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The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study.

ABSTRACT: Background:The current study is aimed to examine the impact of pharmacokinetics and gene polymorphisms of enzymes involving in absorption, distribution, metabolism and excretion (ADME) on the efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients. Methods:Eligible patients with indication of gefitinib treatment were prospectively enrolled in this study. Two peripheral blood samples at baseline and before cycle 2 day 1 were collected for the detection of single nucleotide polymorphisms (SNPs) of drug ADME enzymes and trough drug concentration (Ctrough) at steady state. Thirteen SNPs were genotyped using the Sequenom Massarray system. Ctrough was determined by validated high-performance liquid chromatographic method with tandem mass spectrometric (LC-MS/MS). Results:Fifty-eight NSCLC patients were enrolled in this study. The median of Ctrough was 175ng/mL (range from 47.8 to 470 ng/mL). The trough concentration was not associated with either objective response or progression free survival (PFS). Ctrough was significantly lower in CYP3A4 rs2242480 CC + CT genotype than in TT genotype (P=0.019) and in ABCG2 rs2231142 AA genotype than in AC + CC genotype (P=0.031). ABCB1 rs2032582 dominant model was significantly correlated with overall response rate (ORR) and patients with GG phenotype respond better than patients with GT + TT phenotypes (84.6% vs. 51.2%, P=0.032). ABCB1 rs10256836 recessive model was significantly correlated with PFS and patients with GG phenotype achieved longer PFS than patients with GC + CC phenotypes (17.40 vs. 10.33 months, P=0.040). Conclusions:The Ctrough of gefitinib was significantly different between CYP3A4 and ABCG2 genotypes, but not with the efficacy of gefitinib treatment. ABCB1 rs2032582 and rs10256836 polymorphisms were correlated treatment outcome. Polymorphisms analysis of ABCB1 could be a predictive biomarker for gefitinib treatment.

SUBMITTER: Ma Y

PROVIDER: S-EPMC6989872 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study.

Ma Yuxiang Y Xin Shuang S Lin Qingguang Q Zhuang Wei W Zhao Yuanyuan Y Zhu Xia X Zhao Hongyun H Huang Min M Xun Xu X Yang Yunpeng Y Fang Wenfeng W Zhang Li L Wang Xueding X

Annals of translational medicine 20191201 24

<h4>Background</h4>The current study is aimed to examine the impact of pharmacokinetics and gene polymorphisms of enzymes involving in absorption, distribution, metabolism and excretion (ADME) on the efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients.<h4>Methods</h4>Eligible patients with indication of gefitinib treatment were prospectively enrolled in this study. Two peripheral blood samples at baseline and before cycle 2 day 1 were collected for the detection of single nucleo ...[more]

PMID: 32042822

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Project description:BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC.MethodsThe study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing.DiscussionAlthough immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest.Trial registrationThis trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .

Dataset Information

The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study.

Publications

The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study.

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