Lack of Guidelines Create Need for Novel Options for Vulvar/Vaginal Melanoma

Treatment options for vulvar/vaginal melanoma tend to mimic those of cutaneous melanoma due the lack of specific therapy guidelines put into place. Understanding the differences between those 2 diseases is crucial in understanding on how that difference affects therapy.

Because of the rarity of the disease, a study examined patients with vulvar/vaginal melanoma as they were treated with immunotherapeutic agents including pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy).

Results found these patients to have significantly shorter survival compared with patients with cutaneous melanoma treated with the same immunotherapies. The difference in survival between the vulvar/vaginal melanoma and cutaneous melanoma population was nearly 1 year and 6 months, according to Annelise Wilhite, MD, gynecologic oncology fellow at the University of South Alabama Health. The findings warrant the development of new therapies for the vulvar/vaginal melanoma patient population.

When looking at why patients with vulvar/vaginal melanoma do not have longer survival, it was concluded that high tumor mutational burden (TMB) was absent in the vulvar/vaginal melanoma tumors compared with the cutaneous population of which 50% had high TMB. A much lower PD-1 expression was found in the vulvar/vaginal melanoma group, and the tumor microenvironment had significantly lower levels of effector T cells and immune-promoting macrophages.

While there were lower BRAF mutations in the vulvar/vaginal melanoma group, a higher rate of KIT mutations could be seen which could possibly lead to an opportunity in the future for targeted therapy.

In an interview with Targeted Oncology^TM, Wilhite discussed the findings of a clinical investigation of survival in patients with vulvar/vaginal melanomas.

TARGETED ONCOLOGY: What did oncologists perceive about vulvar/vaginal melanomas in the past and how are things different today?

Wilhite: Vulvar/vaginal melanoma has always been a rare disease. It accounts for 1% of melanomas. Because of this, there's no specific guidelines to therapy. Although it is different from cutaneous melanoma, guidelines for treatment typically mimic that of cutaneous melanoma. Recently, there have been developments in molecular testing. We have had a little bit of a better understanding of the differences between the 2 diseases, but we don't really have a great sense of how those can affect therapy.

Can you further explain those distinct tumor types?

In cutaneous melanoma, there are differences between chronic sun damage melanomas compared to non-chronic sun damage melanomas. There is also a subset of mucosal melanomas, and that is where vulvar/vaginal melanomas lie. They are a unique subset of those tumors, and they have differences in survival. For example, vulvar/vaginal melanoma has a much worse prognosis than most cutaneous melanomas, and they also have differences in their genetic makeup.

What does the treatment landscape currently look like for this patient population?

The treatment involves surgical resection, and then for metastatic or unresectable disease or locally advanced disease. Typically, chemotherapy or immuno-oncology therapy is recommended. As of now, the frontline agents for cutaneous melanoma are PD-1 inhibitors CTLA-4 inhibitors and a combination of BRAF and MEK inhibitors. Full of rational melanoma, the treatment typically involves a multidisciplinary approach. We will often follow the cutaneous melanoma guidelines.

Typically, we will involve our hematology colleagues who specialize in melanoma to get their opinion about what they would recommend, and we will always send these tumors for molecular profiling. Because of how few patients develop this disease, it's hard to have clinical trials where these patients are the main patients involved. That is the main obstacle in finding treatments that work, particularly for these patients.

What are the key biomarkers that you were looking for?

BRAF mutations because that would offer that therapy with BRAF inhibitors. As we found, the KIT mutations are frequent in vulvar/vaginal melanoma, so that might lead to an opportunity for targeted therapy. If the molecular testing does show any other targetable mutations, then that would be something that we could hopefully use.

What were the findings of this study?

When we looked at survival of patients with vulvar/vaginal melanoma treated with immuno-oncology therapy such as pembrolizumab, nivolumab, and ipilimumab, we found that they had significantly shorter survival compared to patients with cutaneous melanoma treated with these same agents, almost a year and a half difference in the survivals suggesting that we need to find some other therapies. Part of this could be because the immunogenicity of the vulvar/vaginal melanomas is much lower than cutaneous melanoma.

We found that the high tumor mutation burden was absent in these tumors, compared to a high rare mutation burden in almost 50% of cutaneous melanomas. There was also significantly lower PD-1 expression and in the tumor microenvironment, there were significantly lower levels of effector T cells and immune promoting macrophages in the vulvar/vaginal melanoma group. As far as genetic mutations go, there were lower BRAF mutations in the TBM group, but we saw a higher rate of KIT mutations. Perhaps this could lead to an opportunity for targeted therapy in these patients.

Are there any real-world studies exploring this subject matter? What else are you excited to see for the future of this space?

There is always research going on in this field. We have a large cohort, and it is one of the first studies that has looked at molecular profiles in combination with outcomes. It's certainly an area that we need more research in.

I am most excited about seeing all the new science that's coming out. I know that I'm going to be watching with the rest of my colleagues at the National Cancer Institute and as a fellow in training, I'm excited to see what their takes on everything is and to learn from them.