Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma.
Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma.
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MEK抑制剂selumetinib（AZD6244，Arry-142886）的II期试验对BRAFV600E/K-突变的黑色素瘤患者。
DOI：
10.1158/1078-0432.ccr-12-3476
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发表时间：
2013-04-15
期刊：
影响因子：
--
通讯作者：
Chapman PB
中科院分区：
文献类型：
--
作者：
Catalanotti F;Solit DB;Pulitzer MP;Berger MF;Scott SN;Iyriboz T;Lacouture ME;Panageas KS;Wolchok JD;Carvajal RD;Schwartz GK;Rosen N;Chapman PB
检验在BRAF突变的黑色素瘤中，MEK抑制剂司美替尼的临床反应将局限于PI3K/AKT通路未激活的肿瘤这一假设。
我们在肿瘤携带BRAF突变的黑色素瘤患者中进行了一项II期试验。患者根据磷酸化AKT（pAKT）表达（高与低）进行分层，并接受司美替尼75mg口服，每日两次治疗。还使用外显子捕获方法分析了治疗前肿瘤中230个感兴趣基因的遗传变化。
在前10名患者中未观察到反应后，高pAKT组关闭。低pAKT黑色素瘤肿瘤的发生率较低（约占所检测黑色素瘤的25%），并且由于入组情况不佳，该组最终关闭。然而，在低pAKT组入组的5名黑色素瘤患者中，有1名部分缓解（PR）。另外2名患者在对残留疾病进行手术切除（1名患者）或因毒性停止治疗（1名患者）之前接近部分缓解。在2名无反应的低pAKT黑色素瘤患者中，检测到MAP2K1、NF1和/或EGFR的共突变。
在5名BRAF突变、低pAKT黑色素瘤患者中，有3名患者出现肿瘤消退；在高pAKT组中未观察到反应。这些结果为在肿瘤表达高pAKT的BRAF突变黑色素瘤患者中共同靶向MEK和PI3K/AKT提供了理论依据。然而，黑色素瘤遗传变化的复杂性表明，为了最佳选择可能对MEK抑制剂有反应的患者，将需要额外的遗传信息。
Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated. We conducted a phase II trial in melanoma patients whose tumors harbored a BRAF mutation. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg po bid. Pretreatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach. The high pAKT cohort was closed after no responses were seen in the first 10 patients. The incidence of low pAKT melanoma tumors was low (approximately 25% of melanomas tested) and this cohort was eventually closed because of poor accrual. However, among the 5 melanoma patients accrued in the low pAKT cohort, there was 1 PR. Two other patients had near PRs before undergoing surgical resection of residual disease (1 patient) or discontinuation of treatment due to toxicity (1 patient). Among the 2 non-responding, low pAKT melanoma patients, co-mutations in MAP2K1, NF1, and/or EGFR were detected. Tumor regression was seen in 3 of 5 patients with BRAF-mutated, low pAKT melanomas; no responses were seen in the high pAKT cohort.These results provide rationale for co-targeting MEK and PI3K/AKT in patients with BRAF mutant melanoma whose tumors express high pAKT. However, the complexity of genetic changes in melanoma indicates that additional genetic information will be needed for optimal selection of patients likely to respond to MEK inhibitors.