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
Mené en Chine sur 15 patients atteints d'un cancer du poumon non à petites cellules avec mutation du gène EGFR et présentant des métastases cérébrales, cet essai de phase I évalue la dose maximale tolérée de l'icotinib en combinaison avec une radiothérapie de l'ensemble du cerveau, puis évalue l'effet de la radiothérapie cérébrale sur la pénétration de l'icotinib dans le liquide cérébro-spinal
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 125mg–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 (R2 = 0.599, P < .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=.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.
Lung Cancer 2016