晚期非小细胞肺癌EGFR-TKI耐药后抗血管生成联合免疫检查点抑制剂作用机制的研究进展

非小细胞肺癌（NSCLC）是肺癌中最常见的病理类型，表皮生长因子受体（EGFR）突变是NSCLC最常见的驱动基因突变。EGFR突变促进免疫抑制性肿瘤微环境（TME），但研究发现经表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）治疗后TME发生改变，这种改变可能为优化随后的免疫检查点抑制剂（ICIs）治疗提供线索。临床前研究提示抗血管生成药物可以通过促进效应细胞浸润、减少免疫抑制等改善TME免疫抑制状态，增强ICIs疗效，ICIs也可促进血管正常化，两者具有协同抗肿瘤作用。EGFR-TKI耐药机制相对复杂，在缺乏特异性耐药机制患者中，单纯化疗或单纯ICIs获益有限，抗血管生成药物联合ICIs相关临床研究提示对于晚期EGFR-TKI耐药NSCLC患者可改善预后。全文就晚期EGFR突变NSCLC的TKI治疗对TME的影响、抗血管生成治疗联合ICIs的生物学原理、EGFR-TKI耐药后抗血管生成治疗联合ICIs相关临床研究等作一综述。     

EGFR-TKI与化疗药物在晚期非小细胞肺癌中最佳联合方式的探讨

表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）已成为晚期非小细胞肺癌（NSCLC）的治疗药物之一。如何将EGFR-TKI与传统化疗药物合理组合,从而达到更佳的疗效日益受到人们关注。本文拟将目前研究较多的化疗药物与EGFR TKI的组合进行综述,梳理可能的最佳联合方式。     

EGFR突变晚期非小细胞肺癌的一线治疗进展

表皮生长因子受体(EGFR)突变在非小细胞肺癌中发生率高,酪氨酸激酶抑制剂(TKI)对EGFR突变患者有效率高、不良反应低,是EGFR突变晚期NSCLC患者的一线标准治疗。但EGFR-TKI应用一段时间后不可避免地会出现耐药。研究者在EGFR-TKI和化疗、抗血管生成治疗、放疗及免疫治疗等的联合应用领域进行了诸多尝试,显著延缓了疾病进展或耐药的发生,并转化为具有临床意义的生存获益。本文就EGFR突变晚期NSCLC患者一线治疗进展作一综述。     

EGFR-TKI治疗非小细胞肺癌研究进展

吉非替尼和厄洛替尼均为小分子量表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），已在化疗失败的晚期非小细胞肺癌（NSCLC）解救治疗中取得疗效，但仅对特定人群发挥作用。EGF冀。TKI联合化疗一线治疗NSCLC并未能提高疗效；正在进行的临床研究聚焦于优势人群EGFR-TKI一线治疗或联合化疗的研究。     

非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂的一线治疗

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)参与的晚期非小细胞肺癌(NSCLC)一线治疗的几种模式显示出不同的结果.化疗与EGFR-TKI联合未显示生存优势,化疗序贯EGFR-TKI和EGFR-TKI单药这两种模式取得了巨大的突破,为晚期NSCLC个体化治疗开辟了新的道路.同时发现EGFR突变在晚期NSCLC靶向治疗方面有很好的疗效预测价值.     

非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂的一线治疗

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)参与的晚期非小细胞肺癌(NSCLC)一线治疗的几种模式显示出不同的结果.化疗与EGFR-TKI联合未显示生存优势,化疗序贯EGFR-TKI和EGFR-TKI单药这两种模式取得了巨大的突破,为晚期NSCLC个体化治疗开辟了新的道路.同时发现EGFR突变在晚期NSCLC靶向治疗方面有很好的疗效预测价值.     

非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂的一线治疗

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)参与的晚期非小细胞肺癌(NSCLC)一线治疗的几种模式显示出不同的结果.化疗与EGFR-TKI联合未显示生存优势,化疗序贯EGFR-TKI和EGFR-TKI单药这两种模式取得了巨大的突破,为晚期NSCLC个体化治疗开辟了新的道路.同时发现EGFR突变在晚期NSCLC靶向治疗方面有很好的疗效预测价值.     

