 What is the difference between adjuvant and neoadjuvant therapies?

 Sure, it all has to do with when we give therapy and the point in time when we get therapy. So, when we talk about neoadjuvant therapy, that's where we're giving some sort of systemic therapy, or radiation before we actually are doing surgery. So it's become a really exciting area in the world of melanoma.

The consideration of neoadjuvant therapy, it wasn't something that we really ever did before, until the last, I would say, three to five years. And there's a lot of clinical trials that are ongoing looking at neoadjuvant therapy. And I'll kind of talk about a situation where I think it would be relevant. So a lot of times patients will come into our office for initial evaluation with melanoma, and they may have lymph nodes that we can feel that feel enlarged, they may have a larger melanoma, a primary melanoma in a place that we can feel or see. A lot of times, patients come in with a melanoma, and it's been biopsied, and we don't see anything except the scar.

But there is the subset of patients that come in that we would have somewhat advanced disease, and we may get a scan or a PET scan that doesn't show any evidence (the disease has) spread outside of a regional location like lymph nodes or the primary site of the melanoma. But when I see these patients, I think to myself, I'm concerned because in my head, they're high risk of having the melanoma come back. And in my mind, these are the first set of patients that I think are ideal for a consideration for a new approach, where before we jump to operating, we treat them with either immunotherapy initially, or if we test their specific genes in their tumor, specifically a BRAF mutation, we can give a BRAF/MEK inhibitors for a short period of time before surgery, in hopes of watching the tumor and shrinking it. And not only shrinking it, but potentially shrinking if there are cells that are around (the tumor) that we don't know about and our technology can't identify them.

And then we go to surgery to remove everything that we can see. And the reason why there's a lot of excitement about this is because in some of the earlier clinical trials that have been done, or where we've used this in select situations, we've seen really good responses. So, the tumors shrink, the lymph nodes shrink, or if it doesn't, it gives us a real time assessment that these medicines that we're using aren't working, and we should try the other ones if we can. And so there's a lot of excitement about a neoadjuvant approach.

And the second part of your question, adjuvant therapy, so that means after we do surgery. So, in patients who have the current standards or someone who has resection and either have their lymph nodes removed for palpable disease where they have enlarged or macroscopic lymph nodes, or if they underwent a resection and had a sentinel node biopsy that was positive. So melanoma cells had spread from the primary site to lymph nodes, then that's stage 3 disease and there's different levels of stage 3, but those patients would be if there's no evidence of spread elsewhere or metastatic disease would be candidates for adjuvant therapy. And really, we're using the same types of drugs, immunotherapy, which these medicines that use your immune system to fight cancer, or targeted therapy if you have a specific BRAF mutation to decrease the chance of the melanoma coming back.

And it was really exciting when these clinical trials first started. We really had no agents that really had any markable effect on melanoma, there was a couple that had a lot of toxicity. But it became really exciting when these medications came to the forefront and they were started in the metastatic setting and then there was clinical trials for stage 3 melanoma that showed improved survivals for both of these agents depending on the BRAF status, that if we give it for about a year after the surgery (there is) a decreased chance of melanoma coming back.

 Can you discuss what treatment sequencing is and how these play a role in doctors determining that treatment sequence?

 It's really important to be seen by a team that specializes in melanoma. So we need, in our tumor board, on a weekly basis to discuss complicated cases like that. So we can have multiple experts from multiple disciplines discussing the case and coming up with multidisciplinary treatment plan personalized for that patient. And I think that's really important.

The sequencing, it really just depends sometimes we plan on resecting first and doing surgery first. And then we give adjuvant therapy. We currently have two neoadjuvant (therapy) trials now that are open at Fox Chase (Cancer Center). And it's still a clinical trial because we're still investigating this strategy.

We don't know definitive information that this is a better strategy. But we're gathering data and information from these clinical trials for the neoadjuvant strategy for treating melanoma. And I suspect in the future, and it's completely biased, but I think that this will be how we think and treat more patients with this approach. Because as I went back to this team, and when we had nothing, now we have these medications that are really amazing. We're seeing amazing responses. And so, if we can give a short course that improves outcomes, that's our goal, we want more patients to respond. And we want less patients to have their melanoma come back and we want patients to live longer and be cured of melanoma. And for advanced melanoma, we never said that before: curing melanoma. But it is a term that more commonly and thankfully we're using.

