EGFR-TKIs治疗晚期非小细胞肺癌效果的Meta分析

目的：根据临床研究文献,采用 Meta 分析法综合评价EGFR-TKIs类药物治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床疗效。方法：检索 CNKI、维普、万方、SCI、Pubmed、Science Direct等数据库中2005年至2013 年期间发表的有关EGFR-TKIs对比治疗晚期NSCLC的临床研究资料,采用 RevMan5.0和ITC软件,对入选的国内外10篇有关EGFR-TKIs对比治疗晚期NSCLC的研究文献进行综合定量分析。结果：Meta 分析结果显示,埃克替尼与吉非替尼治疗晚期NSCLC有效率和疾病控制率的RR值分别为1.07(P＝0.69)、1.01(P＝0.89);吉非替尼与厄洛替尼治疗晚期NSCLC有效率和疾病控制率的RR值分别为1.23(P＝0.10)、1.04(P＝0.46);埃克替尼与厄洛替尼治疗晚期NSCLC有效率和疾病控制率的RR值分别为1.32(P＝0.79)、1.05(P＝0.95)。结论：埃克替尼、吉非替尼和厄洛替尼治疗晚期NSCLC的效果无显著性差异,但三者的临床有效性尚需要更多高质量的临床随机对照研究来证实。     

EGFR基因靶向治疗非小细胞肺癌的研究进展

非小细胞肺癌(Non-small cell lung cancer,NSCLC)是现阶段临床发现的肺癌患者中发病率最高的一种类型,治疗手段匮乏,效果不甚理想,目前临床中研究热点是EGFR基因在NSCLC靶向治疗中的作用。表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)是基于EGFR基因作用而开发出来,用于治疗EGFR基因突变阳性的NSCLC患者。本文综述了EGFR基因靶向治疗非小细胞肺癌的研究进展。     

Advanced Lung Cancer Patients’ Use of EGFR Tyrosine Kinase Inhibitors and Overall Survival: Real-World Evidence from Quebec,Canada

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are breakthrough palliative treatments for advanced lung cancer patients with tumors harboring mutations in the EGFR gene. Using healthcare administrative data, three cohorts were created to describe the use of three EGFR-TKIs that are publicly funded in Quebec for specific indications (i.e., 1st-line gefitinib, 1st-line afatinib, and post-EGFR-TKI osimertinib). The main objective was to compare overall survival (OS) among patients receiving these treatments to those in previous experimental and real-world studies. The patients who received EGFR-TKIs for indications of interest between 1 April 2001, and 31 March 2019 (or 31 March 2020, for post-EGFR-TKI osimertinib) were included to estimate the Kaplan-Meier-based median OS for each cohort. An extensive literature search was conducted to include comparable studies. For the gefitinib 1st-line (n = 457), the afatinib 1st-line (n = 80), and the post-EGFR-TKI osimertinib (n = 119) cohorts, we found a median OS (in months) of 18.9 (95%CI: 16.3–21.9), 26.6 (95%CI: 13.7-NE) and 19.9 (95%CI: 17.4-NE), respectively. Out of the 20 studies that we retained from the literature review and where comparisons were feasible, 17 (85%) had similar OS results, which further confirms the value of these breakthrough therapies in real-world clinical practice.     

EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: Implications for combination therapies

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway have profoundly improved the clinical management of non-small-cell lung cancer (NSCLC). Nevertheless, the superiority of single-agent PD-1/PD-L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR-driven lung tumor models to investigate dynamic microenvironmental responses to EGFR-TKI treatment. We observed that at an early stage, sensitive EGFR-TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8⁺ T cells and dendritic cells, eradication of Foxp3⁺ Tregs, and inhibition of M2-like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune-mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid-derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR-TKIs increased the levels of IL-10 and CCL-2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR-TKIs in vivo. The results have implications for combination therapy using EGFR-TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.     

Inhibition of NF-κB improves sensitivity to irradiation and EGFR-TKIs and decreases irradiation-induced lung toxicity

Resistance to radiotherapy and to EGFR tyrosine kinase inhibitors (EGFR-TKIs), as well as therapy-related lung toxicity, are serious problems in the treatment of lung cancer. NF-κB has been reported to be associated with radioresistance. Therefore, we evaluated its effects on sensitivity to irradiation and to EGFR-TKIs; irradiation-induced lung toxicity; and the effects of irradiation on sensitivity to EGFR-TKIs. We used IKKβ inhibitor IMD 0354 or p65 depletion to explore their effects on sensitivity to irradiation and to EGFR-TKIs in vitro and in vivo. We evaluated the efficacy of IMD 0354 in a radiation-induced pulmonary-fibrosis mouse model. Irradiation enhanced activation and expression of MET and therefore suppressed the sensitivity of lung cancer cells to irradiation or EGFR-TKIs. Inhibition of NF-κB by IMD 0354 or by p65 depletion reversed irradiation-induced MET activation and increased the sensitivity of lung cancer cells to irradiation, to EGFR-TKIs and to the combination thereof in vitro and in vivo. In addition, IMD 0354 significantly reduced lung toxicity in a murine model of irradiation-induced pneumonia and lung fibrosis. These findings indicated that NF-κB inhibition can improve sensitivity to irradiation and to EGFR-TKIs and can decrease irradiation-induced lung toxicity in lung cancer.     

Fatigue with epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients: A meta-analysis of randomized controlled trials

We conducted this systematic review to fully investigate the fatigue of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in cancer patients. The approved and clinical used EGFR-TKIs were selected for the present meta-analysis. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with EGFR-TKIs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till July 2017. Eighteen randomized controlled trials and 14088 patients were included. The current analysis suggested that the use of EGFR-TKIs increased the risk of all-grade fatigue (1.26;95%CI, 1.17–1.36;p < 0.00001) and high-grade (≥grade 3) fatigue (1.47;95%CI, 1.22–1.78;p < 0.0001). On subgroup analysis, the RR of high-grade fatigue varies significantly according to drug type, cancer type, treatment line, and treatment duration. The available data suggested that the use of EGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients.     

非小细胞肺癌术后EGFR-TKIs治疗研究进展

肺癌是全球新发癌症发病率最高的癌症,也是中国最常见和致死率最高的癌症。其中85%为非小细胞肺癌（NSCLC）,手术是早期患者的主要治疗手段,术后的标准辅助治疗为化疗。但部分患者从辅助化疗中获益十分有限,而且化疗的不良反应也严重影响了患者的生活质量和依从性。表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKIs）的出现改变了晚期NSCLC患者的治疗模式,而术后辅助EGFR-TKIs治疗也已成为了国内外的研究热点。本文将对NSCLC术后EGFR-TKIs治疗的效果、安全性以及尚未解决的问题进行探讨。     

第三代EGFR-TKIs治疗晚期非小细胞肺癌的耐药机制及应对策略研究进展

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）是具有EGFR基因敏感突变的晚期非小细胞肺癌（NSCLC）患者的一线治疗药物。第一、二代EGFR-TKIs可有效治疗EGFR敏感突变的NSCLC,EGFR第20号外显子的T790M突变是第一、二代EGFR-TKIs的主要耐药机制。以奥西替尼为代表的第三代EGFR-TKIs治疗耐药后出现T790M突变的患者疗效显著,给晚期肺癌患者带来更多的生存获益。然而第三代EGFR-TKIs仍不可避免地出现耐药。本文对第三代EGFR-TKIs治疗晚期NSCLC耐药机制及应对策略的研究进展进行综述。     

Duration of prior gefitinib treatment predicts survival potential in patients with lung adenocarcinoma receiving subsequent erlotinib

Purpose

We investigated survival potential in patients receiving erlotinib after failure of gefitinib, focusing on response and time to progression (TTP) with gefitinib.

Methods

We retrospectively reviewed lung adenocarcinoma patients who received erlotinib after experiencing progression with gefitinib. Our primary objective was to evaluate the prognostic significance of erlotinib therapy.

Results

A total 42 lung adenocarcinoma patients were included in this study. Overall disease control rate was 59.5% (partial response [PR], 2.4%; stable disease [SD], 57.1%). Median overall survival was 7.1 months, and median progression-free survival was 3.4 months. The number of patients who achieved PR and non-PR (SD+ progressive disease [PD]) with gefitinib were 22 (52%) and 20 (48%), respectively. Patients with PR for gefitinib showed significantly longer survival times than those with non-PR (9.2 vs. 4.7 months; p = 0.014). In particular, among PR patients, those with TTP <12 months on gefitinib showed significantly longer survival times than those with TTP ≥12 months (10.3 vs. 6.4 months; p = 0.04).

Conclusions

Erlotinib may exert survival benefit for lung adenocarcinoma patients with less than 12 months of TTP of prior gefitinib who achieved PR for gefitinib.