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Preliminary Communication
June 8, 2011

KIT as a Therapeutic Target in Metastatic Melanoma

Author Affiliations

Author Affiliations: Departments of Medicine (Drs Carvajal, Wolchok, Chapman, and Schwartz and Mss Roman, Fusco, and Cane), Pathology (Drs Antonescu, Busam, and Bastian), Radiology (Dr Teitcher), and Epidemiology and Biostatistics (Dr Panageas), and Human Oncology and Pathogenesis Program (Dr Bastian), Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, University of California Los Angeles Medical Center, Los Angeles (Dr Chmielowski); Department of Medicine, Mount Sinai Medical Center, Miami Beach, Florida (Dr Lutzky); Department of Medicine, New York University Langone Medical Center, New York (Dr Pavlick); Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, Maryland (Dr Takebe); and Departments of Dermatology and Pathology, University of California San Francisco Medical Center, San Francisco (Dr Bastian and Mss Vemula and Bouvier).

JAMA. 2011;305(22):2327-2334. doi:10.1001/jama.2011.746

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 clinicaltrials.gov Identifier: NCT00470470