表皮生长因子受体酪氨酸激酶抑制剂联合用药治疗非小细胞肺癌的研究进展

以吉非替尼、厄洛替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)广泛用于非小细胞肺癌的治疗。但随着EGFR-TKI的不断应用,肿瘤细胞对药物的敏感性逐渐下降,药物作用疗效降低,耐药问题也逐渐凸显。近年来,EGFR-TKI联合用药的研究不断深入,取得了显著的成果。本文就EGFR-TKI联合化疗药物、胰岛素样生长因子1受体酪氨酸激酶抑制剂、抗血管内皮生长因子单抗、哺乳动物雷帕霉素靶蛋白抑制剂、环氧化酶2抑制剂、细胞因子诱导的杀伤细胞疗法和其他药物靶向治疗非小细胞肺癌的疗效及相关机制作简要概述,为临床治疗非小细胞肺癌提供参考。     

奥希替尼治疗晚期非小细胞肺癌的临床研究进展

奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)，与第一代、第二代EGFR-TKI相比，奥希替尼对表皮生长因子受体致敏突变阳性(EGFR⁺)T790M基因突变有更好的抑制作用，且对中枢神经系统亦有良好的疗效。多项临床研究证实奥希替尼对接受一代、二代EGFR-TKI治疗后进展或耐药的EGFR⁺及转移性非小细胞肺癌患者具有较好的疗效和安全性。     

抗非小细胞肺癌药物奥希替尼研究进展

年3月22日中国食品药品监督管理局(CFDA)批准表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)奥希替尼(Osimertinib)用于治疗EGFR T790M基因突变阳性的局部晚期或转移性非小细胞肺癌(NSCLC)。奥希替尼是第三代EGFR-TKI,治疗效果显著,副作用更小,尤其适用于对第一、二代EGFR-TKI耐药或者脑转移的病人。与含铂类治疗药物的二联化学疗法相比,奥希替尼可使NSCLC病人中位无进展生存期(PFS)延长5.7个月,疾病进展风险下降70%。该文就奥希替尼的作用机制、研究历程、药效学、药动学、不良反应,耐药机制进行综述,为临床使用提供参考。     

第三代EGFR-TKI奥希替尼临床研究进展

奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）,被批准用于治疗EGFR T790M突变阳性的局部晚期或转移性非小细胞肺癌（NSCLC）的抗肿瘤药物。其疗效显著,耐受性较好,副作用较第一、二代EGFR-TKI更易被接受。对已接受其他EGFR-TKI治疗且出现耐药的患者,奥希替尼可为该类患者带来新的选择。2017年3月22日国家食品药品监督管理总局（CFDA）加速批准了阿斯利康公司的甲磺酸奥希替尼片的进口申请。现就奥希替尼的作用机制、上市情况、临床实验、药动学、耐受性和安全性进行综述,为临床应用提供参考。     

血清CEA水平与EGFR-TKI治疗晚期非小细胞肺癌的预后相关性分析

目的探讨血清CEA水平与表皮生长因子受体络氨酸激酶受体抑制剂(EGFR-TKI)治疗晚期非小细胞肺癌的预后相关性。方法对121例晚期非小细胞肺癌患者采用EGFR-TKI药物吉非替尼进行治疗,并在接受治疗前进行血清CEA水平的检测,同时对患者的预后与患者的性别、年龄、癌变类型以及CEA水平等进行分析,并以50μg/L为分界线,将患者分为高CEA水平组以及低CEA水平组。结果对2组患者不良反应以及症状主要以皮疹、厌食、恶心、腹泻以及呕吐为主,2组患者比较无统计学差异性。对2组患者治疗疗效比较,高CEA水平组患者其有效率为32.4,稳定为40.8%以及恶化为26.8%,而低CEA水平组患者分别为20%、20%以及60%,2组患者治疗疗效差异有统计学意义(P<0.05)。对患者进行生存分析结果提示,高CEA水平患者其经过吉非替尼治疗后有更长的无疾病进展时间以及生存时间(P<0.05)。结论血清CEA水平可作为评估吉非替尼治疗晚期非小细胞肺癌的疗效以及预后的生化指标。     

盐酸埃克替尼治疗晚期非小细胞肺癌Ⅲ期临床试验

目的观察比较盐酸埃克替尼与吉非替尼治疗晚期非小细胞肺癌疗效及毒副反应。方法随机双盲双模拟、阳性药物平行对照的方法,13例患者接受盐酸埃克替尼125mg,口服,3次/日,或对照药为吉非替尼250mg,口服,1次/日。结果治疗晚期非小细胞肺癌,盐酸埃克替尼的疾病进展时间（TTP）108天,吉非替尼的疾病进展时间（TTP）96天,盐酸埃克替尼总生存时间（OS）6月,吉非替尼OS4.8月。两组患者均无严重毒副反应。结论盐酸埃克替尼治疗晚期非小细胞肺癌疗效与吉非替尼疗效等同,毒性反应低。     

吉非替尼与厄洛替尼治疗非小细胞肺癌的疗效对比

目的探究吉非替尼与厄洛替尼治疗非小细胞肺癌的疗效。方法收集2013年3月至2016年3月我院收治的90例非小细胞肺癌患者进行研究,将上述患者随机分为两组,观察组接受吉非替尼治疗,对照组接受厄洛替尼治疗,比较两组患者临床治疗效果与不良反应情况。结果观察组治疗有效率(73.3%)、疾病控制率(93.3%)与对照组相比,组间差异无统计学意义(P>0.05)。观察组13例患者出现不良反应,概率为28.9%;对照组23例患者出现不良反应,概率为51.1%,组间差异具统计学意义(P<0.05)。结论吉非替尼与厄洛替尼治疗非小细胞肺癌的疗效相当,但前者不良反应较小,值得临床推广。     

吉非替尼致间质性肺炎1例

<正>吉非替尼(gefitinib)自2003年开始用于治疗晚期非小细胞肺癌以来,已成为肺癌靶向治疗的一种重要药物。国内,中华医学会和中国抗癌协会制定的肺癌诊疗指南中,吉非替尼也被列为Ⅲ_B、Ⅳ期非小细胞肺癌二线治疗的可选药物。但间质性肺炎是吉非替尼罕见且可以致命的不良反应,现报道1例肺癌病人口服吉非替尼后致间质性肺炎病例。     

埃克替尼与厄洛替尼治疗晚期非小细胞肺癌的疗效对比

目的对比埃克替尼与厄洛替尼应用于晚期非小细胞肺癌中的临床疗效。方法 84例晚期非小细胞肺癌患者,随机分为对照组与观察组,各42例。对照组给予患者口服厄洛替尼,观察组给予患者口服埃克替尼,比较两组患者治疗效果与不良反应发生情况。结果两组患者疾病控制率、总缓解率及中位肿瘤进展时间比较差异均无统计学意义(P>0.05);观察组患者的总不良反应发生率为47.6%,显著低于对照组71.4%,差异有统计学意义(P<0.05)。结论埃克替尼与厄洛替尼对晚期非小细胞肺癌有相似疗效,相对于厄洛替尼而言,埃克替尼治疗晚期非小细胞肺癌具有较低的不良反应发生率,具有临床借鉴意义。     

1例奥希替尼致间质性肺炎患者再用EGFR-TKI治疗的病例分析

目的 以奥希替尼为例，探讨患者使用表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）类药物并出现间质性肺炎（IP）后，再次使用EGFR-TKI类药物的方法。方法 对1例使用奥希替尼后出现IP的患者的IP治疗和再使用EGFR-TKI的方案进行分析，并结合文献报告的病例特点及本病例特征进行文献复习。结果 该患者因奥希替尼治疗而出现的IP在经过治疗后症状有所缓解，在使用阿美替尼联合激素作为再使用EGFR-TKI的方案后，患者IP的症状亦无加重，但因患者出现疾病进展，停用了阿美替尼。IP发生后需及时处理，应立即停用EGFR-TKI并给予对症治疗。结论 可采取更换EGFR-TKI、调整EGFR-TKI剂量和联合使用激素等的方式再使用EGFR-TKI靶向治疗。EGFR-TKI致IP的不良反应较少发生，但仍需密切观察。如在改用其他EGFR-TKI后亦需密切监测不良反应与疗效，以便及时调整患者的治疗方案。     

