Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma
Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma
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DOI：
10.1016/j.ygyno.2014.12.019
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发表时间：
2015-02-01
影响因子：
4.7
通讯作者：
Ghamande, Sharad
中科院分区：
文献类型：
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作者：
Matulonis, Ursula;Vergote, Ignace;Ghamande, Sharad
Objective.一线化疗后进展的子宫内膜癌患者预后不良。磷酸肌醇3-激酶（PI 3 K）抑制剂是这种情况下的研究性治疗选择。本研究评价了PI 3 K抑制剂pilaralisib（SAR 245408; XL 147）在晚期或复发性子宫内膜癌中的疗效和安全性。这项II期、多中心、单臂、开放标签研究招募了组织学证实的晚期或复发性子宫内膜癌患者，这些患者既往接受过一种或两种化疗方案。患者接受pilaralisib 600 mg胶囊或400 mg片剂，每日一次。主要终点为客观缓解率（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，以鉴定与pilaralisib应答或耐药相关的分子标志物。入组了67名患者，其中分别有50名和17名患者接受过一种或两种既往方案。各有2例患者发生完全或部分肿瘤缓解（ORR 6.0%）; 3例患者的肿瘤具有正常的PTEN表达和PIK 3R 1突变，1例患者的肿瘤具有PTEN蛋白缺陷。然而，分子改变和临床活性之间没有关联。PFS >6个月的发生率为11.9%。最常报告的治疗相关不良事件（AE）为皮疹（403%）、腹泻（37.3%）和疲乏（28.4%）。最常报告的治疗相关≥ 3级AE为皮疹（9.0%）、腹泻（4.5%）和丙氨酸氨基转移酶升高（4.5%）。Pilaralisib在晚期或复发性子宫内膜癌中具有良好的安全性和最小的抗肿瘤活性。(C)2014爱思唯尔公司All rights reserved.
Objective. 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.Methods. 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 600 mg capsules or 400 mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free suririval (PFS) >6 months 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.Results. 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 >6 months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (403%), 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%).Conclusions. Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma. (C) 2014 Elsevier Inc. All rights reserved.