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KIT as a therapeutic target in metastatic melanoma

Richard D Carvajal1, Cristina R Antonescu, Jedd D Wolchok

  • 1Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. carvajar@mskcc.org

JAMA
|June 7, 2011
PubMed
Abstract

Insights

Imatinib mesylate showed clinical responses in patients with advanced melanoma harboring KIT alterations. Responses were more likely in tumors with functionally relevant KIT alterations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Some melanomas, particularly those from acral, mucosal, and sun-damaged sites, exhibit activating mutations and amplification of the KIT receptor tyrosine kinase.
  • This study investigates the therapeutic potential of KIT inhibition using imatinib mesylate in this specific molecular subset of melanoma.

Purpose of the Study:

  • To evaluate the clinical efficacy of imatinib mesylate in patients diagnosed with melanoma harboring KIT alterations.
  • To assess the correlation between specific molecular alterations and clinical response to imatinib mesylate treatment.

Main Methods:

  • A phase 2, open-label, single-group trial involving 28 patients with advanced unresectable melanoma and identified KIT mutations or amplification.
  • Patients received imatinib mesylate at a dosage of 400 mg orally twice daily.
  • Primary endpoint was radiographic response, with secondary endpoints including time to progression and overall survival.

Main Results:

  • Among 25 evaluable patients, a 16% durable response rate was observed (2 complete responses, 2 durable partial responses).
  • Median time to progression was 12 weeks, and median overall survival was 46.3 weeks.
  • A higher response rate (40%) was noted in tumors with mutations in recurrent hotspots or a high mutant to wild-type allelic ratio, suggesting positive selection.

Conclusions:

  • Imatinib mesylate demonstrates significant clinical activity in a subset of advanced melanoma patients with KIT alterations.
  • Clinical responses appear to be associated with KIT alterations of demonstrated functional importance.
  • The findings support targeted therapy for melanomas with specific KIT alterations.

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