Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.     

NTRK基因融合和TRK抑制剂在非小细胞肺癌中的研究进展

肺癌是癌症相关死亡的主要原因之一，其中非小细胞肺癌（non-small cell lung cancer，NSCLC）约占肺癌全部病例数的80%~85%。大部分NSCLC患者初诊时即为晚期，尽管传统化疗、免疫治疗等取得了显著的进展，其总体预后仍然较差。近年来，随着精准医学的不断进步，新兴靶点及相应药物研究越来越多，使靶向治疗的前景日趋广阔。目前，NTRK基因融合已被证实与多种实体瘤的发生发展密切相关，其在NSCLC中的发生率约为0.2%，且通常不与其它常见致癌驱动基因重叠。研究显示，原肌球蛋白受体激酶（tropomyosin receptor kinase，TRK）抑制剂在NTRK基因融合阳性的实体瘤中表现出了良好的疗效和安全性，难治性NSCLC患者可从中明显获益。本文就NTRK基因融合和TRK抑制剂在NSCLC中的研究进展进行综述。      

Epidermal growth factor receptor gene mutation in non-small cell lung cancer using highly sensitive and fast TaqMan PCR assay

Epidermal growth factor receptor (EGFR) gene mutations have been found in a subset of non-small cell lung cancer (NSCLC) with good clinical response to gefitinib therapy. A quick and sensitive method with large throughput is required to utilize the information to determine whether the molecular targeted therapy should be applied for the particular NSCLC patients. Using probes for the 13 different mutations including 11 that have already been reported, we have genotyped the EGFR mutation status in 94 NSCLC patients using the TaqMan PCR assay. We have also genotyped the EGFR mutations status in additional 182 NSCLC patients, as well as 63 gastric, 95 esophagus and 70 colon carcinoma patients. In 94 NSCLC samples, the result of the TaqMan PCR assay perfectly matched with that of the sequencing excluding one patient. In one sample in which no EGFR mutation was detected by direct sequencing, the TaqMan PCR assay detected a mutation. This patient was a gefitinib responder. In a serial dilution study, the assay could detect a mutant sample diluted in 1/10 with a wild-type sample. Of 182 NSCLC samples, 46 mutations were detected. EGFR mutation was significantly correlated with gender, smoking status, pathological subtypes, and differentiation of lung cancers. There was no mutation detected by the TaqMan PCR assay in gastric, esophagus and colon carcinomas. TaqMan PCR assay is a rapid and sensitive method of detection of EGFR mutations with high throughput, and may be useful to determine whether gefitinib should be offered for the treatment of NSCLC patients. The TaqMan PCR assay can offer us a complementary and confirmative test.     

Skp1蛋白在非小细胞肺癌组织和外周血中的表达水平及其临床意义

目的：检测S期激酶相关蛋白1（Skp1）在非小细胞肺癌（NSCLC）组织和外周血中的表达水平并探讨其临床意义。方法：采用Western blot检测34例NSCLC组织及相应癌旁组织中Skp1蛋白的表达水平。采用组织芯片和免疫组织化学染色检测Skp1在86例NSCLC组织及相应癌旁组织中的表达情况,并分析Skp1蛋白的表达与NSCLC临床病理指标及患者预后的关系。采用酶联免疫吸附试验（ELISA）检测39例NSCLC患者及27例健康人血浆中的Skp1蛋白水平。结果：Western blot和免疫组化法分析结果显示Skp1蛋白在NSCLC组织中的表达水平均显著高于相应癌旁组织（P < 0.001）。ELISA法分析结果显示NSCLC病人血浆中的Skp1蛋白表达水平显著高于健康人群（P=0.003）。Kaplan-Meier单因素生存分析显示Skp1蛋白在NSCLC组织中的高表达与中晚期（Ⅱ+Ⅲ） NSCLC患者的不良预后显著相关（P=0.001）,多因素Cox回归分析显示Skp1蛋白能够作为影响中晚期（Ⅱ+Ⅲ） NSCLC患者预后的独立危险因素。Skp1蛋白表达水平与病理类型、临床分期、分化程度、淋巴结转移等因素无显著相关关系（P > 0.05）。结论：Skp1蛋白在NSCLC患者中高表达,并且Skp1蛋白在NSCLC组织中的高表达与中晚期（Ⅱ+Ⅲ） NSCLC患者的不良预后显著相关,可作为中晚期NSCLC患者预后的独立危险因素。     

