The Optimal Approach to Treating Advanced Melanoma

Brian Gastman, MD: Locally advanced disease has a spectrum of possibility. That could include disease that is not resectable but is locally advanced. For example, patients with lots of intrasametastases are nonresectable, and they have their own separate treatment algorithm. For patients who are resectable, we can get them to a status that we call “no evidence of disease” and treat them adjuvantly. Clearly, there are 2 major pathways for treatment.

Around 45% of cutaneous melanomas contain the BRAF mutation, and there are at least 3 targeted combination therapies available to give them adjuvantly. Alternatively, there is immunotherapy. Immunotherapy is mainly anti–PD-1–based immunotherapy. Although there is anti-CTLA4, which is approved based on data from Europe. Because the head-to-head analysis of nivolumab vs ipilimumab in the CheckMate 238 trial continues to have better relapse and resurvival rates than the nivolumab group, we assume that the same would be so for pembrolizumab, so most people are using anti–PD-1 agents.

In addition, the problem with anti-CTLA4 is that the approval is to use 10 mg/kg, but even at 3 mg/kg, it’s pretty toxic. There was a trial called ECOG-E1609, which compared 3 mg/kg with 10mg/kg. The 3 mg/kg appeared to be less toxic, as expected. It was still toxic, but it did have the same efficacy. Regardless, we rarely use it.

The basic points are that if you are BRAF positive, which is what we call it if you have mutation, then you have 2 options: anti–PD-1 therapy with a BRAF/MEK inhibitor or the final option, which is observation.

I’m a surgeon, but I am also involved in quarterbacking the patients’ care, including running many of the clinical trials that may affect patients with locally advanced melanoma. Let’s take it from the beginning with stage. Let’s say that someone comes in and is stage IIIA, IIIB, or for some patients stage IIIC disease. The reason we know they are stage III is because they had a sentinel lymph node biopsy that was positive. By definition, we would call that micrometastatic disease.

In general, once we know that information, most patients go on to adjuvant therapy. There is some controversy with stage IIIA disease even though there is FDA approval for it. It’s usually pretty straightforward. I will see a patient and give them the results. Many times, I have already told them that the whole point of getting a sentinel lymph node biopsy is to help predict the next steps of therapy, so the patients are not usually surprised by the next discussion.

Before we can do that, we need to open up the possibilities, so we are going to get BRAF testing. We’ll usually do hot spot testing because, unfortunately, if you are stage III, you may fail and become stage IV. Getting hot spot analysis, which includes things like BRAF, NRAS, c-KIT, and other potential targetable druggable targets, is useful because it is usually bundled in the cost.

Depending on whether they are a patient with BRAF mutation, we would offer both options. It depends on experience because there is no head-to-head study. You can extrapolate in terms of response and relapse/resurvival rates based on trials, but we don’t like to analyze across trials. In some centers, they highly prefer BRAF/MEK inhibitors if you are a candidate for that, the reason being that it’s a pill. Pills are simpler. You can hold a dose; it’s quite easy. Many people feel that, from a lifestyle perspective, that’s way better.

Anecdotally, we at the Cleveland Clinic have seen some patients who, when they failed BFAF/MEK inhibitors, their failure display and their relapse seem to be worse. We haven’t proven this with scientific rigor. However, almost all patients have adverse events: not level 3 or 4 adverse events, but a lot of them get level 2 and 3 adverse events. It’s not necessarily a dose-limiting adverse event, but it’s annoying to patients.

That could be fever, or it could be photophobia. There are all kinds of different adverse effects that are off-target effects. Although there are many out there who feel that a BRAF/MEK inhibitor is good for the lifestyle of many of the working patients, I would argue that many of them have the fatigue and unhappiness that I used to see with interferon for the same patient population.

