BACKGROUND PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. METHODS We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. RESULTS Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. CONCLUSION In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile.

中文翻译：

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LY3023414在PI3K途径中具有激活突变的晚期子宫内膜癌患者的2期研究。

背景技术PI3K途径激活在子宫内膜癌中很常见。我们评估了双重PI3K / mTOR抑制剂LY3023414在患有晚期子宫内膜癌且在PI3K途径中具有激活突变的患者的安全性和有效性。方法我们进行了单药治疗LY3023414的单臂2期研究。符合条件的患者患有任何级别的晚期子宫内膜癌，事先使用1-4种细胞毒性品系进行治疗，并且PI3K通路激活被潜在地定义为功能丧失的PTEN改变或PIK3CA，AKT1，PIK3R1，PIK3R2或MTOR的激活改变。主要目标是根据RECIST 1.1获得最佳总体响应率（ORR）。结果治疗了28例患者。组织学包括子宫内膜样肿（39％），癌肉瘤（25％），浆液性（21％）和混合性（14％）。患者接受了严格的预处理，中位数为2个先前的细胞毒性品系（范围1-3）。最常见的变化涉及PIK3CA（68％），PTEN（43％）和PIK3R1（32％）。在这25位可评估疗效的患者中，ORR为16％（CI为90％，7％-100％），临床受益率为28％（CI为90％，16％-100％）。有4例患者确诊有部分反应，其中2例反应持续时间超过9个月。中位无进展生存期和总生存期分别为2.5个月（95％CI，1.2-3.0）和9.2个月（95％CI，5.0-15.9）。与治疗相关的最常见的全等级不良事件是贫血（71％），高血糖症（71％），低白蛋白血症（68％）和低磷血症（61％）。没有观察到分子变化和反应之间的相关性。