KIT as a therapeutic target in metastatic melanoma.
KIT as a therapeutic target in metastatic melanoma.
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套件作为转移性黑色素瘤的治疗靶标。
DOI：
10.1001/jama.2011.746
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发表时间：
2011-06-08
影响因子：
120.7
通讯作者：
Schwartz, Gary K.
中科院分区：
文献类型：
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作者：
Carvajal, Richard D.;Antonescu, Cristina R.;Wolchok, Jedd D.;Chapman, Paul B.;Roman, Ruth-Ann;Teitcher, Jerrold;Panageas, Katherine S.;Busam, Klaus J.;Chmielowski, Bartosz;Lutzky, Jose;Pavlick, Anna C.;Fusco, Anne;Cane, Lauren;Takebe, Naoko;Vemula, Swapna;Bouvier, Nancy;Bastian, Boris C.;Schwartz, Gary K.
一些源自肢端、粘膜和长期阳光损伤部位的黑色素瘤含有 III 型跨膜受体酪氨酸激酶 KIT 的激活突变和扩增。我们探讨了使用甲磺酸伊马替尼抑制 KIT 对这一分子疾病子集的影响。评估甲磺酸伊马替尼对携带 KIT 改变的黑色素瘤患者的临床效果。 2007 年 4 月 23 日至 2010 年 4 月 16 日期间，在美国 1 个社区和 5 个学术肿瘤中心对 295 名黑色素瘤患者进行了一项单组、开放标签、2 期试验，筛查了 KIT 突变和扩增的存在。总共鉴定了 51 例具有此类改变的病例，其中 28 名患有肢端、粘膜和慢性疾病引起的晚期不可切除黑色素瘤的患者接受了治疗。被阳光损坏的地方。甲磺酸伊马替尼，400 mg，口服，每日两次。放射学反应，次要终点包括进展时间、总生存期以及分子改变和临床反应的相关性。在 25 名可评估患者中，观察到 2 例持续 94（持续）和 95 周的完全缓解，2 例持续 53 和 89（持续）周的持久部分缓解，以及 2 例持续 12 和 18 周的短暂部分缓解。总体持久缓解率为 16%（95% 置信区间 [CI]，2%–30%），中位进展时间为 12 周（四分位数范围 [IQR]，6–18 周；95% CI，11–18 周），中位总生存期为 46.3 周（IQR，28 周 - 未实现；95% CI，28 周 - 未实现）。在突变影响复发性热点或突变体与野生型等位基因比率超过 1（40% vs 0%，P=.05）的情况下，反应率更好，表明对突变等位基因的阳性选择。在携带 KIT 改变的晚期黑色素瘤患者中，甲磺酸伊马替尼治疗在一部分患者中产生了显着的临床反应。反应可能仅限于含有已证明功能相关的 KIT 改变的肿瘤。
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.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
45.3
作者：
Chapman, PB;Einhorn, LH;Kirkwood, JM
通讯作者：
Kirkwood, JM
影响因子：
45.3
作者：
Heinrich, MC;Corless, CL;Fletcher, JA
通讯作者：
Fletcher, JA
影响因子：
11.5
作者：
Jiang, Xiaofeng;Zhou, Jun;Hodi, F. Stephen
通讯作者：
Hodi, F. Stephen
影响因子：
6.4
作者：
Ashida, Atsuko;Takata, Minoru;Saida, Toshiaki
通讯作者：
Saida, Toshiaki