Treatment of Melanoma

In this Pharmacy Times program for Health Systems Pharmacists, Nanaz Amini, PharmD, RPh, MS, of the Angles Clinic, provides a pharmacist’s perspective on the management of melanoma.

I would say that the role of systemic therapies in the current landscape of melanoma would be salvaged. So, you would not necessarily start a patient on immunotherapy, but if immunotherapies, targeted therapies, and combinatorial therapies don’t work, that would be almost like a last-ditch effort that you would use.

Immunotherapy is pretty much first in line. Yervoy (ipilimumab) is one. If you basically fail with Yervoy, there’s Keytruda (pembrolizumab) or there’s Opdivo (nivolumab) that can be used. These therapies are wonderful in the sense that the side effects relative to what was standard of care, and the cytotoxic agents that were used previously, I can’t say there’s no side effects, but they’re relatively minimal. Infusion reactions are truly minimal, and I can say for the hundreds of patients that we’ve treated with just Keytruda, I have had 1 person who had a reaction. So, that has been very good for nurses, for the practice as a whole, because infusion reactions do stop an infusion area because everybody has to manage that one patient.

That makes it very nice for patients. In addition to that, patients are coming in every 2 weeks or every 3 weeks. The burden on the patient is not as great to have to stay. A lot of the original therapies that patients were getting would keep them in the hospital. Because of biochemotherapy, which is a very hard regimen that melanoma patients would have, they would have to be admitted into the hospital and stay in the hospital for a couple of days, where all of these now are outpatients. So, the burden on the patient is minimal and they can have a decent quality of life while still going through treatment. In addition to that, they don’t have the chemotherapy where they have hair loss, they don’t have the neutropenia, and they don’t have the classic oncological patient profile that you would think.

Combination therapy, I would say we’re going with it to become first line, as opposed to just immunotherapy, because you’re hitting a cancer from 2 different pathways. We have a lot now where if somebody has BRAF-positive disease, we will give them Tafinlar (dabrafenib) and Mekinist (trametinib), or Cotellic (cobimetinib) and Zelboraf (vemurafenib), with an immunotherapy tacked on.

What usually happens with that is the targeted therapy basically is targeting the proteins that are sitting on the cancer cells. It attacks it and really reduces the size of the tumor, and then the immunotherapy that you’re giving as an infusion helps boost the immune system to fight the cancer. So, you’re working in 2 different pathways to come out with the same results. And the side effects, not that they don’t exist, but you’re going to get a much more durable response with combinatorial therapy down the line.

Part of it is you have to have lesions that can be injectable. That’s part of the difference, that, as I said before, a lot of these are just intertumoral injections. You have to have visible tumors, or at least tumors in which you can go and inject the tumor using ultrasound as a guide. That reduces your population because not every patient who has melanoma necessarily has lesions which are palatable, visible, or can be detected by ultrasound. So, that narrows down this group of vaccines or injectables. More specifically, interferon, IL-2, is very, very harsh treatment. A lot of patients basically just can’t handle the regimen. If they can’t, it’s not durable.

In addition to that, there have been studies done, but because of all of the deaths that were associated, nothing has been conclusive that you’re getting a durable response. Therefore, we’ve steered very much away from using these. There are still surgical oncologists that may use BCG after they have done surgery, but, again, it’s in a very finite amount of patients. And they’re usually very, very experienced people who know what outcome they would have based on the surgery and having gone into the actual environment of the tumor, which would be beyond my knowledge base to make a comment on.

However, Imlygic, or T-VEC, is the one in which there is very much durable response that is being seen that can be used in patients, and patients have seen benefit. That is the one that is aside from these. But, again, they’re a subcategory of patients who have melanoma because the lesions need to be visible, palatable, or you should be able to, with ultrasound, get to the tumor. So, it’s not for everybody.

