培美曲塞联合西罗莫司治疗晚期既往治疗过的非小细胞肺癌的I/II期研究。
A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer.
作者信息
Komiya Takefumi, Memmott Regan M, Blumenthal Gideon M, Bernstein Wendy, Ballas Marc S, De Chowdhury Roopa, Chun Guinevere, Peer Cody J, Figg William D, Liewehr David J, Steinberg Seth M, Giaccone Giuseppe, Szabo Eva, Kawabata Shigeru, Tsurutani Junji, Rajan Arun, Dennis Phillip A
机构信息
Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Biostatistics and Data Management Section, National Cancer Institute, Rockville, MD, USA.
出版信息
Transl Lung Cancer Res. 2019 Jun;8(3):247-257. doi: 10.21037/tlcr.2019.04.19.
BACKGROUND
Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed.
METHODS
This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0-2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle.
RESULTS
Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3-4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0-29.4).
CONCLUSIONS
The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).
背景
单药培美曲塞是一种用于复发性非鳞状非小细胞肺癌（NSCLC）的治疗方法，疗效有限。临床前研究表明，将雷帕霉素哺乳动物靶点（mTOR）抑制剂西罗莫司添加到培美曲塞中具有显著的协同效应。
方法
这是一项在单一机构进行的培美曲塞联合西罗莫司的I/II期研究。I期的主要终点是确定联合用药的最大耐受剂量（MTD）和安全性。II期部分的主要终点是确定MTD时的总缓解率。关键入选标准包括复发性、转移性NSCLC，东部肿瘤协作组（ECOG）体能状态为0 - 2，以及器官功能良好。西罗莫司在初始负荷剂量后每日口服给药，培美曲塞在每21天周期的第1天静脉给药。
结果
42例复发性、转移性NSCLC患者入组，其中22例进入I期，20例进入II期。MTD为每3周给予培美曲塞500mg/m²，第1天给予西罗莫司10mg，之后每日给予3mg。38例（90.5%）患者发生了与治疗相关的不良事件（AE）。最常见的3 - 4级与治疗相关的AE是淋巴细胞减少（31%）和低磷血症（19%）。分别有2例与治疗相关的死亡，原因是发热性中性粒细胞减少和感染。在接受MTD治疗的27例患者中，6例（22.2%）有部分缓解（PR），12例（44.4%）病情稳定（SD），5例（18.5%）病情进展。中位无进展生存期（PFS）为18.4周（95%CI：7.0 - 29.4）。
结论
培美曲塞和西罗莫司联合用药对经过大量预处理的NSCLC有效（ClinicalTrials.gov标识符：NCT00923273）。
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