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Ref Type Journal Article
PMID (23775962)
Authors Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, Friedlander P, Gonzalez R, Weber JS, Gajewski TF, O'Day SJ, Kim KB, Lawrence D, Flaherty KT, Luke JJ, Collichio FA, Ernstoff MS, Heinrich MC, Beadling C, Zukotynski KA, Yap JT, Van den Abbeele AD, Demetri GD, Fisher DE
Title Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.
Journal Vol Issue Date Pages Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31 26 2013 Sep 10 3182-90 J Clin Oncol
URL
Abstract Text Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.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.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.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.

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Molecular Profile Treatment Approach
KIT R634W KIT Inhibitor
KIT K550_P551del KIT Inhibitor
KIT Y553_Q556del KIT Inhibitor
KIT N567_P573del KIT Inhibitor
KIT N564_L576del KIT Inhibitor
KIT K558_Y570delinsNP KIT Inhibitor
KIT V569_L576del KIT Inhibitor
KIT Y568_T574del KIT Inhibitor
KIT D60N KIT Inhibitor
KIT W557_E561del KIT Inhibitor
KIT V559_V560del KIT Inhibitor
KIT K558_Y570delinsN KIT Inhibitor
KIT P551_V555del KIT Inhibitor
KIT K550_V559del KIT Inhibitor
KIT Q556_L576del KIT Inhibitor
KIT V560D KIT Inhibitor
KIT N822I KIT Inhibitor
KIT W557_V560del KIT Inhibitor
KIT D816E KIT Inhibitor
KIT V555_E562del KIT Inhibitor
KIT Q556_W557del KIT Inhibitor
KIT V555_I571del KIT Inhibitor
KIT E554_Y570del KIT Inhibitor
KIT V559_P573del KIT Inhibitor
KIT M552_Q556del KIT Inhibitor
KIT P551_E554del KIT Inhibitor
KIT M552_D572del KIT Inhibitor
KIT Y418_D419delinsS KIT Inhibitor
KIT W557G KIT Inhibitor
KIT M552_K558del KIT Inhibitor
KIT N822Y KIT Inhibitor
KIT D820A KIT Inhibitor
KIT D419del KIT Inhibitor
KIT I571_L576del KIT Inhibitor
KIT A829P KIT Inhibitor
KIT Y823N KIT Inhibitor
KIT D572A KIT Inhibitor
KIT S628N KIT Inhibitor
KIT W557_K558delinsE KIT Inhibitor
KIT K558_Y570delinsR KIT Inhibitor
KIT K558_E562del KIT Inhibitor
KIT Q556_K558del KIT Inhibitor
KIT P551_W557delinsL KIT Inhibitor
KIT W557_Q575del KIT Inhibitor
KIT M552_Y553del KIT Inhibitor
KIT E490K KIT Inhibitor
KIT V559_T574del KIT Inhibitor
KIT V555_P573del KIT Inhibitor
KIT V559I KIT Inhibitor
KIT W557R KIT Inhibitor
KIT M552_Y570del KIT Inhibitor
KIT V559G KIT Inhibitor
KIT A502_Y503dup KIT Inhibitor
KIT V560E KIT Inhibitor
KIT V559_G565del KIT Inhibitor
KIT M552_W557del KIT Inhibitor
KIT N655K KIT Inhibitor
KIT D816N KIT Inhibitor
KIT Q556_V559del KIT Inhibitor
KIT K558_G565delinsR KIT Inhibitor
KIT D816Y KIT Inhibitor
KIT S501_A502dup KIT Inhibitor
KIT V555_Q556del KIT Inhibitor
KIT D820Y KIT Inhibitor
KIT V555_V560del KIT Inhibitor
KIT D820V KIT Inhibitor
KIT L576del KIT Inhibitor
KIT Y553_K558del KIT Inhibitor
KIT K550_E554del KIT Inhibitor
KIT M552_V555del KIT Inhibitor
KIT D816I KIT Inhibitor
KIT W557_K558delinsF KIT Inhibitor
KIT V555_D572del KIT Inhibitor
KIT K558_V560del KIT Inhibitor
KIT V530I KIT Inhibitor
KIT P577del KIT Inhibitor
KIT H697Y KIT Inhibitor
KIT Y578C KIT Inhibitor
KIT S501_A502insSAY KIT Inhibitor
KIT P577_D579del KIT Inhibitor
KIT D816F KIT Inhibitor
KIT K509I KIT Inhibitor
KIT T417_D419delinsRA KIT Inhibitor
KIT L576P KIT Inhibitor
KIT Q556_I571del KIT Inhibitor
KIT Q556_V560delinsH KIT Inhibitor
KIT V560_D572del KIT Inhibitor
KIT K558_D572del KIT Inhibitor
KIT Y553_E561delinsLK KIT Inhibitor
KIT P551_M552delinsL KIT Inhibitor
KIT V560_L576del KIT Inhibitor
KIT Y570_Y578del KIT Inhibitor
KIT Y418_D419delinsG KIT Inhibitor
KIT N564_Y578del KIT Inhibitor
KIT C443Y KIT Inhibitor
KIT K550_V555delinsI KIT Inhibitor
KIT P551_K558delinsQ KIT Inhibitor
KIT F522C KIT Inhibitor
KIT K558delinsNP KIT Inhibitor
KIT V560A KIT Inhibitor
KIT Y553N KIT Inhibitor
KIT W557C KIT Inhibitor
KIT V560G KIT Inhibitor
KIT Y578_D579del KIT Inhibitor
KIT Y823D KIT Inhibitor
KIT T670I KIT Inhibitor
KIT D579del KIT Inhibitor
KIT M552_E554del KIT Inhibitor
KIT T417_D419delinsI KIT Inhibitor
KIT M552_V559del KIT Inhibitor
KIT M552_E554delinsK KIT Inhibitor
KIT V560_Y578del KIT Inhibitor
KIT Y570_L576del KIT Inhibitor
KIT W557_K558delinsC KIT Inhibitor
KIT P551_Y553delinsH KIT Inhibitor
KIT N566_P573del KIT Inhibitor
KIT I563_L576del KIT Inhibitor
KIT act mut KIT Inhibitor
KIT V825A KIT Inhibitor
KIT M552_E554delinsI KIT Inhibitor
KIT V559_V560delinsS KIT Inhibitor
KIT Q556_V559delinsHT KIT Inhibitor
KIT V559D KIT Inhibitor
KIT E562_L576del KIT Inhibitor
KIT Q556_D572del KIT Inhibitor
KIT M552_V555delinsI KIT Inhibitor
KIT Y568_L576delinsCV KIT Inhibitor
