Liu Jian, Wu Lihua, Wu Guolan, Hu Xingjiang, Zhou Huili, Chen Junchun, Zhu Meixiang, Xu Wei, Tan Fenlai, Ding Lieming, Wang Yinxiang, Shentu Jianzhong
Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Department of Education, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Oncologist. 2016 Nov;21(11):1294-1295d. doi: 10.1634/theoncologist.2016-0256. Epub 2016 Oct 27.
This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib.
Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC.
Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The mutation test was not mandatory in this study.
Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease.
This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC.
本I期研究评估了在经预处理的晚期非小细胞肺癌患者中，起始剂量为250 mg的埃克替尼的最大耐受剂量、剂量限制性毒性、安全性、药代动力学和疗效。我们观察到最大耐受剂量为500 mg，具有良好的药代动力学特征和抗肿瘤活性。这些发现为临床医生应用更高剂量的埃克替尼提供了证据。
埃克替尼是一种口服表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，在之前的研究中，100 - 200 mg剂量时显示出良好的耐受性和抗肿瘤活性，但未达到最大耐受剂量（MTD）。2011年7月，埃克替尼被中国食品药品监督管理总局批准，剂量为每日3次，每次125 mg，用于治疗至少一种铂类化疗方案失败后的局部晚期或转移性非小细胞肺癌（NSCLC）患者。本研究调查了更高剂量埃克替尼在晚期NSCLC患者中的MTD、耐受性和药代动力学。
26例晚期NSCLC患者接受每日3次剂量为250 - 625 mg的治疗。本研究中不强制进行基因突变检测。
26例患者中有24例（92.3%）至少经历了一次不良事件（AE）；皮疹（61.5%）、腹泻（23.1%）和口腔溃疡（11.5%）是最常见的AE。625 mg组的6例患者中有2例出现剂量限制性毒性，确定MTD为500 mg。埃克替尼吸收和消除迅速。多次给药后，药物在血清中达到最大浓度的时间（T）为1至3小时（1.5 - 4小时）。单剂量和多剂量给药后的t相似（分别为7.11和6.39小时）。观察到剂量与药物暴露之间存在非线性关系。6例（23.1%）患者有反应，8例（30.8%）患者疾病稳定。
本研究表明，更高剂量的埃克替尼耐受性良好，MTD为500 mg。在经过大量预处理的晚期NSCLC患者中观察到了良好的抗肿瘤活性和药代动力学特征。
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