Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma.
Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma.
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用Trametinib和GSK2141795抑制双MEK/AKT抑制，在转移性NRAS突变和野生型黑色素瘤中不会产生临床益处。
DOI：
10.1111/pcmr.12644
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发表时间：
2018-01
影响因子：
4.3
通讯作者：
Daud A
中科院分区：
文献类型：
--
作者：
Algazi AP;Esteve-Puig R;Nosrati A;Hinds B;Hobbs-Muthukumar A;Nandoskar P;Ortiz-Urda S;Chapman PB;Daud A
异常的MAPK和PI3K通路信号传导可能驱动NRAS突变体和BRAFWT NRASWT转移性黑素瘤的恶性表型。为了靶向这些途径，NRAS突变和BRAFWT NRASWT患者在2队列Simon 2阶段设计中接受每日1.5 mg口服曲美替尼和每日50 mg GSK2141795。受试者有足够的终末器官功能，既往治疗方案不超过2种。每隔8周进行一次影像学评估。入组了10例NRAS突变患者和10例BRAFWT NRASWT患者。两个队列均未观察到客观缓解。NRAS突变队列的中位PFS和OS为2.3和4.0个月，野生型队列为2.8和3.5个月。在25%的患者中观察到3级和4级不良事件，主要是皮疹。我们得出结论，曲美替尼和GSK 2141795的组合在NRAS突变或BRAFWT NRASWT黑素瘤中不具有显著的临床活性。
Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS mutant and BRAFWT NRASWT metastatic melanoma. To target these pathways NRAS mutant and BRAFWT NRASWT patients received oral trametinib at 1.5 mg daily and GSK2141795 at 50 mg daily in a 2-cohort Simon 2-stage design. Participants had adequate end organ function and no more than 2 prior treatment regimens. Imaging assessments were performed at 8-week intervals. 10 NRAS mutant and 10 BRAFWT NRASWT patients were enrolled. No objective responses were noted in either cohort. The median PFS and OS were 2.3 and 4.0 months in the NRAS mutant cohort 2.8 and 3.5 months in the wild-type cohort. Grade 3 and 4 adverse events, primarily rash, were observed in 25% of patients. We conclude that the combination of trametinib and GSK2141795 does not have significant clinical activity in NRAS mutant or BRAFWT NRASWT melanoma.
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DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
51.1
作者：
Ascierto, Paolo A.;Schadendorf, Dirk;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
影响因子：
11.5
作者：
Bedard, Philippe L.;Tabernero, Josep;Sessa, Cristiana
通讯作者：
Sessa, Cristiana
影响因子：
51.1
作者：
Infante, Jeffrey R.;Fecher, Leslie A.;Messersmith, Wells A.
通讯作者：
Messersmith, Wells A.
影响因子：
28.2
作者：
Wagle N;Berger MF;Davis MJ;Blumenstiel B;Defelice M;Pochanard P;Ducar M;Van Hummelen P;Macconaill LE;Hahn WC;Meyerson M;Gabriel SB;Garraway LA
通讯作者：
Garraway LA