Hu Xing-Sheng, Han Xiao-Hong, Yang Sheng, Li Ning, Wang Lin, Song Yuan-Yuan, Mu Hua, Shi Yuan-Kai
Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
Cancer Manag Res. 2019 May 13;11:4449-4459. doi: 10.2147/CMAR.S189626. eCollection 2019.
The aim of this phase Ib study (clinicaltrials.gov: NCT01772732) was to assess safety, tolerability, and pharmacokinetics (PKs) of simotinib (a novel EGFR tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer (NSCLC) and gene mutation. 41 patients with gene mutations were enrolled and received simotinib orally administered twice daily with dose escalating from 100 to 650 mg in 28 days cycle. Safety and tolerability were assessed through the study. Blood samples were collected for PK analysis on Days 1, 8, 9, 10, 15, 22 and 29. Tumor response was assessed at baseline, on Day 29 and every 8 weeks thereafter. Simotinib was well tolerated, with no dose-limiting toxicities. Maximum tolerated dose (MTD) was not found. 95.1% of patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequently reported AEs. Simotinib was rapidly absorbed and eliminated with average ranging from 1 to 4 hrs and ranging between 6.2 and 13.0 hrs after multiple-dose administration. No dose-response relationship between dose and exposure was observed after multiple-dose administration. 39.3% of the enrolled patients achieved a partial response and 46.3% had stable disease. Median progression-free survival and overall survival were 9.9 (CI% 4.7; 12.1) months and 14.6 (95%CI 12.3; 22.5) months, respectively. Simotinib was well tolerated, with manageable AEs at doses of up to 650 mg and MTD was not reached. Further studies to explore higher doses are ongoing.
这项Ib期研究（clinicaltrials.gov：NCT01772732）的目的是评估西莫替尼（一种新型表皮生长因子受体酪氨酸激酶抑制剂）在晚期非小细胞肺癌（NSCLC）伴基因突变患者中的安全性、耐受性和药代动力学（PK）。41例伴基因突变的患者入组，接受西莫替尼口服，每日两次，剂量在28天周期内从100mg递增至650mg。通过该研究评估安全性和耐受性。在第1、8、9、10、15、22和29天采集血样进行PK分析。在基线、第29天及此后每8周评估肿瘤反应。西莫替尼耐受性良好，未发现剂量限制性毒性。未发现最大耐受剂量（MTD）。95.1%的患者经历了至少一次不良事件（AE），且大多数为轻度或中度。皮疹（41.5%）和腹泻（56.1%）是最常报告的AE。多次给药后，西莫替尼吸收和消除迅速，平均达峰时间为1至4小时，消除半衰期在6.2至13.0小时之间。多次给药后未观察到剂量与暴露之间的剂量反应关系。39.3%的入组患者获得部分缓解，46.3%疾病稳定。无进展生存期和总生存期的中位数分别为9.9（CI% 4.7；12.1）个月和14.6（95%CI 12.3；22.5）个月。西莫替尼耐受性良好，在高达650mg的剂量下AE可控制，未达到MTD。正在进行进一步研究以探索更高剂量。
