Department of Medical Oncology, Faculty of Medicine, Kinki University, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Cancer Chemother Pharmacol. 2013 Apr;71(4):859-65. doi: 10.1007/s00280-013-2077-1. Epub 2013 Jan 20.
A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy.
Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1-14 every 21 days at doses starting at 60 mg/m(2) (level 1) and escalating to 80 mg/m(2) (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib.
Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation-positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected.
The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation-positive NSCLC.
进行了一项 I 期剂量递增研究，以调查先前化疗失败的肺腺癌患者中 S-1 和吉非替尼联合治疗的安全性和药代动力学。
患者接受固定每日口服剂量 250 mg 的吉非替尼，S-1 于每 21 天的第 1-14 天给药，起始剂量为 60 mg/m2（第 1 级），并递增至 80 mg/m2（第 2 级）。该研究的主要终点是确定 S-1 与固定剂量吉非替尼联合使用的推荐剂量。
20 名患者入组该研究。在剂量水平 2 的前 6 名患者中的 2 名出现剂量限制毒性（1 例碱性磷酸酶升高 3 级；另 1 例天门冬氨酸和丙氨酸氨基转移酶升高 3 级）。因此，推荐剂量确定为水平 2，并为该水平再分配了 11 名额外的患者。所有观察到的不良事件均得到良好管理。客观缓解率为 50%（20 名患者中有 10 名），中位无进展生存期（PFS）和总生存期分别为 10.5 个月和 21.2 个月。在 EGFR 突变阳性患者（n=9）中，7 名患者达到客观缓解，中位 PFS 为 12.4 个月，而野生型 EGFR（n=6）的患者均无缓解。未检测到 S-1 和吉非替尼之间的药代动力学相互作用。
S-1 和吉非替尼联合使用耐受性良好，并且似乎对 EGFR 突变阳性 NSCLC 具有活性。
