Reference Detail

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 M552_V555del	KIT Inhibitor
KIT M552_Y553del	KIT Inhibitor
KIT Q556_V559del	KIT Inhibitor
KIT Y553_Q556del	KIT Inhibitor
KIT D60N	KIT Inhibitor
KIT V559_P573del	KIT Inhibitor
KIT V560E	KIT Inhibitor
KIT E554_D572delinsA	KIT Inhibitor
KIT A502_Y503dup	KIT Inhibitor
KIT C443Y	KIT Inhibitor
KIT W557_E561del	KIT Inhibitor
KIT T417_D419delinsRA	KIT Inhibitor
KIT exon 11 del	KIT Inhibitor
KIT P551_M552delinsL	KIT Inhibitor
KIT D579del	KIT Inhibitor
KIT L576del	KIT Inhibitor
KIT E562_L576del	KIT Inhibitor
KIT K558_D572del	KIT Inhibitor
KIT D820V	KIT Inhibitor
KIT V560del	KIT Inhibitor
KIT V555_E562del	KIT Inhibitor
KIT D419del	KIT Inhibitor
KIT Q556_I571del	KIT Inhibitor
KIT N566_P573del	KIT Inhibitor
KIT K558_V560del	KIT Inhibitor
KIT V559_T574del	KIT Inhibitor
KIT K509I	KIT Inhibitor
KIT K550_V555delinsI	KIT Inhibitor
KIT T670I	KIT Inhibitor
KIT S628N	KIT Inhibitor
KIT Y568_T574del	KIT Inhibitor
KIT Q556_V559delinsH	KIT Inhibitor
KIT V555_Q556del	KIT Inhibitor
KIT K558_E562del	KIT Inhibitor
KIT M552_E554delinsK	KIT Inhibitor
KIT D572A	KIT Inhibitor
KIT T417_D419delinsI	KIT Inhibitor
KIT I563_L576del	KIT Inhibitor
KIT K558_V559del	KIT Inhibitor
KIT S501_A502insSAY	KIT Inhibitor
KIT P551_E554del	KIT Inhibitor
KIT Y578_D579del	KIT Inhibitor
KIT Y823N	KIT Inhibitor
KIT Q556_V559delinsHT	KIT Inhibitor
KIT Y418_D419delinsS	KIT Inhibitor
KIT P551_Y553delinsH	KIT Inhibitor
KIT R634W	KIT Inhibitor
KIT P551_V555delinsTL	KIT Inhibitor
KIT W557del	KIT Inhibitor
KIT E554_K558del	KIT Inhibitor
KIT P577del	KIT Inhibitor
KIT Y553_E561delinsLK	KIT Inhibitor
KIT K642E	KIT Inhibitor
KIT S476I	KIT Inhibitor
KIT W557C	KIT Inhibitor
KIT K558_Y570delinsR	KIT Inhibitor
KIT D816E	KIT Inhibitor
KIT V560G	KIT Inhibitor
KIT V559_V560del	KIT Inhibitor
KIT S501_A502dup	KIT Inhibitor
KIT K550_P551del	KIT Inhibitor
KIT T417_D419delinsY	KIT Inhibitor
KIT D820G	KIT Inhibitor
KIT V560A	KIT Inhibitor
KIT Y418_D419delinsG	KIT Inhibitor
KIT W557_K558delinsC	KIT Inhibitor
KIT N564_L576del	KIT Inhibitor
KIT V559I	KIT Inhibitor
KIT K550_K558del	KIT Inhibitor
KIT M552_Y570del	KIT Inhibitor
KIT Y553N	KIT Inhibitor
KIT N567_P573del	KIT Inhibitor
KIT D816N	KIT Inhibitor
KIT V569_L576del	KIT Inhibitor
KIT K558delinsNP	KIT Inhibitor
KIT V560D	KIT Inhibitor
KIT M552_W557del	KIT Inhibitor
KIT Q556_V560del	KIT Inhibitor
