Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan.
Cancer Sci. 2019 Mar;110(3):1032-1043. doi: 10.1111/cas.13943. Epub 2019 Feb 22.
Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m (28%) for irinotecan and, at steady state, 72.6 L/h/m (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.
阿柏西普靶向血管内皮生长因子。本研究旨在评估阿柏西普联合氟尿嘧啶/亚叶酸/伊立替康（FOLFIRI）作为二线治疗方案用于日本转移性结直肠癌（mCRC）患者的疗效、安全性和药代动力学。62 例 mCRC 患者每 2 周接受一次阿柏西普（4mg/kg）联合 FOLFIRI 治疗，直至疾病进展、无法耐受毒性或患者退出。每 6 周对肿瘤进行影像学评估。主要终点为客观缓解率（ORR）；次要终点为无进展生存期、总生存期、安全性以及阿柏西普、伊立替康和氟尿嘧啶的药代动力学。共 60 例患者可评估 ORR，其中 50 例患者曾接受贝伐珠单抗治疗。ORR 为 8.3%（95%置信区间[CI]：1.3%-15.3%），疾病控制率（DCR）为 80.0%（69.9%-90.1%）。中位无进展生存期为 5.42 个月（4.14-6.70 个月），中位总生存期为 15.59 个月（11.20-19.81 个月）。未观察到与治疗相关的死亡事件，也未发现明显的药物相互作用。最常见的治疗相关不良事件为中性粒细胞减少和食欲下降。游离阿柏西普的平均最大浓度（变异系数）为 73.2μg/mL（15%），清除率为 0.805L/d（22%），分布容积为 6.2L（18%）；与血管内皮生长因子结合的阿柏西普清除率为 0.162L/d（9%）（N=62）。阿柏西普对伊立替康和氟尿嘧啶的药代动力学无显著影响：伊立替康的清除率为 11.1L/h/m（28%），氟尿嘧啶的稳态清除率为 72.6L/h/m（56%）（N=10）。在日本 mCRC 患者中，阿柏西普联合 FOLFIRI 治疗具有疗效且耐受性良好。临床试验注册号：NCT01882868。