 Is there a particular patient population in the melanoma space that is in need of clinical trials to evaluate neoadjuvant and adjuvant therapy?

 Yeah, that's a great question. So for the neoadjuvant approach, I think there's definitely these more advanced patients that present that don't have metastatic disease that I think are the ideal kind of patients that we consider. So as I said, I think the palpable nodes or a really bulky primary melanoma that someone that we could consider for the adjuvant (therapy). Currently, it's only for stage 3 melanoma. That being said, we know that there are stage 2 melanoma patients, and we break down the staging system to A, B or C, but to see specifically, we know is a high risk population, we know that the risk of melanoma coming back is very high of recurrence or having metastatic disease in some period of time. And so I think, ideally, we are going to see, and there's a couple of clinical trials out there looking at giving adjuvant therapy for stage 3 melanoma or even going to be, we're not doing that yet. But there is the potential of doing that in the future.

 Why is it important for these patients to consider joining a clinical trial?

 A clinical trial helps us to answer questions in a systematic fashion. So you could say, well, give me those medicines, you're telling me they're so good, just give them to me, even if I have a stage 2 melanoma, why not get them? Well, the problem is that there are side effects there. And some of these side effects can be long standing, and we do a great job of controlling the side effects or correcting them. But some of them can be long standing side effects that … some patients may have to be on steroids for the rest of their life. So they're not completely, you know, without risks, these medications. And so it's always a risk-benefit profile, everything we do in medicine. So we want to make sure we're even if we're taking risk of side effects, that we're maximizing response rate or improving survival. But as you start kind of moving down to earlier, melanoma, well, then it may be that those patients aren't going to recur. So we have to kind of figure that out. And that's what clinical trials allow us to do, in really a rigorous fashion, to answer questions to make sure that we're really determining the best course of action for patients. Before we just say, oh, we're going to willy nilly give these medications to someone that could have long standing risks to them throughout their life.

 What do you think that we have to look forward to with adjuvant and neoadjuvant therapy in patients with melanoma?

 So number one, I do think in the next few years, we'll start using neoadjuvant therapy outside of clinical trials, I think that the data will mature. And that we’ll start to utilize that outside of just clinical trials where it could be utilized in other practices, not just in the clinical trial environment. So I think that's a step forward. And so where patients instead of just jumping to surgery, where I love to operate, but I want to operate when I know it's helping someone, and where so sometimes where tumors shrink, we can potentially do less extensive surgery, so that means less risk of the operation potentially. And we also know that the medicines are working. So I think that's one thing in the short term that I suspect we will see more of in the next few years.

In the adjuvant setting, I'm really looking forward to these two kind of pathways that we have now are phenomenal but we always need to do better. We're looking at ways to decrease toxicity and increase response rate and increase cure rates. So there's many medications that are in the pipeline or combination therapies that will we'll be using. And also when I talked about the BRAF mutation that's very exciting, but they're melanomas. When we look at mutational status in patients with advanced melanoma, there is a lot of different mutations we identify. And the the key is going to be finding other targets that either, like the BRAF inhibitors if there's other inhibitors that we can identify. And this is why basic science and research are so important, to identify these new medications, that instead of just having four lines of therapy that we can consider for patients, because you know, only a small subset of patients have a BRAF mutation and are eligible for some of these drugs. But there's other mutations that we're seeing that are coming that we’ll have inhibitors for that will be exciting that we can also use in both the adjuvantand or potentially neoadjuvant.

I think all of these, it starts in the metastatic setting and then adjuvant and then we move into the neoadjuvant approach. And the neoadjuvant approach is not new. So I treat other cancers besides melanoma, but there's a big push and change in how we think about cancer and using this new address and approach for a lot of types of cancers (stomach cancer, pancreas, rectal cancer), where we treat first and has shown in a lot of different series to decrease the rates of it coming back locally, and or even metastatic disease. So this is not a new concept just for melanoma, but we are using it in different types of cancers and all different types of cancers really.