KIT M552_K558del	KIT Inhibitor
KIT W557_Q575del	KIT Inhibitor
KIT N564_Y578del	KIT Inhibitor
KIT T417_Y418delinsH	KIT Inhibitor
KIT V559A	KIT Inhibitor
KIT M552_V555delinsI	KIT Inhibitor
KIT A829P	KIT Inhibitor
KIT Y823D	KIT Inhibitor
KIT K550_V559del	KIT Inhibitor
KIT Q556_W557del	KIT Inhibitor
KIT V560_D572del	KIT Inhibitor
KIT N655K	KIT Inhibitor
KIT V559_G565del	KIT Inhibitor
KIT W557_K558del	KIT Inhibitor
KIT Y553_E554del	KIT Inhibitor
KIT W557_V559del	KIT Inhibitor
KIT P551_W557delinsL	KIT Inhibitor
KIT W557S	KIT Inhibitor
KIT D816F	KIT Inhibitor
KIT P551_K558delinsQ	KIT Inhibitor
KIT V560_Y578del	KIT Inhibitor
KIT V559_N566delinsD	KIT Inhibitor
KIT H697Y	KIT Inhibitor
KIT D816G	KIT Inhibitor
KIT E490K	KIT Inhibitor
KIT V559G	KIT Inhibitor
KIT N822I	KIT Inhibitor
KIT K558_Y570delinsNP	KIT Inhibitor
KIT P551_V555del	KIT Inhibitor
KIT K558_N564del	KIT Inhibitor
KIT E554_Y570del	KIT Inhibitor
KIT M552_V559delinsI	KIT Inhibitor
KIT V559_E561del	KIT Inhibitor
KIT D820Y	KIT Inhibitor
KIT K558_Y570delinsN	KIT Inhibitor
KIT Q556_D572del	KIT Inhibitor
KIT M552_D572del	KIT Inhibitor
KIT Q556_L576del	KIT Inhibitor
KIT Y570_L576del	KIT Inhibitor
KIT V555_V560del	KIT Inhibitor
KIT Y570_Y578del	KIT Inhibitor
KIT D820H	KIT Inhibitor
KIT M552_Q556del	KIT Inhibitor
KIT Y553_K558del	KIT Inhibitor
KIT F522C	KIT Inhibitor
KIT act mut	KIT Inhibitor
KIT I571_L576del	KIT Inhibitor
KIT Q556_V560delinsH	KIT Inhibitor
KIT W557G	KIT Inhibitor
KIT N822K	KIT Inhibitor
KIT W557R	KIT Inhibitor
KIT M552_E554delinsI	KIT Inhibitor
KIT amp	KIT Inhibitor
KIT P551_Q556del	KIT Inhibitor
KIT K550_E554del	KIT Inhibitor
KIT W557_K558delinsF	KIT Inhibitor
KIT M552_V559del	KIT Inhibitor
KIT Q556_K558del	KIT Inhibitor
KIT K558_G565delinsR	KIT Inhibitor
KIT V825A	KIT Inhibitor
KIT V559K	KIT Inhibitor
KIT Y568_L576delinsCV	KIT Inhibitor
KIT Y578C	KIT Inhibitor
KIT M552_E554del	KIT Inhibitor
KIT N822Y	KIT Inhibitor
KIT W557_K558delinsE	KIT Inhibitor
KIT V555_D572del	KIT Inhibitor
KIT D816Y	KIT Inhibitor
KIT V559D	KIT Inhibitor
KIT V559_V560delinsS	KIT Inhibitor
KIT V555_P573del	KIT Inhibitor
KIT V555_I571del	KIT Inhibitor
KIT V530I	KIT Inhibitor
KIT P577_D579del	KIT Inhibitor
KIT D820A	KIT Inhibitor
KIT L576P	KIT Inhibitor
KIT V560_L576del	KIT Inhibitor
KIT Y553_W557del	KIT Inhibitor
KIT W557_V560del	KIT Inhibitor
KIT D816I	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