We actually have one of the clinical trials that had Imlygic, or T-VEC. Obviously, they have to be 18 or over. The lesion has to be, as I’ve just said, cutaneous, subcutaneous, or nodal. And it has to be either palatable, visible, or be able to get into that node if it can be seen with an ultrasound guide. The patients also have to have a minimum—based on criteria of the original trial—of lesions that were at least 10 mm to be injected. They also had to have ECOG scores of 0 to 1, which if you’re not in clinical trials, ECOG basically means 0 to 1, that you are healthy enough that you’re walking into the clinic, you’re not in a wheelchair or you’re not with a walker, and you’re in relatively good health that you’re coming in to the clinic. As far as exclusion criteria, if patients had ocular melanomas or mucosal melanomas, they were not candidates. If they had bone metastases, or visceral metastases to that level, they were not candidates.

Those exclusions are where we are in the practice as well. So, in what we do today, if patients only have visceral metastases, or visceral disease, you’re not going to use Imlygic on them, period. You would go to the systemic therapies or the targeted therapies instead. On the trial, and also if they’re already immunocompromised, T-VEC is not for them. The logic is that because even though it is a genetically altered herpes virus, the thought is that if there is a potential you’re immunocompromised, if somehow that becomes active and you have active herpes, you don’t want to go down that route with patients who are immunocompromised, or who have AIDS, or who themselves already may have herpes simplex of some sort. So, you wouldn’t want to start a therapy because of this; even though it’s an inactive virus. But it is genetically modified.

Although there shouldn’t be, there’s a potential, so those patients were excluded from the trial as well. When I say AIDS, it’s not necessarily AIDS, but it’s because they’re on antiviral therapy and they can’t be on antiviral therapy because it contradicts what you’re trying to do. So, you’re basically using the virus to replicate and be an antitumor. But then, if you’re taking an antiviral and stopping the replication of that virus to do its job, then you’re not going to get any benefit from it.

The best way to decipher if your patients are going to go on T-VEC or if they’re going to get systemic therapy would be if a patient only has visceral disease. You’re never going to give them T-VEC. You’re not going to give them the Imlygic. They have to be patients who have, as I said before, and as the FDA indication is, to be cutaneous, subcutaneous, nodal; lesions in which are visible, palatable, or can use ultrasound guidance in order to get to the injection site.

And usually T-VEC is an option if patients have had surgery and they reoccur, and you’re going to basically inject those particular lesions. But as we said earlier, since the trend is to go to combinatorial therapy, if patients have a mix of cutaneous lesions and they have visceral disease, there is a shift into having patients beyond Yervoy and get Imlygic, or be on Keytruda and get Imlygic simultaneously. They may get the 4 doses of Yervoy, but continue with the Imlygic for the next 6 months. So, that’s a trend that you’re seeing. But if they only have lesions that are injectable, then Imlygic would be perfect for them. If they have visceral disease also, then you might use combinatorial. And if it’s just visceral, you’re going to go to the systemic or the targeted therapy.

F­irst of all, you don’t want to miss your doctor’s appointments. But the first thing would be for you to visibly check yourself. Basically, if you feel a lump, if there’s lesions that have gone away but they come back and they’re ulcerated, and you would be able to visibly see that, you need to be vigilant and doing your own self physical evaluation. Then, going into the dermatologist, even if you’re disease-free just to have anything checked out that may come.

If you’re going for maintenance, usually for patients who are first disease-free, so to speak, they will come in for scans every 3 months. You don’t want to miss a scan. Again, labs will be checked. You’ll watch that LDH marker. If that value starts to creep up, it may correlate to basically your disease coming back, or not being controlled. So, those are things that it requires vigilance from the patient, as well as the provider, because the provider also needs to make sure that the patient comes back and gets proper appointments to come back, get scanned, and to get checked.

The longer you are disease-free, then those scans can go from 3 months to 6 months. It actually is even more important for you personally to check yourself. It’s just like the diabetic patients, that they say you need to check your feet yourself. So, this is kind of the same thing. If you are disease-free, you still want to physically check to see if there’s anything that’s come up—new moles, ulcerations, anything that looks, I would say, suspicious, you’d want to have it checked out.