中国的非小细胞肺癌Gefitinib分子靶向治疗

目的 探讨非小细胞肺癌gefitinib分子靶向治疗的国内经验。方法 收集国内7个医院未经正式发表的用gefitinib治疗晚期非小细胞肺癌的资料，重点分析广东省肺癌研究所的病例情况。结果 自2001年7月至2003年12月．共有282例晚期非小细胞肺癌接受gefitinib治疗。有效率为22．2％～47．7％，疾病控制率为62．6％～81．8％。没有观察到明显的毒副作用。结论 gefitinib可安全有效地用于国内的晚期非小细胞肺癌。     

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer

BackgroundOnly a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival.Patients and MethodsInformation about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals.ResultsA total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis.ConclusionDutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.     

Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non–Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials

Background

Five major first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, icotinib, afatinib, and dacomitinib, are currently optional for patients with advanced non–small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, there was no head-to-head-based network meta-analysis among all the TKIs in EGFR-mutated populations.

Intercalated Chemotherapy and Epidermal Growth Factor Receptor Inhibitors for Patients With Advanced Non–Small-cell Lung Cancer: A Systematic Review and Meta-analysis

Randomized clinical trials (RCTs) of concurrent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy for unselected patients with advanced non–small-cell lung cancer (NSCLC) produced negative results. Intercalated administration could avoid the reduction of chemotherapy activity due to G₁ cell-cycle arrest from EGFR-TKIs. A PubMed search was performed in December 2015 and updated in February 2016. The references from the selected studies were also checked to identify additional eligible trials. Furthermore, the proceedings of the main international meetings were searched from 2010 onward. We included RCTs comparing chemotherapy intercalated with an EGFR-TKI versus chemotherapy alone for patients with advanced NSCLC. Ten RCTs were eligible (6 with erlotinib, 4 with gefitinib): 39% of patients had a known EGFR mutational status, 43% of whom EGFR mutation positive. The intercalated combination was associated with a significant improvement in overall survival (OS; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .01), progression-free survival (PFS; HR, 0.60; 95% CI, 0.53-0.68; P < .00001), and objective response rate (ORR; odds ratio [OR], 2.70; 95% CI, 2.08-3.49; P < .00001). Considering only first-line trials, similar differences were found in OS (HR, 0.85; 95% CI, 0.72-1.00; P = .05), PFS (HR, 0.63; 95% CI, 0.55-0.73; P < .00001), and ORR (OR, 2.21; 95% CI, 1.65-2.95; P < .00001). In EGFR mutation-positive patients, the addition of an intercalated EGFR-TKI produced a significant benefit in PFS (129 patients; HR, 0.24; 95% CI, 0.16-0.37; P < .00001) and ORR (168 patients; OR, 11.59; 95% CI, 5.54-24.25; P < .00001). In patients with advanced NSCLC, chemotherapy plus intercalated EGFR-TKIs was superior to chemotherapy alone, although a definitive interpretation was jeopardized by the variable proportion of patients with EGFR mutation-positive tumors included.     

Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials

Background

Afatinib is approved in the US, Europe, and several other regions for first-line treatment for epidermal growth factor receptor mutation-positive (EGFRm⁺) non-small-cell lung cancer (NSCLC).

Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non–small-cell Lung Cancer

Introduction

In this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non–small-cell lung cancer.

吉非替尼治疗前后肺腺癌患者血清蛋白质谱的变化

背景与目的 表皮细胞生长因子受体(epidermal growth factor receptor,EGFR)酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗晚期NSCLC患者最终都会出现耐药.本研究目的 是检测耐药前后血清蛋白质谱的变化,探索可能用于预测TKI治疗后出现耐药的血清预测因子.方法 收集9例晚期NSCLC患者接受吉非替尼(gefitinib)治疗前后自身配对的血清样本20份,即入组口服吉非替尼前及临床评价为疾病进展前两周所采集的外周血血清.所有的患者对吉非替尼的最佳总疗效评价为疾病稳定或部分缓解.所有样本用弱阳离子微珠进行预分离后.在Bruker AutoflTM基质辅助激光解析离子化-时间飞行质谱仪(MALDI-TOF-MS)上进行血清蛋白质谱检测.以ClinProTools(Version:2.1)软件进行数据采集分析.结果 自身配对分析发现有7个血清蛋白质表达水平在肺癌患者耐药前后的血清中有统计学差异.该7个血清蛋白质谱峰为3 242.09、8 690.36、2 952.64、3 224.04、1 450.51、1 887.8及3 935.73(m/z).有3个血清蛋白(3 242.09、2 952.64及3 224.04)在耐药血清中下调,其余4个血清蛋白(8 690.36、1450.51、1 887.8及3 935.73)则出现上调.结论 特定的血清差异蛋白可能与吉非替尼治疗有效患者在治疗过程中出现耐药相关.这些差异蛋白的特性及其与吉非替尼治疗耐药的分子机制有待进一步研究.     

Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study

Background

Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a “real-life” Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study.

TRIM24介导肺癌细胞吉非替尼耐药机制探讨

背景与目的 表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinaseinhibitor,EGFR-TKI)的原发和继发性耐药已成为其在临床肺癌治疗中的拦路虎,在肺癌组织中研究发现TRIM24呈高表达状态,在肺癌细胞中能调控细胞增殖、周期和细胞凋亡,本研究旨在进一步探讨TRIM24调控肺癌细胞吉非替尼耐药的分子机制.方法 应用M TT方法和流式细胞仪检测干扰TRIM24及干扰TRIM24后加入吉非替尼对肺癌细胞系增殖能力及凋亡率的抑制率的变化,同时应用Western blot方法检测凋亡相关基因的变化及AKT信号通路中蛋白的表达.结果 在A549细胞中使用干扰TRIM24可以提高吉非替尼对肿瘤增殖能力的抑制率,增加吉非替尼诱导的凋亡水平,同时干扰TRIM24及干扰TRIM24加入吉非替尼后促凋亡相关基因p-BAD、Bcl-2和AKT及AKT信号通路相关蛋白PIK3CA均出现降低.结论 TRIM24能够调控肺癌细胞吉非替尼耐药,并且通过AKT信号通路引起肺癌细胞EGFR-TKI耐药.