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.

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 (125–625 mg, tid), and the concurrent WBRT (37.5 Gy/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 125 mg–375 mg and 6 at 500 mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375 mg 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 375 mg (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 375 mg 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. [ABSTRACT FROM AUTHOR]