Document Detail

KIT as a therapeutic target in metastatic melanoma.
MedLine Citation:
PMID:  21642685     Owner:  NLM     Status:  MEDLINE    
CONTEXT: 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.
DESIGN, SETTING, AND PATIENTS: 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.
INTERVENTION: Imatinib mesylate, 400 mg orally twice daily.
MAIN OUTCOME MEASURES: 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 Identifier: NCT00470470.
Richard D Carvajal; Cristina R Antonescu; Jedd D Wolchok; Paul B Chapman; Ruth-Ann Roman; Jerrold Teitcher; Katherine S Panageas; Klaus J Busam; Bartosz Chmielowski; Jose Lutzky; Anna C Pavlick; Anne Fusco; Lauren Cane; Naoko Takebe; Swapna Vemula; Nancy Bouvier; Boris C Bastian; Gary K Schwartz
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Publication Detail:
Type:  Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  JAMA     Volume:  305     ISSN:  1538-3598     ISO Abbreviation:  JAMA     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-06     Completed Date:  2011-06-10     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7501160     Medline TA:  JAMA     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2327-34     Citation Subset:  AIM; IM    
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MeSH Terms
Administration, Oral
Aged, 80 and over
Antineoplastic Agents / therapeutic use*
DNA Mutational Analysis
Melanoma / drug therapy*,  genetics,  pathology
Middle Aged
Neoplasm Metastasis
Piperazines / therapeutic use*
Proto-Oncogene Proteins c-kit / genetics*
Pyrimidines / therapeutic use*
Skin Neoplasms / drug therapy*,  genetics,  pathology
Survival Analysis
Treatment Outcome
Grant Support
K12 CA120121/CA/NCI NIH HHS; N01CM62206/CM/NCI NIH HHS; P30 CA008748/CA/NCI NIH HHS; R01FD003445-01/FD/FDA HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Benzamides; 0/Piperazines; 0/Pyrimidines; BKJ8M8G5HI/imatinib; EC Proteins c-kit
Comment In:
Nat Rev Clin Oncol. 2011 Aug;8(8):446   [PMID:  21709696 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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