晚期NSCLC患者外周血中EGFR突变预测EGFR TKIs一线治疗的疗效的观察

目的：检测NSCLC患者外周血EGFR突变情况,预测EGFR TKIs作为治疗晚期NSCLC的一线疗法的疗效。方法：应用荧光偏振（TDI-FP）法检测51例晚期非小细胞肺癌患者外周血EGFR基因突变情况,口服EGFR TKI进行治疗,分析外周血基因突变结果与EGFR TKI疗效之间的关系。结果：TDI-FP法检测出的外周血EGFR突变率为60.8%（31/51）。经EGFR TKIs一线治疗后,EGFR突变型和EGFR野生型有效率（RR）分别为41.9%和5.0%;疾病控制率（DCR）分别为77.4%和15.0%;中位PFS则分别为13.0和7.0个月。与检测组织中EGFR突变比较,TDI-FP法检测外周血EGFR突变的正确率（π）为84.2%。统计学分析显示,EGFR突变型NSCLC患者应用EGFR TKIs一线治疗能获得更佳疗效。结论：应用荧光偏振法检测NSCLC患者外周血中的EGFR基因突变,对于预测EGFR TKI作为一线治疗的疗效有重要的价值。     

化疗间插联合EGFR-TKIs对比单独化疗一线治疗晚期非小细胞肺癌的meta分析

背景与目的化疗与表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs）联合疗法一直是许多研究的焦点,其中间插联合疗法受到了更多研究者的关注。本研究旨在系统评价化疗与EGFR-TKIs间插联合疗法对比单独化疗一线治疗晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的有效性及安全性。方法检索hTe Cochrane Library、PubMed、EMBASE、中国生物医学文献数据库（CBM）、知网和万方等数据库关于化疗间插联合EGFR-TKIs疗法和单独化疗一线治疗晚期NSCLC的随机对照试验（randomized controlled trial, RCT）,分析如下结局指标：无进展生存期（progression-free survival, PFS）、总体生存期（overall survival, OS）、客观缓解率（objective response rate, ORR）、疾病控制率（disease control rate, DCR）以及不良反应发生率。由两名研究者根据Cochrane系统评价手册筛选文献、进行质量评价以及提取并交叉核对数据。应用Stata12.0软件进行meta分析。结果本研究共纳入6个RCT,共计933例晚期NSCLC患者。Meta分析结果表明,在晚期NSCLC患者一线治疗中,与单独化疗相比,间插联合疗法虽然延长了患者的PFS（HR=0.72,95%CI：0.53-0.98, P=0.037）,但并不能提高其OS（HR=0.85,95%CI：0.72-1.01,P=0.060）、ORR（OR=1.59,95%CI：0.86-2.95,P=0.142）和DCR（OR=1.09,95%CI：0.95-1.25,P=0.226）。进一步的亚组分析发现,间插联合疗法提高了女性、腺癌、从不吸烟和EGFR突变等患者的PFS,差异具有统计学意义。在安全性方面,间插联合疗法的主要不良反应为皮疹（OR=7.81,95%CI：3.74-16.34,P<0.001）和腹泻（OR=2.73,95%CI：1.92-3.89,P<0.001）。结论一线接受化疗间插联合EGFR-TKIs治疗的NSCLC患者的PFS明显高于接受单独化疗者,其主要不良事件是皮疹和腹泻。因此,间插联合治疗具有一定优势,但仍需要更多大样本、高质量的RCT进一步验证。     