Adjuvant and Neoadjuvant Therapy in Melanoma

 Can you discuss where the unmet need is for treating patients whose melanoma has stopped responding to immunotherapy treatment, in particular with anti-PD-1 or anti CTK4/6 inhibitors?

 When patients start responding to these anti PD-1 or anti-CDK4/6 antibodies, or if they're intolerant of these antibodies, you know, if they have a BRAF mutation, they can be treated with BRAF and MEK inhibitors. But if not, then then a clinical trial is often considered at that time for that patient population, where, you know, they've tried all the FDA approved therapies, trying to kind of figure out what the next best therapy is, is something that we face every day in our practice.

 Can you explain what PD-1 and PD-L1 are?

 A healthy immune system can identify and kill tumor cells, including melanoma cells. So, the killing (of the melanoma cells) can happen by different types of immune cells, including cells called T cells. So, PD-1 is known as a checkpoint protein on a T cell. So when PD-1 on that T cell binds its partner or it's ligand, which is present on tumor cells or other immune cells, it acts as a brake. And that binding then actually shuts down that T cell which then ultimately prevents that cancer cell from being killed. So if we can target that PD-1 or PD-L1, it prevents that T cell from shutting down.

 How do these proteins play a role in treatment options for melanoma right now?

 What we do is we use drugs that target P-1 or PD-L1. And when you do that, it results in a T cell remaining active. And that can lead to what we call an anti-tumor immune response, which is essentially, the person's own immune system killing the cancer.

 We're currently looking at combining FDA approved drugs with new agents. Can you explain how these combinations might work in treating melanoma?

 In general, FDA approved, targeted therapies as well as immunotherapies have been shown to be very effective in treating advanced melanoma. However, what happens is the melanoma tumor can develop what we call resistance mechanisms. So, the tumor has ways to kind of evade the effectiveness of these immunotherapy or targeted therapy drugs. And that can happen due to, you know, mutations in the tumor itself, it can happen due to changes in the environment around the tumor, which is known as the tumor microenvironment, or even changes in the host immune system or the patient's own immune system. And so there are a lot of options out there that are now being actively studied to try to address some of these resistance mechanisms to try to kind of improve upon what we already have.

 Can you discuss any of these regimens that maybe patients should be keeping an eye on?

 So some of the therapies that are being actively studied or have shown promise already include what's known as adoptive T-cell therapy, or TIL therapy, which stands for tumor infiltrating lymphocytes. We're also actively studying drugs that target proteins such as LAG3, TIGIT, or drugs that we call immunomodulators, which is kind of a fancy way of saying that we're using these additional drugs to further affect the immune system. And these immunomodulator drugs that are being actively studied are drugs known as toll-like receptor 9 and STING agonists and even less toxic variants of an older drug called IL-2. And basically, all of these drugs are looking at ways of trying to affect our immune system and being able to better kill the cancer.

Immune-Modulating Antibodies for Melanoma Treatment

Kristie L. Kahl: Can you talk about what adoptive T-cell therapy is?

Adoptive T-cell therapy is a way of treating a person's cancer with their own immune cells. It requires collecting and growing or expanding a patient's own T cells. So, the way that that's accomplished is that a piece of the tumor, or melanoma in this case, is surgically removed and then processed at a separate facility or sometimes at the institution's own facility. It's processed at a separate location, so that these immune cells in the tumor, known as tumor infiltrating lymphocytes, can be extracted and then expanded or grown. And what's unique about those immune cells is that they have the ability to recognize that person's own melanoma. So then, the patient undergoes chemotherapy, and those expanded T cells are then infused back into the patient, along with a few doses of this drug called interleukin 2, or IL 2. So that's essentially what adoptive T-cell therapy is.

Kristie L. Kahl: Where are we in evaluating these types of therapies, like TIL?

The therapy is logistically a little bit more challenging to administer. But this therapy is quite promising. It is important to note that it's not yet (Food and Drug Administration [FDA]) approved.

Kristie L. Kahl: What kind of data are we seeing with these therapies?

We are seeing that this is a very promising therapy for patients who have progressed on immunotherapy and/or a BRAF/MEK therapy, if they have a BRAF mutation. And if a patient is well enough to receive TIL therapy, then it is definitely another option for us, the medical oncologist, to consider for a particular patient. Now, not all patients may be eligible for TIL therapy based on certain clinical characteristics and tumor characteristics, but it's certainly something that we could at least consider.

