Dana-Farber Cancer Institute, Boston, MA, USA.
Leuven Cancer Institute, Leuven, European Union, Belgium.
Gynecol Oncol. 2015 Feb;136(2):246-53. doi: 10.1016/j.ygyno.2014.12.019. Epub 2014 Dec 17.
Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma.
This Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received pilaralisib 600mg capsules or 400mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free survival (PFS) >6months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to pilaralisib.
67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS>6months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (40.3%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade ≥3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%).
Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma.
一线化疗后进展的子宫内膜癌患者预后较差。磷脂酰肌醇 3-激酶（PI3K）抑制剂是该治疗环境中的研究性治疗选择。本研究评估了 PI3K 抑制剂 pilaralisib（SAR245408；XL147）在晚期或复发性子宫内膜癌中的疗效和安全性。
这是一项多中心、单臂、开放标签的 II 期研究，招募了组织学证实的晚期或复发性子宫内膜癌患者，这些患者接受过一种或两种先前的化疗方案。患者每天接受一次 pilaralisib 600mg 胶囊或 400mg 片剂。主要终点是客观缓解率（ORR）、无进展生存期（PFS）>6 个月的患者比例和安全性。对存档肿瘤组织和循环肿瘤 DNA 进行分子谱分析，以确定与 pilaralisib 反应或耐药相关的分子标志物。
共纳入 67 例患者，其中 50 例和 17 例患者分别接受了一种或两种先前的方案。两名患者各有完全或部分肿瘤反应（ORR 6.0%）；三名患者的肿瘤具有正常的 PTEN 表达和 PIK3R1 突变，一名患者的肿瘤具有 PTEN 蛋白缺乏。然而，分子改变与临床活性之间没有关联。PFS>6 个月的发生率为 11.9%。最常见的治疗相关不良事件（AE）是皮疹（40.3%）、腹泻（37.3%）和疲劳（28.4%）。最常见的治疗相关≥3 级 AE 是皮疹（9.0%）、腹泻（4.5%）和丙氨酸氨基转移酶升高（4.5%）。
pilaralisib 与晚期或复发性子宫内膜癌患者良好的安全性和最小的抗肿瘤活性相关。