Alpha Interferon, Leucovorin, and 5-Fluorouracil (ALF) in Advanced Cancer: Results of a Dose-Finding Study and Evidence of Activity in Non-Small Cell Lung Cancer

In a phase I trial, 17 patients were treated with 5-fluorouracil (5-FU) 500 mg/m² and leucovorin (LV) 500 mg/m² intravenously weekly for 6 weeks followed by 2 weeks' rest and interferon alfa-2b 1, 3, 5, 8, or 10 million units (MU) subcutaneously tiw with no rest period. The most common toxicities were fatigue (12), diarrhea (10), nausealvomiting (7), and fever (7). The maximum tolerated interferon dose was 8 MU tiw. Fatigue and increased incidence of other toxicities rather than a single dose-limiting toxicity occurred at the next highest interferon level. ECOG grade III/IV toxicity occurred in 5 patients and included transient supraventricular tachycardia and brief seizure episode (1), dyspnea (1), decreased performance status (1), anemia requiring transfusion (1), and deep vein thrombosis (1). No toxic deaths occurred. Two patients with non-small cell lung cancer (NSCLC) had partial responses lasting 5 and 4 months. Two other patients with NSCLC had either minor response or stable disease, and 1 patient with colon cancer had a significant decline in serum CEA. The recommended alpha interferon dose is 8 MU tiw when given with this schedule of 5-FU/LV.     

晚期非小细胞肺癌病理特征及放化疗联合治疗疗效与患者血清超氧化物歧化酶的关系

目的：探讨晚期非小细胞肺癌（NSCLC）病理特征、放化疗联合治疗疗效、总生存期与患者血清超氧化物歧化酶（SOD）活力的关系。方法：采用基因表达谱数据动态分析数据库（GEPIA）分析不同肿瘤组织SOD的表达情况。收集2018年1—12月河北工程大学附属医院肿瘤科初次确诊的174例晚期NSCLC患者作为研究对象，80例健康者作为对照，放化疗联合治疗前采集患者外周血，分离血清，WST-1法检测血清中SOD活性，根据实体瘤疗效评价标准（RECIST 1.1）评估疗效，追踪随访，分析晚期NSCLC临床病理特征、放化疗联合治疗疗效、总生存期与SOD活力的关系。结果：GEPIA分析显示33类肿瘤中，19类肿瘤组织SOD表达异常，其中肺鳞状细胞癌和肺腺癌组织SOD表达较对照组显著降低（P < 0.05）；WST-1检测结果显示晚期NSCLC患者血清SOD活力显著低于对照组（P < 0.05），不同年龄、性别、病理类型患者血清SOD活力无显著性差异（P > 0.05）；不同吸烟史及病理分级患者血清SOD有显著性差异（P < 0.05），吸烟者血清SOD活力显著低于无吸烟者（P < 0.05），低分化患者血清SOD活力显著低于中、高分化者（P < 0.05）；患者血清SOD活力与放化疗联合治疗疗效呈正相关（r=0.554，P < 0.05），治疗有效患者血清SOD活力显著高于无效患者（P < 0.05），且SOD高活力组患者总生存期显著高于低活力组（P < 0.05）。结论：NSCLC患者血清SOD活性显著降低，且受患者吸烟史、病理分级的影响，可能与放化疗联合治疗疗效和总生存期有关。血清SOD或可作为评估NSCLC临床疗效和判断预后的潜在指标，辅助NSCLC放化疗的疗效判定及预后评估。     

晚期非小细胞肺癌病理特征及放化疗联合治疗疗效与患者血清超氧化物歧化酶的关系

目的：探讨晚期非小细胞肺癌（NSCLC）病理特征、放化疗联合治疗疗效、总生存期与患者血清超氧化物歧化酶（SOD）活力的关系。方法：采用基因表达谱数据动态分析数据库（GEPIA）分析不同肿瘤组织SOD的表达情况。收集2018年1—12月河北工程大学附属医院肿瘤科初次确诊的174例晚期NSCLC患者作为研究对象，80例健康者作为对照，放化疗联合治疗前采集患者外周血，分离血清，WST-1法检测血清中SOD活性，根据实体瘤疗效评价标准（RECIST 1.1）评估疗效，追踪随访，分析晚期NSCLC临床病理特征、放化疗联合治疗疗效、总生存期与SOD活力的关系。结果：GEPIA分析显示33类肿瘤中，19类肿瘤组织SOD表达异常，其中肺鳞状细胞癌和肺腺癌组织SOD表达较对照组显著降低（P < 0.05）；WST-1检测结果显示晚期NSCLC患者血清SOD活力显著低于对照组（P < 0.05），不同年龄、性别、病理类型患者血清SOD活力无显著性差异（P > 0.05）；不同吸烟史及病理分级患者血清SOD有显著性差异（P < 0.05），吸烟者血清SOD活力显著低于无吸烟者（P < 0.05），低分化患者血清SOD活力显著低于中、高分化者（P < 0.05）；患者血清SOD活力与放化疗联合治疗疗效呈正相关（r=0.554，P < 0.05），治疗有效患者血清SOD活力显著高于无效患者（P < 0.05），且SOD高活力组患者总生存期显著高于低活力组（P < 0.05）。结论：NSCLC患者血清SOD活性显著降低，且受患者吸烟史、病理分级的影响，可能与放化疗联合治疗疗效和总生存期有关。血清SOD或可作为评估NSCLC临床疗效和判断预后的潜在指标，辅助NSCLC放化疗的疗效判定及预后评估。     

非小细胞肺癌脑转移的治疗策略与相关问题*

非小细胞肺癌脑转移是影响非小细胞肺癌患者生存期及生存质量的重要因素。目前,传统治疗的发展、小分子靶向药物的广泛应用以及各种联合治疗方式的采用共同影响着脑转移患者的疗效及预后。对新治疗靶点的研究以及对现有治疗的认知功能保护措施的探索也愈加为临床所关注。本文就非小细胞肺癌脑转移临床及基础的相关问题和治疗策略进行简要的梳理。      

GSTM1, GSTT1 and GSTP1 polymorphisms and lung cancer risk

Previous studies have suggested that GST genotypes may play a role in determining susceptibility to lung cancer, though the data are often conflicting. In this study we investigated GSTM1, GSTT1 and GSTP1 status in relation to lung cancer risk in patients attending a Manchester bronchoscopy clinic. Cases were all patients (n=94) currently with, or with a history of, tumours of the lung, trachea or bronchus. The control group were all other patients (n=165) who were free of benign and malignant tumours both at the time of, or prior to, diagnosis. All patients were interviewed for information on lifestyle risk factors, and DNA extracted from bronchial lavage and blood samples was used for genotyping. GSTM1 null genotype was associated with decreased lung cancer risk (odds ratio (OR) 0.50, 95% confidence interval (CI) 0.29–0.87), particularly among men (OR 0.43, 95% CI 0.21–0.87) and those above the median age (OR 0.33, 95% CI 0.15–0.70). No difference in GSTT1 and GSTP1 genotype distribution was seen between cases and controls. The GSTM1 null genotype was associated with a decreased risk of squamous cell carcinoma: the OR, adjusted for age, sex and pack years was 0.32 (95% CI 0.12–0.82). As previous studies have reported that the GSTM1 null genotype is associated with an increased lung cancer risk, further work is required to determine whether the observed association is true, or whether it arises from bias or confounding factors.     

The sphingosine kinase 2 inhibitor ABC294640 displays anti‐non‐small cell lung cancer activities in vitro and in vivo

Non‐small cell lung cancer (NSCLC) accounts for about 85‐90% of lung cancer cases, and is the number one killer among cancers in the United States. The majorities of lung cancer patients do not respond well to conventional chemo‐ and/or radio‐therapeutic regimens, and have a dismal 5‐year survival rate of ～15%. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but even with these agents, not all patients respond, and responses are rarely complete. Thus, there is still an urgent need to identify new therapeutic targets in NSCLC and develop novel anti‐cancer agents. Sphingosine kinase 2 (SphK2) is one of the key enzymes in sphingolipid metabolism. SphK2 expression predicts poor survival in NSCLC patients, and is associated with Gefitinib‐resistance. In this study, the anti‐NSCLC activities of ABC294640, the only first‐in‐class orally available inhibitor of SphK2, were explored. The results obtained indicate that ABC294640 treatment causes significant NSCLC cell apoptosis, cell cycle arrest and suppression of tumor growth in vitro and in vivo. Moreover, lipidomics analyses revealed the complete signature of ceramide and dihydro(dh)‐ceramide species in the NSCLC cell‐lines with or without ABC294640 treatment. These findings indicate that sphingolipid metabolism targeted therapy may be developed as a promising strategy against NSCLC.     

Targeted therapies for advanced non-small-cell lung cancer: current status and future implications

Lung cancer remains the leading cause of malignancy-related mortality worldwide, with over one million cases diagnosed yearly. Non-small-cell lung cancer (NSCLC) accounts for >80% of all lung cancers. Because lung cancer is typically diagnosed at an advanced stage, chemotherapy (CT) is the mainstay of management. Conventional treatment of NSCLC has apparently reached a plateau of effectiveness in improving survival of patients, and treatment outcomes must still be considered disappointing. Hence, considerable efforts have been made in order to identify novel targeted agents that interfere with other dysregulated pathways in advanced NSCLC patients. In order to further improve the results of targeted therapy, we should not forget that lung cancer is a heterogeneous disease with multiple mutations, and it is unlikely that any single signaling pathway drives the oncogenic behaviour of all tumours. The relative failure of some targeted therapies may be a result of multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. We summarize the most promising research approaches to the treatment of NSCLC, with particular attention to drugs with multiple targets or combining targeted therapies.     

ZD1839, a novel,oral epidermal growth factor receptor-tyrosine kinase inhibitor,as salvage treatment in patients with advanced non-small cell lung cancer. Experience from a single center participating in a compassionate use program

Objective: We evaluated the efficacy and tolerability of the orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) ZD1839 in patients with pretreated advanced non-small cell lung cancer (NSCLC) participating in a compassionate use program. Patients and methods: Thirty-one patients with advanced, unresectable and progressive NSCLC, previously treated with one or two chemotherapy regimens, received ZD1839 250 mg orally once daily. Patients who had received only one prior chemotherapy regimen had to be considered unsuitable for second-line chemotherapy. Results: The disease control rate was 32% (95% CI: 15.8–48.7) (1/31 patients had a partial response and 9/31 patients had stable disease) and the median overall survival 23 weeks (range 4–40). Symptom improvement was reported by 39% of patients overall and by 83% of patients who achieved disease control. The median time to symptom improvement was 3 weeks (range 2–4). Adverse events were generally mild (grade I or II) and reversible and consisted mostly of skin rash, diarrhea and fatigue. Conclusions: ZD1839 demonstrated clinically meaningful antitumor activity with significant improvement in symptoms in this heavily pretreated group of patients with advanced NSCLC. Furthermore, ZD1839 showed a favorable toxicity profile, with the majority of adverse events being mild and reversible.     

Management of oligometastatic non-small cell lung cancer patients: Current controversies and future directions

Oligometastatic non-small cell lung cancer (NSCLC) describes an intermediate stage of NSCLC between localized and widely-disseminated disease. This stage of NSCLC is characterized by a limited number of metastases and a more indolent tumor biology. Currently, the management of oligometastatic NSCLC involves radical treatment (radiotherapy or surgery) that targets the metastatic lesions and the primary tumor to achieve disease control. This approach offers the potential to achieve prolonged survival in patients who, in the past, would have only received palliative measures. The optimal therapeutic strategies for the different scenarios of oligometastatic disease (intracranial vs extracranial disease, synchronous vs metachronous) remain undefined. Given the lack of head-to-head studies comparing radiotherapy to surgery in these patients, the decision to apply surgery or radiotherapy (with or without systemic treatment) must be based on prognostic factors that allow us to classify patients. This classification will allow us to select the most appropriate therapeutic strategy on an individualized basis. In the future, the molecular or microRNA profiles will likely improve the treatment selection process. The objective of the present article is to review the most relevant scientific evidence on the management of patients with oligometastatic NSCLC, focusing on the role of radiotherapy and surgery. We also discuss areas of controversy and future directions.     

Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC)

Non-small-cell lung cancer (NSCLC) has recently been associated with interesting molecular characteristics that have important implications in carcinogenesis and response to targeted therapies. The unsatisfactory treatment outcomes in advanced NSCLC with respect to long-term survival rates may be improved through a better understanding of the molecular etiology of this disease. For instance, several molecular alterations have been defined as "driver mutations," such as mutations in epidermal growth factor receptor (EGFR), Kirsten-rous avian sarcoma (KRAS), and a chromosome 2p inversion producing an EML4-ALK fusion gene (echinoderm microtubule-associated protein-like 4 fused with the anaplastic lymphoma kinase). Other key signaling pathways such as RAS/RAF/MEK, PI3K/AKT/mTOR (mammalian target of rapamycin), mesenchymal-epithelial transition (MET) kinase, LKB1, and insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) have also been identified as novel targets for lung cancer treatment. In this review we focus on the molecular discoveries that have led to the clinical applications and trials of novel targeted agents, including the clinical trials that selectively studied patients who were predicted to achieve the greatest benefit based on the expression of correlative biomarkers.     

非小细胞肺癌新靶点ROS1融合基因

非小细胞肺癌(non-small cell lung cancer,NSCLC) 是造成人类死亡最多的恶性肿瘤之一,其五年生存率一直徘徊在20%以下。自肺癌领域首个分子靶向药物吉非替尼上市以来,靶向药物因其低毒、高效、便于给药的临床特点,己逐渐成为治疗NSCLC的重要选择之一。因此,筛选和证实肿瘤驱动基因已经成为未来靶向药物研发的重中之重。近来,越来越多的学者把焦点转移到ROS1融合基因上,并且已经有相关数据及研究表明ROS1融合基因被证实为NSCLC新的有潜力的治疗靶点,因此我们现就ROS1融合基因在NSCLC中的相关研究进展做一综述。     

血清谷胱甘肽过氧化物酶与晚期非小细胞肺癌患者临床病理指标及预后的相关性

目的：探讨血清谷胱甘肽过氧化物酶（GSH-PX）活性与晚期非小细胞肺癌（NSCLC）患者临床病理指标、放化疗联合治疗的疗效及预后的相关性。方法：收集174例2018年1—12月于河北工程大学附属医院肿瘤科初次确诊、未经抗癌治疗的晚期NSCLC患者作为研究对象,以80例健康体检者为对照,患者于放化疗联合治疗前采集外周血,分离血清。采用基因表达谱数据动态分析（GEPIA）数据库分析GSH-PX的编码基因GPX3在不同肿瘤组织中的表达情况;5',5-二硫硝基苯甲酸（DTNB）法检测GSH-PX活性,比较放化疗联合治疗前晚期NSCLC患者和对照组血清GSH-PX活性,并分析血清GSH-PX活性与晚期NSCLC临床病理指标、放化疗联合治疗疗效及预后的相关性。结果：GEPIA数据库分析显示33类肿瘤组织中,21类肿瘤组织的GPX3 mRNA表达低于正常组织,其中包括肺鳞癌和肺腺癌（P<0.05）;DTNB法检测结果显示晚期NSCLC患者血清GSH-PX活性显著低于健康对照组（P<0.05）;与年龄、性别、病理类型无明显相关（均为P>0.05）,与吸烟史和肿瘤大小呈负相关（r=-0.165、-0.267,均为P<0.05）,与卡氏（KPS）评分和病理分级呈正相关（r=0.295、0.228,均为P<0.05）;治疗有效患者和无效患者血清GSH-PX活性的差异无统计学意义（P>0.05）,但GSH-PX高活性组患者总生存期显著高于低活性组（P<0.05）,且呈正相关（r=0.238,P=0.000）。结论：晚期NSCLC患者血清GSH-PX活性降低,与患者吸烟史、KPS评分、肿瘤大小、病理分级和总生存期显著相关。GSH-PX可能参与了NSCLC的发生发展,可作为评估预后的指标。     

Mutations of epidermal growth factor receptor of non-small cell lung cancer were associated with sensitivity to gefitinib in recurrence after surgery

The epidermal growth factor receptor (EGFR) gene has recently been reported to be mutated in a subset of non-small cell lung cancers (NSCLC), with the mutations being correlated with the patients’ drug sensitivity to gefitinib, an EGFR kinase inhibitor. In this study, we searched for EGFR mutations in patients with lung cancer using primary tumor specimens obtained at initial surgery and examined whether their recurrent tumors showed a response to gefitinib depending on the presence of the activating mutation. Among 12 lung cancers that were treated with gefitinib after recurrence, we found that all four tumors which showed a response to gefitinib had an activating mutation in EGFR, whereas none of the remaining eight tumors had a mutation. Southern blot analysis showed that two of the four responsive tumors had the EGFR gene amplification. We also examined another 73 NSCLC specimens (47 males and 26 females; 53 adenocarcinomas and 20 non-adenocarcinomas) which were not treated with gefitinib to determine whether NSCLCs with an EGFR mutation have different clinicopathological properties and/or unique genetic alterations of the other cancer-associated genes. We found that 13 (18%) of 73 tumors had a mutation of the EGFR gene, with the most being detected in female adenocarcinomas. Comparing the alterations in KRAS and P53 with the EGFR mutation, we found that 10 tumors with the KRAS mutation did not have an EGFR mutation, suggesting that each mutation occurs exclusively during the development of lung cancer. These results suggest that the mutation analysis of the EGFR gene using the specimens obtained at surgery might be useful in selecting the appropriate treatment(s) for recurrent lung cancer patients.     

基于数据库的未分化甲状腺癌基因组变异分析及靶向药物筛选

目的： 对未分化甲状腺癌的基因组变异情况进行分析并以此为基础筛选候选靶向药物。方法： 通过cBioPortal数据库获得患者样本数据,筛选同时发生突变与拷贝数变异的基因,计算其遗传变异频率。绘制生存曲线以筛选与患者生存率关系密切的基因变异。利用STRING数据库分析蛋白质相互作用并进行GO功能富集分析,利用CARE软件筛选潜在的靶向药物。结果： TP53、PI3KCA、ARID2是未分化甲状腺癌遗传变异频率最高的基因。TP53基因的错义突变与患者生存率下降有关。GO功能富集分析发现P53通过调控DNA损伤修复、细胞周期阻滞等生物学过程参与未分化甲状腺癌的发生。对于携带TP53错义突变的患者,索拉非尼、鲁索替尼等药物具有高反应性,而普纳替尼等药物具有耐药性。结论： TP53基因错义突变是影响未分化甲状腺癌患者预后的关键基因变异,而索拉非尼、鲁索替尼等药物是携带TP53基因错义突变患者的候选靶向药物。     

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review

Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.     

EGFR突变的晚期非小细胞肺癌患者接受一代TKI靶向治疗的效果及预后预测因子分析

背景和目的： 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）治疗已成为EGFR突变的晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的一线标准治疗,然而仍有10%~30%的EGFR敏感突变的NSCLC患者在接受TKI靶向治疗时出现原发性耐药。因此,研究EGFR-TKI的临床疗效,寻找其预后预测因子对于治疗携带EGFR敏感突变的晚期NSCLC患者具有重要的指导意义。本研究旨在探讨埃克替尼一线治疗EGFR突变的晚期NCSLC患者的疗效并寻找其预后预测因子。方法： 筛选2016年1月—2017年11月福建省肿瘤医院收治的携带EGFR突变的258例ⅢB~Ⅳ期NSCLC患者,并采外周血检测循环肿瘤DNA（circulating tumor DNA,ctDNA）中的EGFR突变情况,最终入组118例,均接受埃克替尼125 mg口服,每天3次。定期收集患者的生存资料。应用χ²检验比较不同EGFR突变组的临床病理学特征的差异。采用Kaplan-Meier生存曲线分析患者的无进展生存期（progression-free survival,PFS）和总生存期（overall survival,OS）,应用log-rank检验进行单因素分析,应用COX回归模型进行多因素分析。结果： 118例患者的客观缓解率（objective response rate,ORR）为62.7%（95% CI：53.9%~71.6%）,疾病控制率（disease control rate,DCR）为92.4%（95% CI：87.5%~97.2%）,中位PFS为11.3个月（95% CI：9.1~13.5个月）,中位OS为32.0个月（95% CI：26.9~37.1个月）。不同EGFR表达类型之间的临床病理学特征差异无统计学意义（P>0.05）,但不同EGFR突变组患者的最佳疗效差异有统计学意义（P=0.040）。单因素分析显示,外周血ctDNA的EGFR突变情况与患者的PFS和OS无关（P>0.05）。多因素分析显示,基线乳酸脱氢酶（lactate dehydrogenase,LDH）表达水平、EGFR类型、胸腔积液及最佳疗效为PFS的独立预测因子。而患者的N分期、骨转移、PFS及出现EGFR T790M突变是OS的独立预测因子。结论： EGFR突变的晚期NSCLC患者接受一线埃克替尼靶向治疗具有良好的疗效。外周血ctDNA中的EGFR突变情况与患者的临床疗效无关。骨转移与接受TKI靶向治疗患者的不良预后有关。