KIT V559_E561del KIT Inhibitor
KIT V559A KIT Inhibitor
KIT V559_N566delinsD KIT Inhibitor
KIT K642E KIT Inhibitor
KIT W557_V559del KIT Inhibitor
KIT P551_Q556del KIT Inhibitor
KIT W557S KIT Inhibitor
KIT T417_D419delinsY KIT Inhibitor
KIT exon 11 del KIT Inhibitor
KIT amp KIT Inhibitor
KIT K550_K558del KIT Inhibitor
KIT D816G KIT Inhibitor
KIT P551_V555delinsTL KIT Inhibitor
KIT N822K KIT Inhibitor
KIT T417_Y418delinsH KIT Inhibitor
KIT S476I KIT Inhibitor
KIT W557del KIT Inhibitor
KIT Q556_V560del KIT Inhibitor
KIT Y553_W557del KIT Inhibitor
KIT K558_V559del KIT Inhibitor
KIT M552_V559delinsI KIT Inhibitor
KIT E554_D572delinsA KIT Inhibitor
KIT D820H KIT Inhibitor
KIT K558_N564del KIT Inhibitor
KIT V559K KIT Inhibitor
KIT D820G KIT Inhibitor
KIT V560del KIT Inhibitor
KIT Q556_V559delinsH KIT Inhibitor
KIT Y553_E554del KIT Inhibitor
KIT E554_K558del KIT Inhibitor
KIT W557_K558del KIT Inhibitor
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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT K642E mucosal melanoma predicted - sensitive Imatinib Case Reports/Case Series Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a best overall response rate of 53.8% (7/13, all partial responses) in patients with mucosal, acral, or chronically sun-damaged skin melanoma harboring KIT activating mutations in exons 11 (n=9), 13 (n=3), and 17 (n=1), including 1 partial response and 1 with stable disease in patients with mucosal melanoma harboring KIT K642E (n=3)(PMID: 23775962; NCT00424515). 23775962
KIT exon13 melanoma predicted - sensitive Imatinib Case Reports/Case Series Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a best overall response rate of 53.8% (7/13, all partial responses), a disease control rate of 76.9% (10/13), a median time-to-progression of 3.9 months, and a median overall survival of 12.9 months in patients with mucosal, acral, or chronically sun-damaged skin melanoma harboring KIT activating mutations in exons 11 (n=9), 13 (n=3), and 17 (n=1) (PMID: 23775962; NCT00424515). 23775962
KIT exon11 melanoma predicted - sensitive Imatinib Phase II Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a best overall response rate of 53.8% (7/13, all partial responses), a disease control rate of 76.9% (10/13), a median time-to-progression of 3.9 months, and a median overall survival of 12.9 months in patients with mucosal, acral, or chronically sun-damaged skin melanoma harboring KIT activating mutations in exons 11 (n=9), 13 (n=3), and 17 (n=1) (PMID: 23775962; NCT00424515). 23775962
KIT amp melanoma no benefit Imatinib Phase II Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in limited efficacy in patients with mucosal, acral, or chronically sun-damaged skin melanoma harboring KIT amplification, with a best overall response rate of 0% (0/11), a disease control rate of 18.2% (2/11), a time to progression of 3.4 months, and a median overall survival of 11.9 months (PMID: 23775962; NCT00424515). 23775962
KIT L576P melanoma predicted - sensitive Imatinib Case Reports/Case Series Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a best overall response rate of 53.8% (7/13, all partial responses) in patients with mucosal, acral, or chronically sun-damaged skin melanoma harboring KIT activating mutations in exons 11 (n=9), 13 (n=3), and 17 (n=1), including 3 partial responses and 1 with stable disease in patients with melanoma harboring KIT L576P (PMID: 23775962; NCT00424515). 23775962
KIT V560D mucosal melanoma predicted - sensitive Imatinib Case Reports/Case Series Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a best overall response rate of 53.8% (7/13, all partial responses) in patients with mucosal, acral, or chronically sun-damaged skin melanoma harboring KIT activating mutations in exons 11 (n=9), 13 (n=3), and 17 (n=1), including a partial response with a progression-free survival of 4.5 months and an overall survival of 9.1 months in a patient with mucosal melanoma harboring KIT V560D (PMID: 23775962; NCT00424515). 23775962
KIT D820Y mucosal melanoma predicted - sensitive Imatinib Case Reports/Case Series Actionable In a Phase II trial, Gleevec (imatinib) treatment resulted in a best overall response rate of 53.8% (7/13, all partial responses) in patients with mucosal, acral, or chronically sun-damaged skin melanoma harboring KIT activating mutations in exons 11 (n=9), 13 (n=3), and 17 (n=1), including a partial response with a progression-free survival of 10.2 months and an overall survival of 19.3 months in a patient with mucosal melanoma harboring KIT D820Y (PMID: 23775962; NCT00424515). 23775962