Expert Discusses Treatment Approaches, Research Needs for Patients With Extracutaneous Melanomas

Richard D. Carvajal, MD

Richard D. Carvajal, MD

While there has been much focus on adjuvant therapy in the cutaneous melanoma setting, there remains little known about effective adjuvant therapies in extracutaneous melanoma. The recent approval of nivolumab (Opdivo), based on findings of the randomized phase II CheckMate-238 trial, showed favorable results for patients with completely resected melanoma with lymph node involvement of metastatic disease, however, less than 30 of the 900 patients in the trial were cases of extracutaneous melanomas.

“There has to be a robust effort to make sure there is funding for laboratory research to understand the mechanisms as to why it is different, how it behaves, and how we can treat it better. We need clinical trials, in some cases specific to each disease,” said Richard D. Carvajal, MD.

In an interview withTargeted Oncologyduring the Chemotherapy Foundation Symposium,Carvajal, a medical oncologist at Columbia University Medical Center, where he is Director of Experimental Therapeutics and Director of the Melanoma Service, discussed considerations when diagnosing and treating extracutaneous melanomas and the importance of treating such diseases differently than the more commonly seen melanomas.

TARGETED ONCOLOGY: Tell us a little bit about what you discussed during your presentation on extracutaneous melanoma.

Carvajal:I think when people hear of melanoma, they traditionally think of cutaneous disease. But it turns out the melanocytes are scattered throughout the body. This includes areas such as the mucosal surfaces and areas in the eye. I spoke a bit about mucosal melanoma, as well as some of these ocular melanomas.

These diseases are very distinct, from a biological standpoint, as well as a clinical standpoint, from cutaneous melanoma, so they have to be thought of as different diseases. They don't respond the same way to the therapies we use in cutaneous melanoma and some of them don't work at all for various reasons. I spent some time talking about what is known from a biological standpoint, as well as from clinical trials and treatments, for both of those subtypes.

TARGETED ONCOLOGY: How would an oncologist approach treatment for an extracutaneous melanoma differently than a cutaneous melanoma?

Carvajal:It is very complicated. These are rare diseases, so most practicing oncologists won't see too many of these each year. These are diseases that have to be dealt with in a specialty-type setting. Like anything else, it's ideal if they are treated by a group of physicians who have seen this disease at some frequency.

In general, for instance in mucosal melanoma, regardless of where it arises, we do want to get good surgical control. Local control is also critical. After that, the question of whether or not there is an effective adjuvant therapy is a big one. It turns out, to the best of my knowledge, there is just 1 randomized trial ever conducted in mucosal melanoma. It was actually in the adjuvant setting, where patients with resected mucosal melanoma were randomized to either observation or 1 year of interferon or chemotherapy. At least in that study, the patients who received active therapy, whether or not it was interferon or chemotherapy, did better, and those who received chemotherapy did a lot better. It is important to note that that study was done in China, so it was a Chinese patient population and it has never been replicated. That really is the only randomized data that we have.

When we are talking about adjuvant therapy in melanoma, we always have to look at what has been done in cutaneous melanoma. With the recent data with nivolumab in the adjuvant setting, we see adjuvant nivolumab is better in terms of relapse-free survival than ipilimumab (Yervoy). The question is whether or not that applies to these other settings. We don't know the answer to that. In that adjuvant trial of over 900 patients, there were under 30 patients with mucosal melanoma. So, I don't think we can say that actually applies in the metastatic setting.

In general, the treatments that we use for cutaneous melanoma don't work as well. Molecularly, these less commonly have theBRAFmutations that are found in about half of cutaneous melanomas. If they do haveBRAFmutations, then it is reasonable to use a RAF or a RAF/MEK combination therapy. Higher proportions of these mucosal melanomas will harbor alterations inKITmutations. We have done a lot of work with KIT inhibitors in this disease and there is certainly some activity there. People will frequently say that our responses are not durable, and I don't know if that is entirely true. We have had patients on KIT inhibitors for years with major ongoing responses. But, the response rate is still modest at 15% to 25%.

Immunotherapy can work, but it works less well in this disease than in cutaneous melanoma, so the response rate is lower. If you look at the combination of ipililumab and nivolumab with about a 60% response rate in cutaneous melanoma, it is closer to 35% to 40% in mucosal with a median progression-free survival of 5 to 6 months. There is activity there and immunotherapy is certainly reasonable. We do tend to use combination immunotherapy if the patient can tolerate the toxicities, because the single agent PD-1 response rates are a bit more modest. Nevertheless, PD-1-based immunotherapy is reasonable.