晚期NSCLC患者外周血中EGFR突变预测EGFR TKIs一线治疗的疗效的观察

目的:检测NSCLC患者外周血EGFR突变情况,预测EGFR TKIs作为治疗晚期NSCLC的一线疗法的疗效。方法:应用荧光偏振(TDI-FP)法检测51例晚期非小细胞肺癌患者外周血EGFR基因突变情况,口服EGFR TKI进行治疗,分析外周血基因突变结果与EGFR TKI疗效之间的关系。结果:TDI-FP法检测出的外周血EGFR突变率为60.8%(31/51)。经EGFR TKIs一线治疗后,EGFR突变型和EGFR野生型有效率(RR)分别为41.9%和5.0%;疾病控制率(DCR)分别为77.4%和15.0%;中位PFS则分别为13.0和7.0个月。与检测组织中EGFR突变比较,TDI-FP法检测外周血EGFR突变的正确率(π)为84.2%。统计学分析显示,EGFR突变型NSCLC患者应用EGFR TKIs一线治疗能获得更佳疗效。结论:应用荧光偏振法检测NSCLC患者外周血中的EGFR基因突变,对于预测EGFR TKI作为一线治疗的疗效有重要的价值。     

EGFR-TKI联合化疗对比单用EGFR-TKI治疗EGFR突变的晚期非小细胞肺癌疗效与安全性Meta分析

摘 要：［目的］ 评价表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI）联合化疗治疗EGFR突变的晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者的疗效与安全性。［方法］ 计算机系统检索PubMed及其他数据库中截止至2017年10月所有使用EGFR-TKI联合化疗对比单用EGFR-TKI治疗EGFR突变晚期NSCLC患者的随机对照试验（randomized controlled trial,RCT）。［结果］ 包含862例患者的5项临床研究符合纳入条件。EGFR-TKI联合化疗可显著延长EGFR突变的晚期NSCLC患者的无进展生存期（progression-free survival,PFS）（HR=0.72,95％CI：0.58~0.91,P=0.006）。两种治疗方式的客观反应率（objective response rate,ORR）（RR=1.06,95％CI：0.94~1.19,P=0.35）及总生存期（overall survival,OS）（HR=1.00,95％CI：0.68~1.47,P=0.99）无差异显著性。两种治疗方法的不良事件（adverse event,AE）发生率较低且相近。［结论］ EGFR-TKI联合化疗在EGFR突变的晚期NSCLC患者中极具应用前景,值得进一步研究。     

EGFR 基因状态对晚期非小细胞肺癌一线化疗的影响

目的：评价 EGFR 突变状态对晚期非小细胞肺癌（NSCLC）一线化疗近期疗效、无疾病进展时间（PFS）的影响。方法：同期非随机对照研究,依照入选标准,入组67例初治晚期 NSCLC EGFR 野生型患者及51例初治晚期 NSCLC EGFR 敏感突变型患者,分别观察客观有效率（RR）、疾病控制率（DCR）及无疾病进展时间（PFS）。结果：EGFR 野生型与 EGFR 敏感突变型的晚期 NSCLC 一线化疗的近期有效率分别为16．4％和28．6％,差异无统计学意义（P ＞0．05）,疾病控制率分别为61．2％和81．6％,差异有统计学意义（P ＜0．05）。PFS 分别为3个月与5个月,差异有统计学意义（P ＜0．05）。结论：化疗仍然是 EGFR 敏感突变型的晚期NSCLC 一线治疗的重要选择,在 DCR 及 PFS 方面,明显优于 EGFR 野生型晚期 NSCLC。     

比较吉非替尼与化疗一线治疗晚期非小细胞肺癌的Meta分析

目的 评价吉非替尼对比以铂类为基础的联合化疗一线治疗晚期非小细胞肺癌（NSCLC）的疗效与安全性。方法 检索PubMed、EMbase、中国生物医学文献数据库和中国知网等数据库,纳入吉非替尼对比铂类联合第3代化疗药物一线治疗晚期NSCLC的随机对照研究,检索时间截止于2012年3月,采用Stata 10.0软件进行Meta分析。结果 最终纳入4项研究,共1926例患者。在表皮生长因子受体（EGFR）突变阳性的人群中,吉非替尼在无进展生存期（HR=0.43,95％CI：0.32～0.58,P＜0.001）和有效率（71.5％ vs.38.1％,OR=4.04,95％CI：2.90～5.61,P＜0.001）方面均优于化疗组,在总生存期方面两组差异无统计学意义（HR=0.93,95％CI：0.75～1.15,P=0.492）。在安全性方面,吉非替尼主要为皮疹、腹泻和肝功能损害;化疗为中性粒细胞减少、血小板减少和贫血。结论 吉非替尼一线治疗晚期NSCLC具有一定优势,可作为EGFR敏感突变者的一线用药选择。     

