Finding: Imatinib mesylate demonstrates activity in melanoma with aberrations in KIT in a phase II study.
Impact: There is clear activity for targeting KIT in malignant melanoma.
Controversy: Further studies are needed to determine which mutations determine sensitivity and to identify patients most likely to benefit.
KIT is a receptor tyrosine kinase that plays a critical role in the development of normal melanocytes. Activating mutations in KIT are found in certain cancer types, including gastrointestinal stromal tumors; inhibitors of KIT (e.g., imatinib) are of clinical benefit in such tumors. Although the most common form of melanoma harbors mutation in BRAF, several other subtypes of melanoma, including those that arise at mucosal, acral, and chronically sun-damaged sites, were recently found to harbor mutations in KIT. However, several phase II clinical trials of imatinib in unselected metastatic melanoma patients failed to show a benefit. Given preclinical and sporadic clinical evidence of response to imatinib, Carvajal and colleagues report results of a study in which patients with KIT mutations or amplifications were treated with imatinib. Of 25 evaluable patients, 2 achieved durable complete responses and 2 achieved durable partial responses. Importantly, tumors that harbored mutations at recurrent hotspot sites in the KIT gene or showed selection for the mutant allele were more likely to respond to imatinib treatment. These data demonstrate that KIT is a therapeutic target in a subset of melanomas harboring mutations in KIT rather than BRAF. KIT inhibitors may be of clinical value in a selected patient population based on screening for these genetic alterations.
Note: Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.