Ishiguro Hiroshi, Saji Shigehira, Nomura Shogo, Tanaka Sunao, Ueno Takayuki, Onoue Masahide, Iwata Hiroji, Yamanaka Takeharu, Sasaki Yasutsuna, Toi Masakazu
Department of Medical Oncology, International University of Health and Welfare Hospital, Nasushiobara, Japan.
Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan.
Cancer Med. 2017 Dec;6(12):2909-2917. doi: 10.1002/cam4.1258. Epub 2017 Nov 13.
S-1 and irinotecan combination is attractive for breast cancer refractory to anthracyclines and taxanes. Patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer previously treated with anthracyclines and taxanes were eligible. Patients with brain metastases and homozygous for UGT1A1 *6 or *28 or compound heterozygous (*6/*28) were excluded. A dose-escalation design was chosen for the phase I portion (level 1: irinotecan 80 mg/m days 1-8 and S-1 80 mg/m days 1-14 every 3 weeks; level 2: irinotecan 100 mg/m and S-1 80 mg/m ). Study objectives included determination of the recommended dose for phase II, response rate, progression-free survival (PFS), and safety. Pharmacokinetics and CD34 circulating endothelial cells (CECs) as pharmacodynamics were also analyzed. Thirty-seven patients were included. One patient at each level developed dose-limiting toxicities; therefore, level 2 was the recommended dose for phase II. Diarrhea was more common in patients possessing a *6 or *28 allele compared with wild-type homozygous patients (46% and 25%). Among 29 patients treated at level 2, PFS was longer for UGT1A1 wt/*6 and wt/*28 patients than for wt/wt patients (12 vs. 8 months, P = 0.06). PFS was significantly longer in patients with a larger-than-median SN-38 area under the curve (AUC) than in those with a smaller AUC (P = 0.039). There was an association between clinical benefit and reduction in baseline CD34 CECs by S-1 (P = 0.047). The combination of irinotecan and S-1 is effective and warrants further investigation.
S-1与伊立替康联合用药对蒽环类和紫杉类难治性乳腺癌具有吸引力。既往接受过蒽环类和紫杉类治疗的晚期人表皮生长因子受体2（HER2）阴性乳腺癌患者符合条件。脑转移患者以及UGT1A1 6或28纯合子或复合杂合子（6/28）患者被排除。I期部分采用剂量递增设计（1级：伊立替康80mg/m²，第1 - 8天；S-1 80mg/m²，第1 - 14天，每3周一次；2级：伊立替康100mg/m²，S-1 80mg/m²）。研究目标包括确定II期推荐剂量、缓解率、无进展生存期（PFS）和安全性。还分析了药代动力学和作为药效学指标的CD34循环内皮细胞（CEC）。共纳入37例患者。每个剂量水平各有1例患者出现剂量限制性毒性；因此，2级为II期推荐剂量。与野生型纯合子患者相比，携带6或28等位基因的患者腹泻更常见（分别为46%和25%）。在2级剂量治疗的29例患者中，UGT1A1 wt/*6和wt/*28患者的PFS长于wt/wt患者（分别为12个月和8个月，P = 0.06）。SN-38曲线下面积（AUC）大于中位数的患者PFS显著长于AUC较小的患者（P = 0.039）。临床获益与S-1使基线CD34 CECs减少之间存在关联（P = 0.047）。伊立替康与S-1联合用药有效，值得进一步研究。