吉非替尼与多西紫杉醇治疗晚期非小细胞肺癌的meta分析

 目的评价吉非替尼与多西紫杉醇作为晚期非小细胞肺癌（NSCLC）二线治疗的临床疗效及安全性。方法计算机检索PubMed、EMBASE、Cochrane Library、中国期刊全文数据库、中国生物医学文献数据库、中文科技期刊全文数据库和万方数据库,纳入吉非替尼与多西紫杉醇治疗既往接受过化疗的局部晚期NSCLC的临床随机对照试验（RCT）,依据Cochrane系统评价手册5.0.2质量评价标准进行质量评价,采用RevMan5.0软件进行meta分析。结果最终纳入4个RCT（2 257例）。meta分析结果显示,吉非替尼与多西紫杉醇相比,可以提高局部晚期NSCLC患者的客观缓解率、生活质量改善率（P＜0.05）;并且其3～4级不良反应发生率低（P＜0.05）。而在总生存率、症状改善率和无进展生存率方面,差异无统计学意义（P＞0.05）。结论吉非替尼用于治疗既往接受过化学治疗的局部晚期或转移性NSCLC的客观缓解率优于多西紫杉醇,而且患者生活质量改善显著,其药物耐受性和安全性更高,目前可作为一种有效的二线治疗药物积极推广应用,但生存期方面仍需进一步研究。     

放疗、化疗及放化疗治疗非小细胞肺癌对 EGFR 基因突变状态的影响

目的：研究放疗、化疗和放化疗三种临床非小细胞肺癌（non - small cell lung cancer,NSCLC）治疗方式对 EGFR 基因突变状态的影响。方法：采用 ARMS 血浆 EGFR 基因突变分析方法,分别对393例晚期NSCLC 患者放疗、化疗和放化疗治疗前、治疗后获得的外周血标本进行 EGFR 基因突变检测。结果：放疗、化疗和放化疗三种治疗手段均影响 EGFR 基因突变状态。单纯放疗组放疗前的 EGFR 基因突变率为31.78%,放疗后的 EGFR 基因突变率为20.16%,放疗显著影响 EGFR 基因突变状态（P <0.016）。单纯化疗组化疗前的 EGFR 基因突变率为34.56%,化疗后的 EGFR 基因突变率为22.06%,化疗显著影响 EGFR 基因突变状态（P <0.013）。放化疗组放化疗前的 EGFR 基因突变率为33.59%,放化疗后 EGFR 基因突变率为17.19%,放化疗显著影响 EGFR 基因突变状态（P <0.001）。结论：放疗、化疗和放化疗均可降低 NSCLC 患者外周血中EGFR 基因突变率,提示放疗、化疗和放化疗治疗会对外周血中 EGFR 基因突变状态发生影响,采用外周血检测 NSCLC 的 EGFR 基因状态能够在治疗过程中动态观察患者的变化,进一步指导临床治疗。     