TARGETED ONCOLOGY: Why do think there are such lower response rates in extracutaneous melanoma when we are using ipilimumab and nivolumab?

Carvajal:think the answer is that we don't know, but there are several likely hypotheses. When we look at what predicts benefit to immunotherapy, we know that mutational burden is associated with a better response. We also know that expression of PD-L1 is a predictor of response. We can just look at those 2 items.

In terms of mutational burden, we know that cutaneous melanoma has an extremely high mutational burden and it is on the far end of the spectrum. It turns out that ocular melanoma is on the far end and has a very low mutational burden, and then mucosal and acral melanoma are in between. Certainly, that may play a role in explaining the difference between cutaneous, mucosal, and uveal responses.

If we look at PD-L1 expression, it is also very low in ocular melanoma. In mucosal, the data sets are a bit smaller. That expression is different across these different subsets. Simplistically, that may play a role in why there is a difference.

TARGETED ONCOLOGY: What advice would you give to a community oncologist who is treating a patient with extracutaneous melanoma?

Carvajal:I think a lot of us who deal with this are very accessible by email or phone. Certainly, a lot of the patients that I see in my practice with these rare melanomas do travel because the clinical trials that we have to offer aren't offered at many centers. We need to make sure there are good novel treatment options throughout the country so everyone has access to it. But many of the folks who deal with these diseases are happy to speak with clinicians to see what can be done locally. If there is something that can be done at home, it is much better than having to make the patients travel for care.

TARGETED ONCOLOGY: Since the disease is so rare, do you run into problems with diagnoses?

Carvajal:That's a great question. As a whole, the mucosal melanoma patient population does less well than patients with cutaneous melanoma, irrespective of stage. Part of that is biology, and part of that may be delays in diagnosis. It is very common for patients to be diagnosed with an anorectal mucosal melanoma, who for months have been complaining about a hemorrhoid and seeing doctors who claim it's a hemorrhoid. Hemorrhoids are far more common than anorectal mucosal melanomas, so that is in no way inappropriate. But I think we need a high level of suspicion. I think we need an awareness from clinicians that melanomas can arise in strange places so that patients can be referred.

For ocular melanoma, this is a disease that is pretty rare, maybe 2,000 or 3,000 cases a year in the United States. In most cases, the ophthalmologist or the optometrists are actually the ones who look in there and say something is weird. They are good about making the appropriate referral. So it is just an awareness of the disease to make a prompt diagnosis.

TARGETED ONCOLOGY: Regarding giving a diagnosis, what tips you off to say this is not a hemorrhoid or some strange eye problem?

Carvajal:It is different depending on the scenario. The eye diagnoses can be tough. It is sometimes challenging to differentiate a benign ocular nevus from a small melanoma, or a real ocular melanoma. Typically, the optometrist will refer the patient to a specialty center if they are suspicious at all. For the mucosal melanomas, these lesions are sometimes amelanotic, sometimes they are polypoid, they look like hemorrhoids. It is very hard, so it is not uncommon that patients want to go hemorrhoidectomy. It is not until the pathology test comes back that they find out it’s more than a hemorrhoid. If there is rapid growth, if there is a lot of bleeding, if it's not behaving like a hemorrhoid, that should prompt you to get a histologic diagnosis.

TARGETED ONCOLOGY: Where do you hope the field of extracutaneous melanoma is going to be in the next 5 to 10 years?

Carvajal:I think the key with these diseases, as well as any other rare cancers, is to make sure we have a strong research effort, specifically for these subtypes of melanoma. They have to be considered as different diseases. There has to be a separate research effort for ocular melanoma, that is separate from mucosal and cutaneous. There has to be a robust effort to make sure there is funding for laboratory research to understand the mechanisms as to why it is different, how it behaves, and how we can treat it better. We need clinical trials, in some cases specific to each disease. That is definitely true for ocular melanoma, where we need a separate pool of trials. Another way to go about doing these trials is having melanoma trials with specific cohorts, so that we can enroll mucosal melanoma patients and they are looked at as a separate group. They have to be treated differently.