind of put this out there, the word is out in the last few years that general surgeons in the community really shouldn't remove that lymph node. They can biopsy it to confirm what it is, and confirming it's melanoma gives that patient more opportunities for a neoadjuvant approach.

If they remove that lymph node, then we're kind of playing catch up. We're kind of saying, "Okay, now they're eligible for adjuvant immunotherapy, which we know doesn't have as good a response." And so really, it is practice changing. And in terms of neoadjuvant approaches, it is something that's done probably at the larger centers. It can be done in coordination with community centers. But I would say that stretching out the idea of using neoadjuvant more than just for a cutaneous malignancy, for example, melanomas can appear on the hands and feet. It's called acral lentiginous melanoma. We can use neoadjuvant approaches for that, which should be similar in terms of their response rates.

Mucosal melanomas, so anal mucosal melanoma, vaginal, vulvar, neoadjuvant approaches can be done. And so it is kind of done at specialty centers and really the main thing is making sure that everyone knows that you don't have to remove all the disease all at once, that you actually, if you get a biopsy and a diagnosis and send them on to a place like the Cleveland Clinic, then you can offer neoadjuvant approaches that would not be possible if the disease was completely removed.

Dale Shepard, MD, PhD: This concept of decreasing treatment, while on the one hand is really attractive, how do patients sort of process that sometimes? Because particularly immunotherapies. In my world, they love them. Even though they don't really work so well with sarcoma, they always want to try them. And now for telling them, "Look, maybe you don't need treatment for so long." Are they comfortable with that?

Joseph Skitzki, MD: Yeah, so most melanoma patients are very comfortable with that. As an individual patient, you don't know the history of what others had to go through, but it was significant. But I would say that most patients are accepting of the fact, especially when we have a pathology review of the response rate and how the response actually went. That's kind of reassuring to the patient too. If they've had a complete pathologic response, in other words, the immunotherapy worked and there's no viable melanoma cells, that's pretty reassuring. And a lot of patients are happy not to continue with an additional year or basically unlimited treatment for the rest of their lives. So I think patients are pretty happy with it.

Dale Shepard, MD, PhD: What about other new approaches? So certainly we're coming up with other ways to use the immune system to treat cancers. We talked about checkpoint inhibitors being very, very effective. Some of these other things like oncolytic viruses and all these other types of immunotherapies. How might those change what we're doing?

Joseph Skitzki, MD: So surgery is getting relegated to less and less. Even for early melanomas, there's clinical trials looking at some injectables. So if you have a tumor, we have some pretty good oncolytic viruses that you can inject into the melanoma tumor. One of them is called TVEC. Basically it's a herpes virus that expresses some growth factors for the immune system. It can be very effective in the lesions that are injected and in combination with immunotherapy, you can spread the response to other parts of the body.

There are people that are looking at injectables for earlier stage melanomas. So before it spreads to the lymph nodes, injecting the tumor and then removing it to see if there's a good response, if there's anything left behind. It may get to the point where you have an injectable that works so well that you may not need to have surgery in the first place to remove that melanoma.

For now, the safe thing is to do it on clinical trial, but eventually these immunotherapies are going to shift earlier and earlier. Right now, some of the anti-PD-1 and CTLA-4 probably have, they have very low side effects profile. The risk of a side effect is really maybe 16% of patients or so, depending on what agent you get. If it's in combination, it could be a little bit higher. So then it becomes a discussion about how early you want to treat the disease and it becomes a risk/benefit analysis. Is it easier just to treat with surgery versus giving these immunotherapies, which could have some toxicity.

Dale Shepard, MD, PhD: So wide range of people might be listening in, different backgrounds, may see more or less melanoma. Are there particular patient characteristics that really, there's value to coming to an academic center and getting kind of that multidisciplinary look?

Joseph Skitzki, MD: Yeah, I would say any patient that is immunosuppressed, and so kind of mentioned previously about solid organ transplant patients, I mean, they're going to be incredibly high risk. The immune system and melanoma, very closely tied together. The stronger your immune system, the better you're going to do. The weaker your immune system, the more aggressive the melanoma can behave. And so anyone who has a solid organ transplant, kidney, lung, heart, liver, they should be seen.

The other group, I would say that it goes under, it's not really noticed much, but you'll see commercials all the time for immunosuppressive agents for a variety of things. So for psoriasis, psoriatic arthritis, for rheumatoid arthritis, for eczema, for a lot of things. And so there's a lot of people that are on immunosuppression and they look pretty happy.

Dale Shepard, MD, PhD: They do.

Joseph Skitzki, MD: All those commercials are very happy, but they don't show what happens to those patients after five years of taking those medications. They're very high risk for cutaneous malignancies. And if you're on one of those medications and you develop like a melanoma, yeah, those can behave very aggressively, and so those types of patients should be referred.

Sometimes there's options in terms of switching the medications they're on. A lot of patients have IBD, Crohn's, ulcerative colitis. There's all these medications out there, and so it's a huge population of immunosuppressed patients that I think we're going to see more and more of. And so those are patients I would say that really should be referred.

Dale Shepard, MD, PhD: Yeah. We've made great progress. You mentioned 25%, 50%, 95%. Are there trials that you're particularly interested in the outcomes? What's going to be the next big step, the next plateau, if you will?

Joseph Skitzki, MD: Yeah, that's a tough one because people have been looking at checkpoint inhibitors, other targets, and so LAG-3 is another one. There's some others that are out there, like TIM-3, TIGITs and you'll hear about some others in clinical trial. Really PD-1, CTLA-4 seems to be the home run. LAG-3 as an add-on is now FDA approved. We are at the Cleveland Clinic doing some neoadjuvant clinical trials with combination with LAG-3. I would say the combinations are what's interesting.

I would say the injectables are also evolving. There's a new injectable that should be out hopefully soon. It's called RP-1. It seems to be a little bit better than the previous incarnation of a herpes virus, TVEC, but we're still waiting on that. I would say that there's other injectables looking at TLR agonists. There's anything to stimulate an immune response. And so the next big thing is hard to tell.

In melanoma, we used to shoot for the best T-cell, and so that was like how you operate and how you make T-cells more reactive. And we used to focus on cytokines and giving patients high doses of IL2 and interferon and other things. It really was the second signal or the checkpoint inhibitors that were the big thing. So it is hard to tell what the next big thing will be, but I'm guessing it's going to be in combination, and anything that can really kind of fine-tune and stimulate the immune response.

Dale Shepard, MD, PhD: Excellent. Well, tremendous progress. Great insights. Appreciate you being with us today.

Joseph Skitzki, MD: Thank you. Thank you very much.

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