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Ref Type Journal Article
PMID (21642685)
Authors Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC, Schwartz GK
Title KIT as a therapeutic target in metastatic melanoma.
Journal Vol Issue Date Pages Journal Short Title
JAMA 305 22 2011 Jun 08 2327-34 JAMA
URL
Abstract Text 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.To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations.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.Imatinib mesylate, 400 mg orally twice daily.Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT E554K missense unknown KIT E554K lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). E554K has been identified in sequencing studies (PMID: 21642685, PMID: 36948401), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).
KIT N463S missense unknown KIT N463S lies within Ig-like C2-type domain 5 (exon 9) of the Kit protein (UniProt.org). N463S has been identified in sequencing studies (PMID: 21642685, PMID: 38348622), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).
KIT P838L missense unknown KIT P838L lies within the protein kinase domain of the Kit protein (UniProt.org). P838L has been identified in sequencing studies (PMID: 21642685) but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).
KIT Y570H missense unknown KIT Y570H lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). Y570H has been identified in sequencing studies (PMID: 21642685), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT L576P melanoma predicted - sensitive Imatinib Case Reports/Case Series Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a durable objective response rate of 16% (4/25, 2 complete and 2 partial responses), a median time-to-progression of 12 weeks, and a median survival from treatment initiation of 46.3 weeks in patients with melanoma harboring KIT mutations, including 2 complete, 1 partial, 1 transient partial response, and 1 stable disease in patients harboring KIT L576P (n=7) (PMID: 21642685; NCT00470470). 21642685
KIT K642E melanoma predicted - sensitive Imatinib Case Reports/Case Series Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a durable objective response rate of 16% (4/25, 2 complete and 2 partial responses), a median time-to-progression of 12 weeks, and a median survival from treatment initiation of 46.3 weeks in patients with melanoma harboring KIT mutations, including 1 partial response, 1 transient partial response, and 2 stable disease in patients harboring KIT K642E (PMID: 21642685; NCT00470470). 21642685