晚期非小细胞肺癌表皮生长因子受体-酪酸激酶抑制剂靶向治疗进展

随着分子生物学研究的深入,靶向治疗特别是表皮生长因子-酪氨酸激酶抑制剂(EGFR-TKI)为肺癌治疗开辟了蹊径。EGFR-TKI无论作为一线还是二、三线治疗或维持治疗对晚期非小细胞肺癌(NSCLC)均有效。本文概述EGFR-TKI在晚期NSCLC治疗中的应用进展。     

表皮生长因子受体-酪氨酸激酶抑制剂分子耐药机制研究

以表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)为靶点的治疗近年逐渐引起关注。但部分患者在服用EGFR-TKI初期即出现原发和获得性耐药。本文综述EGFR-TKI分子耐药机制的研究现状,探讨EGFR-TKI分子耐药机制重要的临床意义。     

Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.     

The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.     

Recent understanding of the molecular mechanisms for the efficacy and resistance of EGF receptor-specific tyrosine kinase inhibitors in non-small cell lung cancer

INTRODUCTION: The epidermal growth factor receptor (EGFR) and its family members are involved in many aspects of tumor biological processes. Aberrant activation of the EGFR tyrosine kinase by mutations or protein overexpression is observed in various types of human cancer, including lung cancer. EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are highly effective in lung cancer patients who harbor active mutations in the EGFR gene. However, patients who are initially sensitive to EGFR-TKIs eventually relapse within few years. AREAS COVERED: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with a high frequency of EGFR mutations. This review describes the EGFR mutations that determine the sensitivity to EGFR-TKIs and the current understanding of the molecular mechanisms of acquired resistance to EGFR-TKIs in NSCLC. Furthermore, the authors describe recent strategies developed to overcome acquired resistance using second-generation EGFR-TKIs and combination therapies with several molecular-targeting drugs. EXPERT OPINION: Although recent findings have contributed to our understanding of the mechanism of acquired resistance and helped the development of novel strategies to overcome such resistance, the underlying mechanisms are complex and additional research is necessary to develop effective therapeutic strategies for individual patients with lung cancer.     

NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells

Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer(NSCLC),but acquired resistance limits their clinical application.NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy.In this study,we investigated the role of NRF2 in resistance to EGFR-TKIs.We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein.NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells.Furthermore,we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2,and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs.Thus,we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.     

Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer

Introduction: Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3^rd generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1^st or 2^nd generation EGFR-TKIs. A recent phase I/II clinical trial with osimertinib for advanced NSCLC patients with known sensitizing EGFR mutations and documented disease progression on prior EGFR-TKIs revealed promising effect with acceptable toxicities.

Areas covered: This article summarizes current understanding and available preclinical and clinical data on osimertinib and also discusses future directions. The literature search included PubMed and the latest articles from international conferences.

Expert commentary: The development of osimertinib has provided new therapeutic options for NSCLC patients harboring T790 M. Compared with other EGFR-TKIs including rociletinib, osimertinib seems to possess an advantage with respect to the effect and safety profile among existing EGFR-TKIs. However, tumor progression still occurs even when treating with osimertinib. A further understanding of the mechanisms of resistance is eagerly anticipated in order to develop next generation EGFR-TKIs.     

FGFR leads to sustained activation of STAT3 to mediate resistance to EGFR-TKIs treatment

Investigational New Drugs - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to great advances in the treatment of non-small cell lung cancer (NSCLC), but the...     

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。     

晚期非小细胞肺癌EGFR-TKIs获得性耐药后治疗策略研究进展

肺癌是癌症相关死亡的首要原因。非小细胞肺癌（NSCLC）约占肺癌的85%,且患者在诊断时大多为晚期。随着表皮生长因子受体（EGFR）在肺癌中被发现,针对特定基因突变的靶向治疗成为晚期NSCLC的重要治疗方式,并显著延长了患者生存期。尽管第一、二、三代EGFR-酪氨酸激酶抑制剂（TKI）蓬勃发展,但随着治疗时间的推移,患者都可能面临耐药和进展。为克服这一难题,基于耐药机制的相关治疗策略正在研究中。本文旨在对近年来EGFR-TKIs,特别是在疗效及安全性上作为指南更优推荐的第三代EGFR-TKIs的耐药机制和治疗策略的研究进展进行综述。