EGFR突变与非小细胞肺癌酪氨酸激酶抑制剂靶向治疗

肺癌的高发病率和高病死率，以及化疗对晚期肺癌疗效的十分有限，使之成为世界性医学难题。最近发现，表皮生长因子受体（epidermal growth factor receptor，EGFR）酪氨酸激酶抑制剂（tyrosine kinases inhibitors，TKIs）的分子靶向治疗可以使晚期非小细胞肺癌瘤体缩小；然而，以Gefitinib和Erlotinib为代表的TKIs治疗敏感性与EGFR基因突变显著相关。研究证实，EGFR最常见发生的19区缺失突变和21区点突变导致相应氨基酸序列和EGFR结构的改变，是其增加药物敏感性的主要机制。此外，EGFR基因扩增和CA重复序列的多态性、EGFR通路下游信号（如p-AKT等）激活、HER2和（或）HER3表达的增加、K—RAS基因突变等因素皆影响其对TKIs的治疗敏感性。鉴于此，进一步研究EGFR基因不同突变的功能，寻找能预测TKIs治疗敏感性的因素，并作为TKIs敏感患者的筛选指标，对于提高晚期肺癌患者TKIs靶向治疗疗效具有重要意义。     

DNA直接测序技术检测EGFR基因突变指导厄洛替尼一线治疗晚期非小细胞肺癌的临床观察

目的：通过对晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者表皮生长因子受体（epi-dermal growth factor receptor,EGFR）基因突变的检测,探讨厄洛替尼（Erlotinib）一线治疗晚期NSCLC的疗效与安全性。方法：从110例NSCLC患者的肿瘤组织提取DNA,用DNA直接测序技术检测EGFR基因19、21外显子突变情况,31例EGFR基因突变患者中,30例患者口服厄洛替尼150mg/d,持续至疾病进展或发生不能耐受的药物不良反应,评价客观有效率（RR）,疾病控制率（DCR）,总生存（OS）,无疾病进展时间（PFS）,一年生存率和药物不良反应。结果：110例NSCLC组织中EGFR基因突变31（28%）例,其中19外显子缺失18（58%）例,21外显子点突变13（42%）例。EGFR基因突变率女性40%、肺腺癌33%、不吸烟者46%,高于男性、非腺癌、吸烟的病人。30例口服厄洛替尼患者,完全缓解（CR）3例,部分缓解（PR）21例,疾病稳定（SD）5例和疾病进展（PD）1例,客观有效率为80%,疾病控制率为97%,截止随访结束,仍有20例患者生存,故中位总生存未获得结果,无疾病进展时间为11.4个月,1年生存率为78%,厄洛替尼治疗晚期NSCLC最常见的不良反应是腹泻和皮疹,多为I-II级。结论：DNA直接测序检测晚期NSCLC患者EGFR基因突变具有高度敏感性,以EGFR基因突变结果为依据,一线应用厄洛替尼治疗晚期NSCLC患者,疗效明显,耐受性好,是治疗晚期NSCLC的最佳选择之一。     

PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期非小细胞肺癌疗效及安全性的Meta分析

目的：系统评价PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期非小细胞肺癌（non-small lung cancer,NSCLC）的疗效及安全性。方法：检索PubMed、Cochrane Library、EMbase、EBSCO循证医学数据库、中国生物医学文献数据库（Chinese Biomedical Literature Database,CBM）、中国知网（Chinese Journal Full-text Database,CNKI）、中文科技期刊全文数据库（VIP）中收录的PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期NSCLC 的随机对照试验（randomized controlled trials,RCTs）,采用RevMan 5.2 软件进行Meta 分析。结果：纳入6 个临床RCTs 共3 238 例晚期NSCLC。Meta 分析结果显示,PD-1/PD-L1 抑制剂联合化疗与化疗相比可显著延长OS（HR=0.86,95%CI=0.79~0.94,P=0.0006）和PFS（HR=0.81,95%CI=0.78~0.84,P<0.00001）;1~5 级血小板计数减少、呕吐、腹泻、甲状腺功能减低或亢进、皮疹、肺炎、结肠炎、肝炎、味觉障碍,3~5 级肝炎的不良反应发生率较化疗组高,差异具有统计学意义（P<0.01 或P<0.05）。结论：PD-1/PD-L1 抑制剂联合化疗较单独化疗一线治疗晚期NSCLC可显著延长患者OS和PFS,但不良反应发生率较化疗高。     

Efficacy of epidermal growth factor receptor inhibitors versus chemotherapy as second-line treatment in advanced non-small-cell lung cancer with wild-type EGFR: A meta-analysis of randomized controlled clinical trials

