驱动基因阳性非小细胞肺癌免疫治疗进展

肺癌是目前世界上致死率最高的恶性肿瘤,其中约80％为非小细胞肺癌(non-small cell lung cancer,NSCLC).大部分NSCLC患者伴有"驱动基因突变",针对突变基因的靶向治疗可取得较好的疗效,但仍有部分患者在治疗后会出现进展或复发,预后较差.已有的研究表明,免疫检查点抑制剂可改善晚期NSCLC的...     

非小细胞肺癌脑转移的靶向和免疫治疗

脑转移是非小细胞肺癌（non-small cell lung cancer, NSCLC）常见并发症,发生率为30%-50%,大大影响了患者的生存质量。NSCLC一旦发生脑转移预后极差,未经治疗者的中位生存期仅为1个月-2个月。基于肺癌驱动基因的靶向治疗为肺癌脑转移提供了新的方法。目前免疫治疗已成为肿瘤治疗的新方向,它能通过刺激机体免疫系统提高抗肿瘤免疫效应。临床上靶向治疗和免疫治疗的结合运用可使患者获益。     

驱动基因阳性晚期非小细胞肺癌靶向治疗

近年来,分子靶向治疗有效改善了驱动基因阳性晚期非小细胞肺癌(NSCLC)患者的预后,其中,针对存在人体表皮生长因子受体基因突变、棘皮动物微管相关样蛋白4-间变性淋巴瘤激酶融合基因、ROS1基因重排等的NSCLC患者,疗效尤为显著。对于驱动基因阳性晚期NSCLC患者,靶向治疗药物的选择尤为重要。     

KRAS突变非小细胞肺癌的生物学和治疗研究进展

KRAS突变是非小细胞肺癌(NSCLC)最为常见的驱动基因突变之一。KRAS突变NSCLC具有高度异质性,多种突变亚型和不同共突变特征均影响其生物学行为和治疗应答。KRAS突变NSCLC是免疫治疗相对获益人群,而KRAS突变对化疗存在的影响仍存有争议。KRAS突变肺癌多年来遵循无驱动基因突变NSCLC的治疗方案。随着KRASG12C抑制剂的问世,该人群的靶向治疗已取得初步进展,联合治疗的效果在临床前和早期临床研究中初见成效。现就KRAS突变NSCLC的生物学和临床特征及治疗研究进展进行综述。     

非小细胞肺癌免疫治疗最新进展与挑战

肺癌在中国乃至全球范围内是威胁人类健康最常见的恶性肿瘤之一,发病率和死亡率居高不下,预后也较差。近年来,晚期非小细胞肺癌（non-smallcelllungcancer ,NSCLC ）虽然在手术治疗、化疗、放疗及靶向治疗方面均取得了很大进展,但其疗效并不令人满意,晚期NSCLC 患者的5 年生存率仍然很低。随着肿瘤免疫学及分子生物学的发展,肺癌的免疫治疗得到广泛关注,并为非小细胞肺癌患者提供了新的治疗方向。免疫治疗种类繁多,有免疫检测点受体抑制剂、主动性免疫疫苗和过继性免疫疫苗等。I 期临床试验显示了较高缓解率,Ⅱ期/ Ⅲ期临床试验亦在进一步探索中。本文就当前非小细胞肺癌免疫治疗的最新进展及面临的挑战进行概述。      

非小细胞肺癌免疫治疗研究进展

近年来,肺癌的治疗手段层出不穷,从传统化疗到靶向药物,再到免疫检查点抑制剂的出现,很大程度上改善了患者的预后,延长了患者生存期。免疫检查点抑制剂的应用,即免疫治疗,一改传统的治疗方式,作用于程序性细胞死亡蛋白-1（PD-1）及其配体（PD-L1）发挥有效且持久的抗肿瘤反应。本文主要介绍了近年来免疫治疗一线、二线应用于非小细胞肺癌（NSCLC）的研究情况,影响免疫治疗疗效的因素,及免疫治疗的相关毒副反应。     

非小细胞肺癌的个体化治疗进展

肺癌是全球癌症相关死亡的最常见原因.在过去20年中,分子靶向治疗和免疫治疗显著改善了非小细胞肺癌(non-small-cell lung cancer,NSCLC)患者的预后.然而,绝大多数的晚期NSCLC会对目前治疗产生耐药,最终出现疾病进展.基于此,本综述就近年来出现的一些突破性NSCLC治疗方法,尤其是免疫治疗和...     