表皮生长因子受体酪氨酸激酶抑制剂在治疗非小细胞肺癌中的研究进展

摘　要：表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI ）至今已上市近二十年。第一代EGFR-TKI在提高EGFR突变晚期非小细胞肺癌（NSCLC）的客观缓解率（ORR）、延长无进展生存期（PFS）方面起了重大的贡献。第二代EGFR-TKI在延长总生存期（OS）方面带来了惊喜。第三代EGFR-TKI克服了第一二代药物的耐药,其一线PFS可能打破现有治疗的格局。第四代EGFR-TKI已在研发中且EGFR-TKI研究已扩展到术后辅助治疗领域,期待其进一步的发展。     

抗血管生成药物治疗肺癌脑转移的研究新进展

晚期肺癌脑转移发生率高,预后差。近年来,随着肺癌总体治疗的发展,为晚期肺癌脑转移提供了更多的治疗手段和期待。目前的临床研究提示抗血管生成药物在肺癌脑转移的治疗中占有重要地位,从大分子的单克隆抗体,到泛靶点抗血管药物,再到小分子酪氨酸激酶抑制剂(Tyrosine kinase inhibitor,TKI),均显示出一定的疗效与良好的安全性,并与化疗、放疗以及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)表现出良好的协同抗肿瘤作用。本文就抗血管生成药物治疗肺癌脑转移的研究新进展做一综述。     

盐酸埃克替尼的药理学及临床研究进展

非小细胞肺癌（NSCLC）约占肺癌的80％～85％。晚期NSCLC主要以内科治疗为主,既往主要应用化疗,但疗效差。近年来,表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的应用为NSCLC的治疗提出了新的突破。盐酸埃克替尼作为一种国产的EGFR-TKI,其临床前期研究及其临床研究均显示其较好的安全性、耐受性和疗效,为晚期NSCLC治疗的新选择。     

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。     

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.     

Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC)

Bevacizumab is a monoclonal antibody that specifically inhibits vascular endothelial growth factor, and is the first antiangiogenic agent to be approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). Evidence from two large phase III trials demonstrates that bevacizumab combined with chemotherapy improves outcomes for patients with non-squamous NSCLC. In patients with adenocarcinoma without epidermal growth factor receptor (EGFR) mutation, a median overall survival of 18.0 months is achieved. Several post-registration phase IV studies have confirmed bevacizumab’s efficacy and tolerability profile and have clarified the eligibility criteria. Clinical research is still ongoing to define the role of bevacizumab in different settings, such as single-agent bevacizumab for continuation maintenance therapy in advanced disease, treatment beyond disease progression, adjuvant therapy in early-stage NSCLC, or bevacizumab in combination with other targeted agents. A number of antiangiogenic tyrosine kinase inhibitors (TKI) have also been investigated in phase II and III trials. None of these drugs has proven significant clinical benefit in unselected patient populations. This article reviews the extensive information from randomized trials and large observational studies for bevacizumab in advanced NSCLC, and shortly describes the current clinical development of antiangiogenic monoclonal antibodies, TKIs and related compounds.     

EGFR-TKIs联合放疗在局部晚期非小细胞肺癌治疗中的地位和作用

不可手术切除的局部晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）从组织分型看,标准治疗模式为同期化放疗,但从分子分型看,表皮生长因子受体（epidermal growth factor receptor,EGFR）外显子19、21突变阳性的NSCLC患者一线应用EGFR酪氨酸激酶抑制剂（EGFR-TKIs）,将在生存上最大程度地获益。放疗具有手术不可比拟的空间和化疗无法取得的局部优势,放疗可激活EGFR信号通路,通过诱导细胞增殖和增强DNA修复而导致放疗抵抗,EGFR-TKIs具有放疗增敏作用。临床研究结果提示EGFR-TKIs联合胸部放疗治疗局部晚期或转移NSCLC患者,总体上毒性反应可以耐受,但生存获益程度不一,可能与病例选择不同有关。对于EGFR基因突变的不可切除的NSCLC患者,EGFR-TKIs同步个体化放疗目前缺乏大样本多中心的临床研究结果,也许是今后一线治疗的一种选择。     

