c-KIT IN MELANOMA

c-KIT: A therapeutic target in metastatic melanoma

04.08.11

Category: Scientific News

Imatinib shows efficacy in melanoma patients enriched for KIT mutations or amplifications

In patients diagnosed with metastatic melanoma, recently approved antibody ipilimumab and the small molecule vemurafenib have shown to improve overall survival over previous standards of care, but there are melanoma subtypes for which they are not effective. Therefore, research for alternative therapies is ongoing.

An open-label phase II study, published in the JAMA, has recently sought to identify the subtype of patients with melanoma who might respond best to the multi-kinase inhibitor imatinib mesylate. According to Dr Richard Carvajal, first author of the study, a subset of melanomas is characterized by activating alterations in the gene coding for the kinase KIT, and his team assessed whether KIT inhibition in this subset could impact melanomas progression.

Out of 295 cases of melanoma enrolled into the study, 51 patients were identified to have KIT mutations or amplifications. These cases were from a cohort of patients with melanoma subtypes previously shown to be enriched for these types of genetic alterations (from acral, musocal and chronically sun-damaged sites). The identified patients were offered treatment with imatinib and 28 patients went on to receive the therapy. In two patients durable complete responses were achieved, in two durable partial responses and in five stable disease that lasted for at least 12 weeks (two of these lasting for more than 6 months).

This study serves as an important proof of concept that inhibition of the protein KIT in patients with advanced melanoma that are biologically driven by activating mutations in KIT can lead to significant clinical benefit. Importantly, not all mutations in KIT had the same responses. All six of the durable responses were observed in patients with L576P or K642E amino acid substitutions, which are the most common KIT alterations in melanoma.

The study shows how is important to understand the molecular biology behind driver mutations prior to using them for patient selection in clinical trials. In previous trials, in which the patients were not selected based on activating mutations in KIT, no evidence of imatinib efficacy was observed. It is needed to further refine how to select patients for imatinib therapy and investigate other agents or combinations of agents.