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

Lung Cancer. 2016 Jun:96:93-100. doi: 10.1016/j.lungcan.2016.04.003. Epub 2016 Apr 6.

Abstract

Objectives: 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.

Materials and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Brain metastases; Epidermal growth factor receptor mutation; Icotinib; Non-small cell lung cancer; Whole brain radiation therapy.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Brain Neoplasms / cerebrospinal fluid*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / radiotherapy*
  • Brain Neoplasms / secondary
  • Carcinoma, Non-Small-Cell Lung / cerebrospinal fluid*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / radiotherapy
  • Chemoradiotherapy
  • Cranial Irradiation
  • Crown Ethers / administration & dosage
  • Crown Ethers / blood
  • Crown Ethers / cerebrospinal fluid*
  • Crown Ethers / pharmacokinetics
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Lung Neoplasms / cerebrospinal fluid*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Lung Neoplasms / radiotherapy
  • Male
  • Middle Aged
  • Mutation
  • Quinazolines / administration & dosage
  • Quinazolines / blood
  • Quinazolines / cerebrospinal fluid*
  • Quinazolines / pharmacokinetics
  • Retrospective Studies

Substances

  • Crown Ethers
  • Quinazolines
  • icotinib
  • EGFR protein, human
  • ErbB Receptors