Kristie L. Kahl: What do patients with melanoma have to look forward to in the treatment landscape?

So, you know, in cutaneous melanoma, there's a lot of new therapies that are being looked at to try to improve the patient's survival outcomes. Newer agents that are being studied in addition to TIL therapy are ones that target LAG-3, TIGIT, these class of oral drugs called tyrosine kinase inhibitors. And all of these that I just mentioned, can be used in combination, we think, with our existing immunotherapy drugs. And so that's being actively studied in clinical trials. And in addition, other options such as immunomodulators, or drugs that tweak or affect the immune system, such as STING agonists, toll-like receptor 9 agonists may also affect the immune system in a positive way that ultimately lead to cancer cell death.

Kristie L. Kahl: That sounds like a lot to look forward to.

Absolutely, I mean, in general, we are trying to use combination approaches, either with our existing FDA-approved drugs or new drugs all together, that target different proteins to ultimately try to cause melanoma cell death.

Emerging Therapies in the Treatment of Melanoma

Can you explain what uveal melanoma is and how common is this disease?

So uveal melanoma is a melanoma that arises in the eye. It's not spread to the eye from other organs. It involves specific structures in the eye, namely the iris, the ciliary body or the choroid. And together these encompass what we call uveal melanoma. And it is very, very rare. It approximately affects about 2,000 adults in the United States every year.

What are the signs and symptoms of this type of melanoma?

So signs and symptoms include blurred vision, floaters, flashing lights misting of the eye, but it is important to know that sometimes it may not cause any symptoms at all, and instead is found on routine ophthalmic exams. So it's very important for us to see our optometrist or ophthalmology doctors on a routine basis.

With this disease, what are the current standards of care or the main types of treatment for uveal melanoma across its different stages?

So in localized disease where the uveal melanoma has not spread to distant sites, the mainstays of therapy are usually radiation and surgery. In metastatic disease, meaning that uveal melanoma has spread to other organs in the body, clinical trials should be considered whenever possible, and immunotherapy may also be used for metastatic or stage 4 uveal melanoma.

Speaking of clinical trials, what are some new treatments that are being evaluated, likethe IMCgp100 trial?

In uveal melanoma, immunotherapy is being studied in the preventative setting, as is targeted therapies such as these class of drugs called tyrosine kinase inhibitors. And in the metastatic uveal melanoma setting, we are evaluating clinical trials for these patients. In the metastatic setting, there was a recent phase 3 clinical trial known as the IMCgp100-202 trial in which patients were randomized to a new drug called tebentafusp compared to their doctor's choice of either chemotherapy or immunotherapy. And the trial showed a survival benefit for patients who received tebentafusp, which is extremely exciting and very promising for this rare subtype of melanoma.

What do patients have to look forward to?

You know, melanoma is being understood more and more, I think, compared to about a decade ago. The armamentarium of therapy options we have now has been greater than ever before. And I think it's only going to increase, which requires a lot of multidisciplinary care, meaning between the medical oncologists, the surgical oncologist, the dermatologist, the radiation oncologist, not to mention our radiology colleagues and our pathology colleagues. And together, I think we have made some great strides and understanding melanoma, understanding why some melanomas don't respond to some therapies. And I think there's a lot of promise on the horizon looking at these newer therapies in novel combinations. So I do think that the next few years will show a lot of promise in the way we treat our melanoma patients.

Understanding Treatment Options in Melanoma | CURE^® Speaking Out

Adjuvant and Neoadjuvant Therapy in Melanoma

Immune-Modulating Antibodies for Melanoma Treatment

Emerging Therapies in the Treatment of Melanoma

Uveal Melanoma

Latest News

Understanding Treatment Options in Melanoma | CURE® Speaking Out

Adjuvant and Neoadjuvant Therapy in Melanoma

Immune-Modulating Antibodies for Melanoma Treatment

Emerging Therapies in the Treatment of Melanoma

Uveal Melanoma

Latest News

Understanding Treatment Options in Melanoma | CURE^® Speaking Out