The Dissociation of Gefitinib Trough Concentration and Clinical Outcome in NSCLC Patients with EGFR Sensitive Mutations.

Shuang Xin,Min Huang,Yan Huang,Zhihuang Hu,Hongliang Li,Jing Zhang,Li Zhang,Xueding Wang,Lingyan Chen,Yuanyuan Zhao,Jiali Li,Ying Guo,Yuxiang Ma

doi:10.1038/srep12675

Abstract

Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. Ctrough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of Ctrough was 173.9 ng/ml (P25–P75, 130.5–231.2 ng/ml), and cutoff value 200 ng/ml was determined by X-Tile. The PFS between Ctrough < 200 ng/ml and Ctrough ≥ 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). Ctrough was not significantly associated with rash, diarrhea and hepatotoxicity. Non-smokers enjoyed longer PFS than smokers (18.7 VS 9.3 months; p = 0.025). The results showed that, for NSCLC patients with EGFR sensitive mutations, the PFS in lower trough concentration group were not inferior to that in higher trough concentration group and dose reduction is a rational suggestion for adjustment of dose regimen for aforementioned patients. More clinical trials are warranted to explore the precision dose schedule of gefitinib.

Highlights

Gefitinib is an oral, reversible, tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) that plays a key role in the biology of non small cell lung cancer (NSCLC)
As aforementioned, available data to verify the relationship between dosage regimen, blood exposure and drug effects are limited in NSCLC patients with EGFR sensitive mutations
Gefitinib is a standard therapy for NSCLC patients with EGFR sensitive mutations, few clinical trials have been conducted to discuss the association between gefitinib exposure and drug effect

Summary

Introduction

Reversible, tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) that plays a key role in the biology of non small cell lung cancer (NSCLC). For patients with advanced NSCLC harboring EGFR-TKI sensitive mutations, using EGFR-TKI as first-line treatment, progression-free survival (PFS) was reported to be two to three times better than platinum-doublet chemotherapy[1,2,3]. Based on these results, EGFR-TKIs monotherapy has become a standard regimen for advanced NSCLC with EGFR mutations. As aforementioned, available data to verify the relationship between dosage regimen, blood exposure and drug effects are limited in NSCLC patients with EGFR sensitive mutations. The objective of this study was to retrospectively explore the relationship between gefitinib trough concentration, and clinical outcomes in both efficacy and safety in patients carrying EGFR sensitive mutations

Objectives

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Conclusion