title: Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.
abstract: Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear.
  
  
  
  EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed.
  
  
  
  Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months.
  
  
  
  WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment.
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Jiazhuo
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Clinical Pharmacology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Clinical Pharmacology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Maozhi
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hou
authors.affiliation: Betta Pharmaceuticals Co., Ltd., Hangzhou 311100, China.
authors.forename: Lieming
authors.initials: L
authors.lastname: Ding
authors.affiliation: Betta Pharmaceuticals Co., Ltd., Hangzhou 311100, China.
authors.forename: Fenlai
authors.initials: F
authors.lastname: Tan
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: radyoulu@hotmail.com.
authors.forename: You
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000532:radiotherapy* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000134:cerebrospinal fluid* / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D059248:Chemoradiotherapy; D016371:Cranial Irradiation; D043844:Crown Ethers / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D012189:Retrospective Studies
chemical_list: D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Brain metastases; Epidermal growth factor receptor mutation; Icotinib; Non-small cell lung cancer; Whole brain radiation therapy