Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin

J Clin Oncol. 2013 Sep 10;31(26):3182-90. doi: 10.1200/JCO.2012.47.7836. Epub 2013 Jun 17.

Abstract

Purpose: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.

Patients and methods: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy.

Results: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment.

Conclusion: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

Trial registration: ClinicalTrials.gov NCT00424515.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Benzamides / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Chronic Disease
  • Female
  • GTP Phosphohydrolases / genetics
  • Gene Amplification*
  • Humans
  • Imatinib Mesylate
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / mortality
  • Melanoma / pathology
  • Membrane Proteins / genetics
  • Middle Aged
  • Mucous Membrane / drug effects
  • Mucous Membrane / pathology*
  • Mutation / genetics*
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / pathology
  • Piperazines / therapeutic use*
  • Prognosis
  • Proto-Oncogene Proteins c-kit / genetics*
  • Pyrimidines / therapeutic use*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / mortality
  • Skin Neoplasms / secondary
  • Sunlight*
  • Survival Rate

Substances

  • Antineoplastic Agents
  • Benzamides
  • Biomarkers, Tumor
  • Membrane Proteins
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • GTP Phosphohydrolases
  • NRAS protein, human

Associated data

  • ClinicalTrials.gov/NCT00424515