If we flip that over to anti–PD-1–based immunotherapy as adjuvant therapy, 9 of 10 patients have limited adverse effects in our experience, which is pretty good. The 1 in 10 patients who have significant adverse effects are much worse than those that we see in the pill BRAF/MEK inhibitor form. Of course, they have to come in every 3, 4, or 6 weeks, depending on the therapy. We don’t really do the 2-week dosage anymore, but there are various options. Every 6 weeks is obviously less cumbersome. Some people want to see the patients more often because of the potential adverse effects, and they want to get ahead of that. To me, if you look at the data that were presented for stage IV melanoma, especially at ASCO [American Society of Clinical Oncology Annual Meeting] a couple of years ago, it seems that when anti–PD-1 therapy cures, it has the more durable cure of 2 cancer treatment types. Moreover, there have been separate data to show in stage IV with pembrolizumab that lesser tumor burden equates with better anti–PD-1 efficacy. What is better from a burden standpoint than having no evidence of disease?

I have spoken to my colleagues who are in well-known institutions who may disagree with us, but in our practice, we tend to favor anti–PD-1 immunotherapy. Many of our patients seem to be OK with that even if they are working. You have to tailor your therapy to the patient.

Let’s jump to patients who walk in the door with palpable macroscopic disease. It depends on how fast growing the disease is and how much the quality of life is being affected by it. For example, somebody walks in the door with a 15-cm mass, which is quite large, in the axilla. They may be suffering. They may have other adverse effects, though that may require them to delay their surgery, so even though it’s not FDA approved to give it this way, we sometimes give those patients a neoadjuvant dose or 2. Many have read the neoadjuvant papers. They are small series, but the data perhaps show you have some time before you have to take the patient to the operating room. The fact is that giving someone 1 or 2 doses could give you predictive, prognostic information based on the response you get. In the age of COVID-19 [coronavirus disease 2019], where we are worried about getting patients in and when hospitals are getting shut down and reopened, having the flexibility of not having to worry about the exact time to treat is a big reason to consider neoadjuvant therapy.

Most of the data are in anti–PD-1 based immunotherapy. Some trials have shown that if you give monotherapy, patients grow to the point that you couldn’t operate on them. If you give ipilimumab-nivolumab, people have died with it, although it may be much more powerful. The bottom line is that we do it on occasion, but in general, the plan would be to take the patient to surgery and give them adjuvant therapy. They then end up with basically the same options as the patient with the micrometastatic disease. Therapy in the adjuvant setting is usually for a year with close imaging follow-up.

We talked about disease that has intrasametastasis; it may be that they are beyond resection. In our practice, and we have published this, we will use combinations of intratumoral T-VEC [talimogene laherparepvec], which is an FDA approved anti–PD-1 therapy. We published our first 10 patients’ real-world data at least 2 years ago, I believe, and the data were impressive: 7 of 10 patients with unresectable stage III or stage IV disease had complete responses, including 2 patients who had distal, uninjected tumors. With that kind of data, we were very impressed.

It’s clear, from our own experience, that for patients who are in that situation, who have not already failed anti–PD-1 therapy, I would tier it. You have micrometastatic disease, you have macroscopic metastatic disease, and you have unresectable, local-regional disease.

Evan J. Lipson, MD: The approach to multidisciplinary management of melanoma has become increasingly complex over the years. Here at Johns Hopkins Medicine, we’re fortunate to have practitioners from several disciplines: dermatology, pathology, surgery, radiation oncology, medical oncology, etc. We get together every week and discuss all the new patients we’ve seen. We get good perspective from all the different disciplines. It’s important to know what the disease looked like when it began.

The dermatologists are often the first to see the tumor in situ. It’s also important to understand what the proper surgical approach is. Certainly, the COVID-19 era has complicated some our surgical management possibilities over the last several months. As we learn more about the way the coronavirus is transmitted, we’ve become more facile and better able to treat patients as we usually do.

It’s also important to understand what the possibilities are in terms of medical management for both clinical trials and standard of care with adjuvant therapies, for example. As we discuss these patients 1 at a time in our multidisciplinary meetings, everybody chimes in to volunteer information about the latest data and how we might best serve patients from all different disciplines.

Transcript Edited for Clarity