title: KIT as a therapeutic target in metastatic melanoma.
abstract: BACKGROUND
  Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease.
  
  
  OBJECTIVE
  To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations.
  
  
  METHODS
  A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites.
  
  
  METHODS
  Imatinib mesylate, 400 mg orally twice daily.
  
  
  METHODS
  Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response.
  
  
  RESULTS
  Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%-30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6-18 weeks; 95% CI, 11-18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P = .05), indicating positive selection for the mutated allele.
  
  
  CONCLUSIONS
  Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance. Trial Registration clinicaltrials.gov Identifier: NCT00470470.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. carvajar@mskcc.org
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Ruth-Ann
authors.initials: RA
authors.lastname: Roman
authors.forename: Jerrold
authors.initials: J
authors.lastname: Teitcher
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.forename: Jose
authors.initials: J
authors.lastname: Lutzky
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Anne
authors.initials: A
authors.lastname: Fusco
authors.forename: Lauren
authors.initials: L
authors.lastname: Cane
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.forename: Swapna
authors.initials: S
authors.lastname: Vemula
authors.forename: Nancy
authors.initials: N
authors.lastname: Bouvier
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit