Dataset Information

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

ABSTRACT: Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250 mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. C trough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of C trough 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 C trough < 200 ng/ml and C trough ? 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). C trough 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.

SUBMITTER: Xin S

PROVIDER: S-EPMC4521154 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Xin Shuang S Zhao Yuanyuan Y Wang Xueding X Huang Yan Y Zhang Jing J Guo Ying Y Li Jiali J Li Hongliang H Ma Yuxiang Y Chen Lingyan L Hu Zhihuang Z Huang Min M Zhang Li L

Scientific reports 20150731

Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250 mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. C trough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of C trough 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 C trough < 200 ng/ml an ...[more]

PMID: 26228025

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Project description:Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50 of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasma of M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood-brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2 < 12 ng/mL and CM2 ≥ 12 ng/mL were 17.0 and 27.1 months, respectively, P = 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.

Project description:BackgroundSeveral randomized controlled trials have suggested that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were associated with prolonged disease-free survival (DFS) in EGFR-mutated NSCLC patients after radical resection, comparing with chemotherapy or placebo. We aimed to compare the effectiveness of different first-generation EGFR-TKIs as adjuvant treatment in real-world setting.MethodsEarly-stage EGFR mutated NSCLC patients who underwent radical resection and treated with first-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) as adjuvant therapy between Feb 2010 and Jan 2019 were retrieved from a prospectively-maintained database in our center. The primary endpoint was DFS in stage II/III (TNM 8th) patients with exploratory endpoint regarding DFS in stage I patients. Sensitivity analyses were based on propensity score matched (PSM) cohorts. Treatment failure patterns among different TKIs were also compared.ResultsOf 588 eligible patients, 198 patients (33.7%) received gefitinib, 106 patients (17.9%) received erlotinib, and 284 patients (48.2%) received icotinib. The median DFS of stage II/III patients in the gefitinib, erlotinib and icotinib group were 36.1 months (95% CI, 23.9-49.4), 42.8 months (95% CI, 29.6-97.8), and 32.5 months (95% CI, 23.9-49.4), respectively, with no significant difference (log-rank test P=0.22). There was also no significant difference in DFS among stage I patients receiving different TKIs (P=0.12). PSM adjustments and multivariate analyses adjusting for other confounders revealed similar results. In addition, there were no significant differences in treatment failure pattens in different EGFR-TKI arms, especially in terms of brain metastases (6.1% in gefitinb, 7.5% in erlotinib, 3.9% in icotinib) and bone metastases (8.6% in gefitinb, 9.4% in erlotinib, 7.0% in icotinib).ConclusionsThis first and largest real-world study showed that gefitinib, erlotinib, and icotinib demonstrated comparable clinical effectiveness as adjuvant therapy for patients with early-stage EGFR mutated NSCLC.

Dataset Information

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

Publications

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

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