Abstract
Imatinib has activity in KIT-mutated mucosal, acral, or chronically sun-damaged melanoma.
Major finding: Imatinib has activity in KIT-mutated mucosal, acral, or chronically sun-damaged melanoma.
Clinical relevance: KIT-mutated, but not KIT-amplified, metastatic melanomas respond to imatinib.
Impact: Patients with mucosal, acral, or chronically sun-damaged melanoma should be screened for KIT mutations.
Mucosal and acral melanomas that develop on sites such as the palms, soles, and nail beds are clinically distinct from cutaneous melanomas of the skin. Furthermore, these types of melanoma infrequently harbor BRAF mutations, suggesting that they are also genetically distinct. Recurrent mutation or amplification of KIT has been found in mucosal and acral melanomas as well as in chronically sun-damaged (CSD) cutaneous melanomas, which also rarely have BRAF mutations. Because the small-molecule kinase inhibitor imatinib has shown efficacy in KIT-mutant gastrointestinal stromal tumors, Hodi and colleagues initiated a multicenter phase II trial of imatinib in patients with KIT-mutated and/or amplified metastatic mucosal, acral, or CSD melanoma. The primary endpoints were response rate and time to progression, and secondary endpoints included overall survival and the association between KIT status and response. Of 24 evaluable patients, 8 had KIT mutations, 11 had KIT amplification, and 5 had both (these patients were classified as having mutations). Surprisingly, the best overall response rate was significantly higher in patients with mutated KIT (54%) compared with patients with amplified KIT (0%), suggesting that KIT mutations and amplifications may act differently in melanoma. Moreover, the disease control rate, including partial responses and stable disease, was significantly higher in KIT-mutated melanomas (77%) than it was in KIT-amplified melanomas (18%). Of note, especially short times to progression were observed in patients with preexisting NRAS mutations, raising the possibility that NRAS mutation contributes to imatinib resistance in melanoma. Although no statistically significant differences were shown in overall survival or time to progression between patients with KIT mutation or amplification, the activity of imatinib in KIT-mutated mucosal, acral, or CSD melanoma provides a rationale for screening such patients for KIT mutations and testing more potent, specific KIT inhibitors in these melanoma subtypes.
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