AKT Inhibition in Solid Tumors With AKT1 Mutations.
AKT Inhibition in Solid Tumors With AKT1 Mutations.
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DOI：
10.1200/jco.2017.73.0143
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发表时间：
2017-07-10
期刊：
影响因子：
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通讯作者：
Taylor BS
中科院分区：
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作者：
Hyman DM;Smyth LM;Donoghue MTA;Westin SN;Bedard PL;Dean EJ;Bando H;El-Khoueiry AB;Pérez-Fidalgo JA;Mita A;Schellens JHM;Chang MT;Reichel JB;Bouvier N;Selcuklu SD;Soumerai TE;Torrisi J;Erinjeri JP;Ambrose H;Barrett JC;Dougherty B;Foxley A;Lindemann JPO;McEwen R;Pass M;Schiavon G;Berger MF;Chandarlapaty S;Solit DB;Banerji U;Baselga J;Taylor BS
AKT1 E17K突变是致癌的，发生在许多癌症中，发病率很低。我们进行了AZD5363的多组织学篮子研究，AZD5363是一种ATP竞争性泛AKT激酶抑制剂，以确定AKT突变癌症中AKT抑制的初步活性。58例晚期实体瘤患者接受了治疗。主要终点是安全性；次要终点是无进展生存期(PFS)和根据实体瘤反应评估标准(RECIST)的反应。在大多数患者中收集肿瘤活检和血浆无细胞DNA(CfDNA)，以确定预测反应的生物标志物。在AKT1 E17K突变肿瘤患者(n=52)中，雌激素受体阳性的乳腺癌、妇科和其他实体肿瘤患者的中位PFS分别为5.5个月(95%CI，2.9~6.9个月)、6.6个月(95%CI，1.5~8.3个月)和4.2个月(95%CI，2.1~12.8个月)。在一项探索性生物标志物分析中，AKT1 E17K突变等位基因的不平衡，最常见的原因是针对野生型等位基因的拷贝中性杂合性丢失，与较长的PFS相关(风险比[HR]，0.41；P=0.04)，以及PI3K途径热点突变的存在(HR，0.21；P=0.045)。CfDNA中AKT1 E17K的持续下降与PFS的改善(HR，0.18；P=0.004)和反应(P=0.025)相关。治疗前cfDNA中可检测到AKT1 E17K的患者并不局限于此。最常见的≥3级不良反应是高血糖(24%)、腹泻(17%)和皮疹(15.5%)。这项研究首次提供了AKT1 E17K是人类癌症治疗靶点的临床数据。AKT1 E17K突变的基因组环境进一步限制了对AZD5363的反应。
AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. In patients with AKT1 E17K–mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor–positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K–mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response (P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.