Current Status and Prospects of Immunotherapy for Gynecologic Melanoma

Abstract

Gynecologic melanomas are rare and have a poor prognosis. Although immunotherapy (immune checkpoint inhibitors) and targeted therapy has greatly improved the systemic treatment of cutaneous melanoma (CM) in recent years, its efficacy in gynecologic melanomas remains uncertain because of the rarity of this malignancy and its scarce literature. This review aimed to evaluate the literature of gynecologic melanomas treated with immunotherapy and targeted therapy through a PubMed search. We identified one study focusing on the overall survival of gynecologic melanomas separately and five case series and nine case reports concentrating on gynecologic melanomas treated with an immune checkpoint inhibitor and/or targeted therapy. Furthermore, the KIT mutation has the highest rate among all mutations in mucosal melanoma types. The KIT inhibitors (Tyrosine kinase inhibitors: TKIs) imatinib and nilotinib could be the treatment options. Moreover, immune checkpoint inhibitors combined with KIT inhibitors may potentially treat cases of resistance to immune checkpoint inhibitors. However, because of the different conditions and a small number of cases, it is difficult to evaluate the efficacy of immunotherapy and targeted therapy for gynecologic melanoma rigorously at this time. Further prospective cohort or randomized trials of gynecologic melanoma alone are needed to assess the treatment with solid evidence.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancer

“…In one review including a total of 57 patients from various case reports and series with metastatic disease, there were 6 CRs and 13 PRs with anti-PD-1 monotherapy or in combination with anti-CTLA-4. 187 Concurrent ICI and radiotherapy has been shown to improve PFS, but not OS, in cutaneous melanoma in one meta-analysis, 188 and this strategy may also be appropriate for some patients with gynecologic melanoma. Neoadjuvant anti-CTLA-4 in combination with radiotherapy has also been reported in one small study (n=4), where among the three patients who underwent resection, one achieved pathologic complete response (pCR), and all three patients had local radiographic CR after surgery.…”

Radiotherapy and Immunotherapy, Combined Treatment for Unresectable Mucosal Melanoma with Vaginal Origin

“…Regarding biological characteristics, MM and cutaneous melanoma (CM) are different. Thus, MMs have a significantly smaller percentage, less than 15% of BRAF gene mutations, than CM without chronic sun damage [1,[13][14][15]. Moreover, the increased BRAF gene mutation in MM damages gene regions other than codon 600 or is a non-activating mutation, so it is not expected to have an effect on target therapy [1,14].…”

“…Thus, MMs have a significantly smaller percentage, less than 15% of BRAF gene mutations, than CM without chronic sun damage [1,[13][14][15]. Moreover, the increased BRAF gene mutation in MM damages gene regions other than codon 600 or is a non-activating mutation, so it is not expected to have an effect on target therapy [1,14]. Moreover, gene copy numbers and structural changes, for example in KIT, are significantly more magnified in MM than in CM [1,16,17].…”

“…BRAF inhibitor concurrent with MEK inhibitors is an elective procedure in the case of a BRAF V600-activating mutation [1]. If there is no mutation, anti-PD1 as unique therapy or combined therapy (nivolumab and ipilimumab) is recommendable [1,23].…”

“…The most frequent sites of GM are, in order, vulva, vagina and, less frequent, the cervix. The prognosis for gynecologic melanomas is poor, with overall survival (OS) at 5 years less than 50% for vulvar, less than 30% for vaginal situs and even smaller for cervix melanoma [1][2][3]. Melanoma has a noticeably increasing incidence.…”