International Institute of Clinical Studies, Sarcoma Oncology Center, Santa Monica, CA, USA.
J Clin Oncol. 2012 Jan 1;30(1):78-84. doi: 10.1200/JCO.2011.35.6329. Epub 2011 Nov 7.
Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas.
Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated.
A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue.
Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.
依维莫司是哺乳动物雷帕霉素靶蛋白（mTOR）的抑制剂，mTOR 是磷脂酰肌醇 3-激酶/AKT 信号通路的一个组成部分，在肉瘤中具有早期活性的证据。这项多中心、开放标签、单臂、Ⅱ期试验旨在评估依维莫司在不同亚型晚期肉瘤患者中的抗肿瘤活性。
转移性或不可切除的软组织或骨肉瘤患者接受依维莫司 12.5mg 治疗，每日一次，30 分钟静脉输注，每 2 周连用 5 天。主要终点是临床获益反应（CBR）率（完全缓解或部分缓解[PR]或稳定疾病≥16 周）。还评估了安全性、无进展生存期（PFS）、总生存期（OS）、疾病进展时间和缓解持续时间。
共有 212 名患者在四个独立的组织学队列中接受了治疗。在这个预处理过的患者人群中，61 名患者（28.8%）达到了 CBR。中位 PFS 为 15.3 周；中位 OS 为 40 周。根据实体瘤反应评价标准（RECIST），确认的缓解率为 1.9%，有 4 名患者达到了确认的 PR（两名骨肉瘤患者，一名梭形细胞肉瘤患者，一名恶性纤维组织细胞瘤患者）。分析的肿瘤蛋白标志物与 CBR 没有相关性。相关不良事件通常为轻度或中度，主要包括口腔炎、粘膜炎症、口腔溃疡、皮疹和疲劳。
依维莫司单药治疗晚期和预处理过的肉瘤患者，其 PFS 结果与历史数据相比具有优势。一项基于这些数据的Ⅲ期试验将进一步确定依维莫司在肉瘤中的活性。