Background

EGFR mutation status is closely related to the efficacy of EGFR-TKIs in advanced non-small cell lung cancer (NSCLC). EGFR-TKIs have become the standard first-line treatment for advanced EGFR-mutation NSCLC, while for EGFR wild-type tumors, the preferred first-line treatment is chemotherapy. However, the efficacy of EGFR-TKIs as second-line treatment in EGFR wild-type NSCLC remains controversial. We sought to evaluate the effectiveness of EGFR-TKI as second-line treatment in EGFR wild-type NSCLC.

Methods

Randomized controlled trials that compared EGFR-TKIs with chemotherapy in previously treated advanced NSCLC with wild-type EGFR were included. We performed a meta-analysis to evaluate the effectiveness of EGFR-TKIs compared with standard chemotherapy. The endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Results

Six randomized controlled trials with a total of 990 patients with wild-type EGFR were included: 499 in the EGFR-TKIs group and 491 in the chemotherapy group. The results indicated that in the second-line treatment of EGFR wild-type advanced NSCLC, PFS was significantly inferior in the EGFR-TKIs group versus the chemotherapy group (HR = 1.37, 95% CI = 1.20–1.56, P < 0.00001). However, this significant difference did not translate into OS (HR = 1.02, 95% CI = 0.87–1.20, P = 0.81). ORR tended to favor chemotherapy but there was no significant difference compared with EGFR-TKI (RR = 1.77, 95% CI = 0.90–3.50, P = 0.10).

Conclusions

Chemotherapy improves PFS significantly but not OS, compared with EGFR-TKIs as a second-line treatment in advanced NSCLC with wild-type EGFR. Whether EGFR-TKIs should be used in EGFR wild-type patients should be considered carefully.     

EGFR mutation: Significance as a stratification factor in the era of molecular-targeted therapy

Somatic mutations of epidermal growth factor receptor (EGFR) are the strongest predictive markers for the response to EGFR-tyrosine kinase inhibitors (TKIs). Patients with EGFR mutations generally receive EGFR-TKI treatment, and their survival has been significantly improved compared with that before the development of EGFR-TKIs. This study aimed to clarify the impact of EGFR mutational status on the survival of patients with non-small cell lung cancer (NSCLC) receiving cytotoxic agents, but not EGFR-TKIs, as their first-line chemotherapy. In addition, we analyzed patients with EGFR mutations to determine whether the timing of EGFR-TKI administration affects overall survival (OS). A total of 83 NSCLC patients with stage IIIB/IV who received chemotherapy alone and whose EGFR mutational status was known were investigated. Univariate and multivariate analysis for OS was performed using parameters such as age, gender, performance status (PS), histology, disease stage, smoking status, EGFR mutational status and administration of a first-line regimen. Among the 52 patients with EGFR mutations who received EGFR-TKIs, OS between those who received EGFR-TKIs as their first-line treatment and after chemotherapy were similar. Among the 83 patients who received cytotoxic agents as their first-line chemotherapy, the multivariate analysis showed OS to be significantly associated with PS (p<0.001), histology (p=0.039) and EGFR mutational status (p=0.040). OS was almost similar among the 52 patients with EGFR mutations who received EGFR-TKIs in a first- and second-line setting (25.6 vs. 26.8 months, p=0.914). The EGFR mutational status had a significant impact on the survival of NSCLC patients, although these patients did not receive EGFR-TKIs as their first-line chemotherapy. In future randomized trials, even when EGFR-TKIs are not included in experimental regimens, patients may need to be stratified by EGFR mutational status in order that study results be evaluated appropriately.     

The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations

Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC.     