系统性免疫炎症指数与非小细胞肺癌患者预后关系的研究进展

肺癌是世界上常见的恶性肿瘤,其中非小细胞肺癌（NSCLC）占肺癌的大多数。虽然在手术、化学药物治疗、放射治疗、靶向治疗、免疫治疗中NSCLC患者的总体生存率在不断改善,但部分患者预后仍较差。炎性反应在肿瘤的发生、进展和转移中均起着重要作用。因此,与炎性反应相关的全血细胞计数将会是预测NSCLC预后的有效指标。由中性粒细胞、淋巴细胞、血小板系统组成的系统免疫炎症指数（SII）能全面反映宿主全身炎症及免疫状态,与其他炎症指标如C反应蛋白/白蛋白值（CAR）、晚期肺癌炎症指数（ALI）、预后营养指数（PNI）等的联合检测,可以增加对NSCLC患者预后的预测效能。此外,SII检测成本低廉、操作简单、获取方便,易于在临床中运用。本文就SII与NSCLC预后关系的研究进展综述如下。     

可切除非小细胞肺癌新辅助免疫治疗研究进展

近年来,免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）对晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者预后的改善已成为共识,越来越多的临床研究也逐渐证明了免疫治疗对于可切除NSCLC患者的重要价值。然而,目前关于新辅助治疗背景下免疫联合策略的探索、治疗相关副作用、预后生物标志物等问题仍存在争议。本文综述了可切除NSCLC患者新辅助免疫治疗的最新进展,引发了新的思考,并讨论了其在临床应用中的优势及挑战。     

非小细胞肺癌新辅助靶向及免疫治疗研究进展和展望

肺癌是全球发病率和死亡率最高的恶性肿瘤。近年来,随着新型药物的出现和治疗模式的优化,肺癌患者的预后已有一定改善。新辅助治疗是指对潜在可接受手术切除的患者,先给予术前抗肿瘤治疗后再行手术治疗。新辅助治疗通过术前治疗可以缩小肿瘤体积,降低肿瘤分期;并且可以杀灭患者机体中循环肿瘤细胞及微转移病灶,令患者远期生存获益。靶向治疗及免疫治疗已被应用于晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的一线治疗。因此,有临床试验尝试将以上两种治疗手段应用于早期可切除NSCLC患者的新辅助治疗。本文针对新辅助靶向及免疫治疗对早期可切除NSCLC患者的疗效、治疗中的潜在风险予以综述,并探讨新辅助治疗的未来发展方向。     

The Significance of the PD-L1 Expression in Non–Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers

Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non–small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors.     

Duration of Targeted Therapy in Patients With Advanced Non–small-cell Lung Cancer Identified by Circulating Tumor DNA Analysis

BackgroundOutcomes of therapy targeting molecular driver alterations detected in advanced non–small-cell lung (NSCLC) using circulating tumor DNA (ctDNA) have not been widely reported in patients who are targeted therapy-naive.Patients and MethodsWe performed a multicenter retrospective review of patients with unresectable stage IIIB to IV NSCLC who received matched therapy after a targetable driver alteration was identified using a commercial ctDNA assay through usual clinical care. Eligible patients must not have received targeted therapy prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate the median duration of targeted therapy. Patients still on targeted therapy were censored at last follow-up.ResultsSeventy-six patients met inclusion criteria. The median age of diagnosis of NSCLC was 64.5 years (range, 31-87 years), 67% were female, 74% were never-smokers, and 97% had adenocarcinoma histology. Twenty-one (28%) patients received systemic treatment prior to targeted therapy, including chemotherapy (n = 17), immunotherapy (n = 5), and/or a biologic (n = 4). Thirty-three (43%) patients remain on targeted therapy at the time of data analysis. The median time on targeted therapy was similar to what has been reported for tissue-detected oncogenic driver mutations in the targeted therapy-naive setting.ConclusionsPatients with ctDNA-detected drivers had durable time on targeted therapy. These treatment outcomes data compliment previous studies that have shown enhanced targetable biomarker discovery rates and high tissue concordance of ctDNA testing when incorporated at initial diagnosis of NSCLC. Identification of NSCLC driver mutations using well-validated ctDNA assays can be used for clinical decision-making and targeted therapy assignment.     

基于分子影像的非小细胞肺癌分子靶向治疗及免疫治疗进展

我国癌症发病率与死亡率中肺癌均高居第一位，其中非小细胞肺癌（NSCLC）占肺癌85%以上， NSCLC传统治疗方式包括手术、化疗、放疗等。近十几年来，NSCLC相关临床治疗取得巨大突破，代表性治疗新方案即为分子靶向治疗和免疫治疗，然而，上述治疗方式成功发挥治疗作用前提和关键则是精准选择NSCLC患者治疗优势人群。分子影像可以在活体状态下，应用影像学方法对人或动物体内细胞和分子水平生物学过程进行成像、定性和定量研究，着眼于生物过程基础变化而不是生物变化最终结果，进而实现精准选择治疗优势人群、分子水平精准监测治疗效果、及时进行预后评估等目的，对分子靶向治疗以及免疫治疗意义重大。该文综述分子影像在NSCLC分子靶向治疗以及免疫治疗中开展的相关研究。     

Targeting HER2 in the treatment of non-small cell lung cancer

Oncogenic driver mutations have emerged as major treatment targets for molecular therapies in a variety of cancers. HER2 positivity has been well-studied in breast cancer, but its importance is still being explored in non-small cell lung cancer (NSCLC). Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for gene mutations. The prognostic and predictive significance of these tests remain to be validated, with an emerging association between HER2 gene mutations and response to HER2 targeted therapies. Despite the assay used to determine the HER2 status of lung tumors, all patients with advanced HER2 positive lung adenocarcinoma should be evaluated for treatment with targeted agents. Several clinical approaches for inclusion of these drugs into patient treatment plans exist, but there is no defined algorithm specific to NSCLC.     

Advances in Targeted Therapy Against Driver Mutations and Epigenetic Alterations in Non-Small Cell Lung Cancer

The incidence and mortality of lung cancer rank top three of all cancers worldwide. Accounting for 85% of the total number of lung cancer, non-small cell lung cancer (NSCLC) is an important factor endangering human health. Recently, targeted therapies against driver mutations and epigenetic alterations have made encouraging advances that benefit NSCLC patients. Druggable driver mutations, which mainly occur in EGFR, KRAS, MET, HER2, ALK, ROS1, RET and BRAF, have been identified in more than a quarter of NSCLC patients. A series of highly selective mutant targeting inhibitors, such as EGFR tyrosine kinase inhibitors and KRAS inhibitors, have been well studied and applied in clinical treatments, which greatly promote the overall survival of NSCLC patients. However, drug resistance has become a major challenge for targeted treatment, and a variety of methods to overcome drug resistance are constantly being developed, including inhibitors against new mutants, combination therapy with other pathway inhibitors, etc. In addition, epigenetics-based therapy is emerging. Epigenetic regulators such as histone deacetylases and non-coding RNA play a crucial role in the development of cancer and drug resistance by affecting multiple signaling pathways. Epigenetics-based therapeutic strategies combined with targeted drugs show great clinical potential. Many agents targeting epigenetic changes are being investigated in preclinical studies, with some already under clinical trials. This article focuses on driver mutations and epigenetic alterations in association with relevant epidemiological data. We introduce the current status of targeted inhibitors and known drug resistance, review advances in major targeted therapies with recent data from preclinical and clinical trials, and discuss the possibility of combination therapy against driver mutations and epigenetic alterations in overcoming drug resistance.     

EGFR敏感突变Ⅱ~ⅢA期非小细胞肺癌治疗的研究新进展

非小细胞肺癌（non-small cell lung cancer,NSCLC）为发病率最高的恶性肿瘤,Ⅱ~ⅢA期患者为潜在可根治人群。目前,围手术期的标准治疗为化疗,而表皮生长因子受体（epidermal growth factor receptor,EGFR）敏感突变的患者,新辅助或辅助靶向治疗可提高无病生存期（disease free survival,DFS）,但是否能带来生存获益,尚未明确。ⅢA（N2）期NSCLC患者术后辅助放疗可带来生存获益,而不可手术切除的局部晚期NSCLC患者,同步放化疗后durvalumab维持治疗成为新标准。在驱动基因突变人群中的免疫治疗还有待于进一步探索,免疫治疗联合化疗可能为方向之一,而抗血管生成治疗不适宜在术后辅助治疗。      

非小细胞肺腺癌驱动突变的研究进展

随着主要肿瘤基因测序项目的开展,来源于体细胞突变的驱动突变以其在癌症发生、发展、治疗中的重要作用受到广泛关注.新驱动突变的不断确认使人们对非小细胞肺癌（NSCLC）的认识从传统的病理分类到现今的基于分子水平改变的分子分型;NSCLC患者也已不再被看做是同一类型肿瘤的集合,而是多种具有不同分子生物学行为、对不同的靶向药物敏感的患者群体.文章着重就NSCLC中腺癌这一特殊病理类型的常见驱动突变及相关转化性医学研究进展作一概述.