Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA.
J Clin Oncol. 2010 Jan 1;28(1):69-76. doi: 10.1200/JCO.2009.24.2669. Epub 2009 Nov 23.
PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.
化疗失败后，胰腺神经内分泌肿瘤（NET）的进展尚无既定的治疗方法。依维莫司（RAD001）是一种哺乳动物雷帕霉素靶蛋白的口服抑制剂，与奥曲肽联合使用在 NET 患者中显示出令人鼓舞的抗肿瘤活性。
这项开放标签的 II 期研究评估了转移性胰腺 NET 患者在化疗后或之后进展时使用依维莫司的临床活性。患者按既往奥曲肽治疗（分层 1：依维莫司 10mg/d，n=115；分层 2：依维莫司 10mg/d 加奥曲肽长效释放[LAR]，n=45）进行分层。每 3 个月进行一次肿瘤评估（使用实体瘤反应评估标准）。如果基线时升高，则每月评估嗜铬粒蛋白 A（CgA）和神经元特异性烯醇化酶（NSE）。评估依维莫司和奥曲肽的谷浓度。
经中心放射学审查，在分层 1 中，有 11 例部分缓解（9.6%），78 例（67.8%）患者疾病稳定（SD），16 例（13.9%）患者疾病进展；中位无进展生存期（PFS）为 9.7 个月。在分层 2 中，有 2 例部分缓解（4.4%），36 例（80%）患者疾病稳定（SD），无疾病进展患者；中位 PFS 为 16.7 个月。与无早期反应的患者相比，早期 CgA 或 NSE 有反应的患者 PFS 更长。奥曲肽 LAR 与依维莫司联合使用并未影响两种药物的暴露。大多数不良事件为轻度至中度，与以前使用依维莫司所见一致。
依维莫司每日给药，联合或不联合奥曲肽 LAR，在先前接受全身化疗后进展的晚期胰腺 NET 患者中，通过客观缓解率和 PFS 测量显示出抗肿瘤活性，并且耐受性良好。