EGFR-TKIs联合化疗一线治疗晚期EGFR基因突变非小细胞肺癌患者的疗效观察

目的:分析比较表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)联合化疗与EGFR-TKIs单药一线治疗晚期非小细胞肺癌(NSCLC)的疗效和安全性。方法:回顾性分析2010年09月至2015年12月晚期EGFR突变阳性NSCLC患者100例,根据治疗方案分为联合组(50例)和单药组(50例),联合组采用EGFR-TKIs联合化疗治疗,单药组采用EGFR-TKIs单药治疗。比较两组患者的治疗效果、预后情况以及毒副作用。结果:联合组总有效率为66%(33/50),单药组为48%(24/50),组间比较差异无统计学意义(P=0.106);联合组的疾病控制率为88%(44/50),单药组的疾病控制率为68%(34/50),组间比较差异有统计学意义(P=0.028)。联合组和单药组的中位PFS分别为18.5个月和13.5个月,差异有统计学意义(P=0.013),两组的OS分别为36个月和28.5个月,差异无统计学意义(P=0.071)。单药组和联合组的3-4级治疗相关不良反应发生率分别为6%和10%,差异无统计学意义(P=0.463)。结论:与EGFR-TKIs单药相比,EGFR-TKIs...     

Comparing the effectiveness of different EGFR-TKIs in patients with EGFR mutant non–small-cell lung cancer: A retrospective cohort study in Taiwan

The study was to compare the effectiveness of different epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced non-small-cell lung cancer (NSCLC) and received EGFR-TKIs as first-line therapy. This retrospective cohort study was conducted using data from real-world settings. Patients with stage IIIB and IV NSCLC and first received gefitinib, erlotinib, or afatinib between 2011 and 2015 were included. The date of the first claim for EGFR-TKIs was set as the index date. Study endpoints were all-cause death and treatment failure that was defined when patients added on or switched to chemotherapy or terminal care. A total of 5,940 patients, including 3,982 (67.0%) receiving gefitinib, 1,207 (20.3%) receiving erlotinib, and 751 (12.7%) receiving afatinib, were eligible for this study. The 1-year overall survival (OS) rates for gefitinib, erlotinib, and afatinib groups were 74% (95% confidence interval [CI]: 72–75%), 75% (95% CI: 73–77%), and 80% (95% CI: 77–83%), respectively. Compared to gefitinib, afatinib was associated with a lower risk of all-cause death (adjusted hazard ratio [aHR] = 0.82, 95% CI: 0.72–0.93) but not erlotinib (aHR = 0.95, 95% CI: 0.86–1.05). Similar results were also found regarding the effectiveness of treatment. All the three EGFR-TKIs showed no differences for both outcomes among patients with an Eastern Cooperative Oncology Group Performance Score of 2. The real-world data exhibited afatinib was more likely to be used for younger patients in a better condition than other EGFR inhibitors, and observed prolonged OS and treatment effectiveness compared to gefitinib after performing a multivariate Cox regression analysis.     

EGFR-TKIs联合化疗在晚期非小细胞肺癌中的应用

晚期非小细胞肺癌（NSCLC）的治疗需首先明确其组织学类型与分子学特征。若存在表皮生长因子受体（EGFR）基因突变或渐变性淋巴瘤激酶（ALK）基因融合,应首选分子靶向药物治疗。但分子靶向治疗药物并未改善晚期患者的总生存,如何提高晚期NSCLC患者的总生存是目前临床医生关注的热点。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）与含铂双药交替使用模式作为晚期NSCLC的一线治疗方案,可能将明显延长EGFR阳性突变患者总生存时间。本文就小分子酪氨酸激酶抑制剂联合化疗治疗NSCLC患者、方式及其疗效的研究进展进行综述。      

Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients?

