Abstract 4652: Cerebrospinal fluid pharmacokinetics and pharmacodynamics following high-dose erlotinib treatment in brain cancer patients

Abstract

Abstract Patients with non-small cell lung cancer (NSCLC) who develop leptomeningeal metastases show significant clinical improvement following high-dose gefitinib therapy. Based on this data, we aimed to explore the effect of high-dose erlotinib on clinical response and CNS penetration in primary or metastatic CNS cancer. We selected patients who had received prior therapy for either primary glioma or for NSCLC with metastases to the brain and treated them with an alternate dosing regimen of erlotinib. Blood and cerebrospinal fluid (CSF) samples were collected at various time points to assess levels of erlotinib. We found that CSF concentrations of erlotinib were generally 2% that of plasma concentrations. Among the five patients examined, CSF concentrations of erlotinib reached up to 131 nM when high doses were administered at 600 to 1200 mg every four to six days. Additionally, drug clearance was decreased with an increased dosing regimen in one of the patients. In one patient, the area under the curve (AUC) estimations showed a 24% increase in the CSF versus only a 2% increase in the plasma following an increase from 150 mg to 600 mg of erlotinib. Moreover, longitudinal CSF samples were evaluated for expression and activation of EGFR as well as various other receptor tyrosine kinases, such as ErbB2, ErbB3, cMET and IGF1R, using the highly sensitive multiplexed immunoassay CEER© platform. The latter provides insight into the molecular makeup of the CNS cancer throughout the therapeutic regimen. Our clinical data on patients receiving erlotinib therapy for primary and metastatic CNS disease suggests that increased dosing of erlotinib, administered as a pulse dose every four to six days leads to increased CSF drug concentrations. In spite of the variations seen among different patients, we conclude that higher erlotinib dosing regimens can provide enhanced CNS penetration that may prove to be more effective in primary and metastatic CNS cancers especially when coupled with real-time molecular monitoring of the disease to help guide the clinician during the course of treatment. Citation Format: Sandra Pastorino, Sandeep C. Pingle, Emma Langley, Phillip Kim, Tiffany Juarez, Pengfei Jiang, Christopher Tucker, Txheng Yang, Marlon Saria, Sharat Singh, Santosh Kesari. Cerebrospinal fluid pharmacokinetics and pharmacodynamics following high-dose erlotinib treatment in brain cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4652. doi:10.1158/1538-7445.AM2014-4652