Article Abstract

Treatment of KIT-mutated metastatic mucosal melanoma

Authors: Kevin B. Kim, Anas Alrwas

Abstract

Mucosal melanoma is a rare, aggressive histologic subtype of malignant melanoma, and prognosis for patients with metastatic mucosal melanoma is very poor. In general, conventional cytotoxic agents alone or in combination with immunologic drugs have limited clinical benefit. Advances in molecular analytic techniques have helped researchers discover genetic aberrations in KIT, a receptor tyrosine kinase, in nearly 40% of patients with mucosal melanoma. Preclinical studies have demonstrated that hot-spot mutations, mostly substitutions in exons 11 and 13, result in constitutive activation of KIT and its downstream signal transduction pathways, such as the MEK/ERK, PI3K/AKT and JAK/STAT pathways. KIT inhibitors, most notably imatinib, have shown promising clinical activity in KIT-mutant advanced melanoma, including mucosal melanoma, with clinical response rates exceeding 35% in patients with hot-spot mutations in exon 11 or 13 and/or a high mutant/wild-type allelic ratio. However, the duration of disease control is rather short in general, and treatment with KIT inhibitors as single agents is not optimal. Well-designed mechanistic studies aimed at assessing molecular differences between various KIT mutations or other aberrations and mechanisms of resistance are urgently needed to improve KIT-targeting therapy for melanoma. In addition, with availability of checkpoint inhibitors, such as anti-CTLA4 and/or anti-PD-1 antibodies, immunotherapies using those inhibitors alone or in combinations of such immunotherapies with KIT inhibitors may lead to more effective therapeutic regimens. This review discusses the rationale for KIT inhibitor therapy in patients with metastatic mucosal melanoma and the findings of preclinical and clinical studies of KIT inhibitors in this patient population.

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