An ideal target-based agent for the treatment of cancer patients should fulfil a number of requirements, including the availability of biomarkers to select the target population, superiority over existing treatments and specific advantages in terms of pharmacokinetics and/or metabolism. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib and afatinib, have been investigated in the treatment of non-small cell lung cancer (NSCLC), and to date a large amount of clinical data are available. The activity of EGFR-TKIs was initially investigated in unselected patients leading to unsatisfactory results. However, the discovery that response to EGFR-TKIs is associated with the presence of activating EGFR mutations in NSCLC, has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status or of clinical and pathological features that are highly associated with the presence of EGFR mutations. In this respect, several phase III randomized trials have demonstrated that first-line EGFR-TKIs, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life in patients carrying EGFR mutations. Although no survival advantage was demonstrated, all the trials suffered of a high post-progression treatment cross-over, which predictably undermined the results. This review will summarize the current evidence that strongly support the hypothesis that gefitinib, erlotinib and afatinib are ideal drugs for NSCLC patients carrying EGFR mutations.     

表皮生长因子受体酪氨酸激酶抑制剂用于非小细胞肺癌术后辅助治疗的研究进展

表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKI）在晚期EGFR突变阳性的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中的疗效肯定,但EGFR-TKI能否提高完全切除的NSCLC术后辅助治疗疗效不确切。部分研究发现在可切除的Ⅰ~Ⅲ期EGFR敏感突变肺腺癌患者中,辅助TKI治疗有使无疾病生存（disease free survival,DFS）获益的趋势,另一部分临床研究未能证实EGFR-TKI在术后辅助治疗有获益。造成各研究结果不一的原因很多,如人群选择、EGFR-TKI使用时长、耐药等。国内外目前一些设计比较合理的,对比EGFR-TKI化疗辅助治疗Ⅱ~ⅢA期EGFR敏感突变的NSCLC临床研究正在进行,值得期待。目前,早期NSCLC术后TKI辅助治疗仅限于临床试验,不建议作为临床常规治疗。     

RETRACTED ARTICLE: The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Molecularly Selected Patients with Non-Small Cell Lung Cancer: A Meta-Analysis of 30 Randomized Controlled Trials

Objective

To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in molecularly selected patients with advanced non-small cell lung cancer (NSCLC), we performed this pooled analysis.

Method

Randomized trials of EGFR-TKIs as treatment for advanced NSCLC were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs in the selected patients by EGFR-mutation status were calculated.

Results

Out of 2134 retrieved articles, 30 randomized controlled trials (RCTs) enrolling more than 4053 patients with wild-type EGFR tumors and 1592 patients with mutant EGFR tumors were identified. For EGFR mutant patients, EGFR-TKIs treatment improved progression-free survival (PFS) compared with chemotherapy: the summary HRs were 0.41 (p?<?0.00001) for the first-line setting and 0.46 (p?=?0.02) for second/third-line setting, respectively. Also, the same superior trend was found with TKIs maintenance over placebo (HR?=?0.14, p?<?0.00001) and with TKIs combined with chemotherapy over chemotherapy (HR?=?0.49, p?=?.002) in both the first-line and maintenance therapy settings. For EGFR wild-type patients, EGFR-TKIs have fared worse than chemotherapy in the first-line setting (HR?=?1.65, p?=?.03) and in the second/third-line setting (HR?=?1.27, p?=?.005). However, EGFR-TKIs maintenance still produced a reduction of 19 % in the risk of progression over placebo (HR?=?0.81, p?=?.02). Furthermore, EGFR-TKIs added to chemotherapy as first-line treatment resulted in an improvement of PFS over chemotherapy alone in such wild-type EGFR patients (HR?=?0.82, p?=?.03). In overall survival (OS) analysis, only EGFR-TKIs single agent was inferior to chemotherapy in EGFR wild-type patients (HR?=?1.13, p?=?.02). No statistically significant difference in terms of OS was observed in any other subgroup analysis.

Conclusions

For EGFR mutant patients, EGFR-TKIs therapy produced a prominent PFS benefit in all settings. Among EGFR wild-type patients, EGFR-TKIs were inferior to chemotherapy both for first-line treatment and for second/third-line treatment. However, EGFR-TKIs maintenance and addition of EGFR-TKIs to chemotherapy could provide additive benefit over chemotherapy alone in such EGFR wild-type patients.