Role of bevacizumab for the treatment of non-small-cell lung cancer

Advanced-stage non-small-cell lung cancer (NSCLC) is a lethal disease that is treated with combination chemotherapy. Although modest survival benefit has been documented with various platinum-based, two-drug combination chemotherapy regimens, an efficacy plateau has been reached. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, is the first molecularly targeted agent that has demonstrated survival advantage when combined with chemotherapy for the treatment of advanced nonsquamous NSCLC. Improvements in all efficacy parameters, including response rate, progression-free survival and overall survival, were noted for advanced nonsquamous NSCLC patients when bevacizumab was added to the combination of carboplatin-paclitaxel compared with the same chemotherapy regimen alone. This has opened the door for expanding the role of bevacizumab in earlier stages of the disease with chemotherapy or radiotherapy. The anti-angiogenesis agents, including the monoclonal antibody and vascular endothelial growth factor tyrosine kinase inhibitors, will be among the most important drugs of the present decade. This article discusses the recent data with bevacizumab in NSCLC and its potential application at various stages of NSCLC.     

Targeted therapies for treatment of non‐small cell lung cancer—Recent advances and future perspectives

Non‐small cell lung cancer (NSCLC) is one of the most deadly cancers worldwide, with poor prognosis once the disease has progressed past the point at which surgery is a viable option. Whilst chemotherapy has improved survival over recent decades, there is still great need for improvements in treatments for patients with advanced disease. Over the last decade, a variety of such drugs have received market approval for treating NSCLC, with a variety of others in the pipeline. Here, we review the development of targeted therapies for the treatment of advanced or metastatic NSCLC, including those already in clinical practice and those in early trials. The epidermal growth factor receptor (EGFR) inhibitors, gefitinib, erlotinib and afatinib; the anaplastic lymphoma kinase (ALK) inhibitor, crizotinib; and the anti‐vascular endothelial growth factor receptor monoclonal antibody, bevacizumab, are already providing improved survival for patients with NSCLC. Moreover, the discovery of EGFR mutations and ALK rearrangements has enabled the identification of patients who are more likely to benefit from a specific drug. The recent approval of the immune checkpoint inhibitor nivolumab, along with the designation of alectinib and MPDL3280A as breakthrough therapies by the FDA, demonstrates how rapidly this area of research is expanding. Over the last decade there has been significant progress made in the treatment of advanced NSCLC, and the large and varied selection of drugs currently undergoing trials provide great promise for improving the prognosis of this highly prevalent and deadly form of cancer.     

表皮生长因子受体基因CA简单重复序列多态性与晚期小细胞肺癌患者表皮生长因子受体酪氨酸激酶抑制剂临床疗效间的关系

目的:研究表皮生长因子受体(epidermal growth factor receptor,EGFR)基因第1内含子区CA简单重复序列(simple sequence repeat,SSR)多态性与晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者应用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)治疗的临床疗效间的关系。方法:观察101例晚期NSCLC患者使用EGFR-TKIs的临床疗效及生存情况,通过对患者EGFR-TKIs治疗前外周血进行EGFR基因第1内含子的PCR扩增,并对PCR扩增产物直接进行序列测定,分析CA-SSR多态性与EGFR-TKIs治疗的临床疗效和患者生存情况间的关系。结果:EGFR-TKIs治疗后,24例(23.8%)患者部分缓解(partial response,PR),46例(45.5%)患者为疾病稳定(stable disease,SD),临床受益(PR+SD)患者为70例(69.3%)。腺癌和女性患者的中位生存期(median survival time,MST)较非腺癌和男性患者明显延长(P<0.05)。CA-SSR出现频率最多的CA等位基因为(CA)20[68.7%(68/99)],短CA-SSR组患者经EGFR-TKIs治疗后的无进展生存(progression-free survival,PFS)时间比长CA-SSR患者明显延长(P=0.039);短CA-SSR组MST为15.7个月,长CA-SSR组MST为14.4个月,组间差异无统计学意义(P=0.691)。结论:EGFR-TKIs治疗可明显延长腺癌、女性NSCLC患者的MST和短CA-SSR患者的PFS。     

Combined therapy with epidermal growth factor receptor tyrosine kinase inhibitors for non–small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non–small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified.

Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations.

Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations.