Pooled analysis of clinical outcome for EGFR TKI‐treated patients with EGFR mutation‐positive NSCLC

Patients with non‐small‐cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation‐positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation‐positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression‐free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6–13.4) for erlotinib‐treated patients; 9.4 months (95% AI 9.0–9.8) for gefitinib‐treated patients; and 5.6 months (95% AI 5.3–6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time‐point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation‐positive NSCLC with erlotinib or gefitinib compared with chemotherapy.     

Trial-Based Cost-Utility Analysis of Icotinib versus Gefitinib as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer in China

Background

Our objective is to compare the cost-utility of icotinib and gefitinib for the second-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system.

Methods

Model technology was applied to assess the data of randomized clinical trials and the direct medical costs from the perspective of the Chinese healthcare system. Five-year quality-adjusted life years (QALYs) and incremental cost-utility ratios (ICURs) were calculated. One-way and probabilistic sensitivity analyses (PSA) were performed.

Results

Our model suggested that the median progression-free survival (PFS) was 4.2 months in the icotinib group and 3.5 months in the gefitinib group while they were 4.6 months and 3.4 months, respectively, in the trials. The 5-year QALYs was 0.279 in the icotinib group and 0.269 in the gefitinib group, and the according medical costs were $10662.82 and $13127.57. The ICUR/QALY of icotinib versus gefitinib presented negative in this study. The most sensitive parameter to the ICUR was utility of PFS, ranging from $-1,259,991.25 to $-182,296.61; accordingly the icotinib treatment consistently represented a dominant cost-utility strategy.

Conclusions

The icotinib strategy, as a second-line therapy for advanced NSCLC patients in China, is the preferred strategy relative to gefitinib because of the dominant cost-utility. In addition, icotinib shows a good curative effect and safety, resulting in a strong demand for the Chinese market.     

Overall Survival Benefits for Combining Targeted Therapy as Second-Line Treatment for Advanced Non-Small-Cell-Lung Cancer: A Meta-Analysis of Published Data

Background

Combining targeted therapy has been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but it is still unclear whether combining targeted therapy might offer any benefits against standard monotherapy with erlotinib. We thus performed a meta-analysis of randomized controlled trials to compare the efficacy and safety of combining targeted therapy versus erlotinib alone as second-line treatment for advanced NSCLC.

Methods

Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3 or 4 adverse event (AEs). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.

Results

Eight eligible trials involved 2417 patients were ultimately identified. The intention to treatment (ITT) analysis demonstrated that combining targeted therapy significantly improved OS (HR 0.90, 95%CI: 0.82–0.99, p = 0.024), PFS (HR 0.83, 95%CI: 0.72–0.97, p = 0.018), and ORR (OR 1.35, 95%CI 1.01–1.80, P = 0.04). Sub-group analysis based on phases of trials, EGFR-status and KRAS status also showed that there was a tendency to improve PFS and OS in combining targeted therapy, except that PFS for patients with EGFR-mutation or wild type KRAS favored erlotinib monotherapy. Additionally, more incidence of grade 3 or 4 rash, fatigue and hypertension were observed in combining targeted therapy.

Conclusions

With the available evidence, combining targeted therapy seems superior over erlotinib monotherapy as second-line treatment for advanced NSCLC. More studies are still needed to identify patients who will most likely benefit from the appropriate combining targeted therapy.     

Evaluation of short‐term effectiveness of eight targeted agents combined with chemotherapy for treating esophageal‐gastric junction adenocarcinoma: A network meta‐analysis

This study aimed to evaluate the short‐term effectiveness of eight targeted agents (ramucirumab, bevacizumab, rilotumumab, panitumumab, cetuximab, trebananib, trastuzumab, matuzumab) plus chemotherapy in esophageal‐gastric junction adenocarcinoma (EGJA) by a network meta‐analysis (NMA). PubMed, Embase, and Cochrane Library databases were systematically retrieved for randomized clinical trials (RCTs) concerning targeted agents plus chemotherapy in the treatment of EGJA. This NMA combined both direct and indirect evidence to evaluate odds ratio (OR) and to draw the surface under the cumulative ranking curve (SUCRA). In total 11 RCTs with 3649 EGJA patients (1907 patients treated with targeted agents plus chemotherapy were regarded as the case group, and 1742 patients with placebo plus chemotherapy were assigned into the control group) were enrolled in this study. Targeted agents in terms of stable disease (SD), partial response (PR), disease control rate (DCR), and overall response ratio (ORR) with the SUCRA values of 0.838, 0.807, 0.934, and 0.793, respectively. Cetuximab and trastuzumab, with the SUCRA values of 0.884 and 0.758, came on top as the best outcomes for treating EGJA in terms of progressive disease (PD) and complete response (CR). Cluster analysis results indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA. Our findings indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA amongst the nine treatment regimens, which provided clinical guidance for clinicians in the treatment of EGJA.     

Gefitinib or Erlotinib as Maintenance Therapy in Patients with Advanced Stage Non-Small Cell Lung Cancer: A Systematic Review

Background

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib and erlotinib have been tested as maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC). The studies are quite heterogenous regarding study size and populations, and a synopsis of these data could give some more insight in the role of maintenance therapy with TKI.

Methods

In September 2012 we performed a search in the pubmed, EMBASE and Cochrane library databases for randomized phase III trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through a rigorous selection process with specific criteria, five trials (n = 2436 patients) were included for analysis. Standard statistical methods for meta-analysis were applied.

Results

TKIs (gefitinib and erlotinib) significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50–0.76, I² = 78.1%] and overall survival (HR 0.84, 95% CI 0.76–0.93, I² = 0.0%) compared with placebo or observation. The PFS benefit was consistent in all subgroups including stage, sex, ethnicity, performance status, smoking status, histology, EGFR mutation status, and previous response to chemotherapy. Patients with clinical features such as female, never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced PFS benefit. Overall survival benefit was observed in patients with clinical features such as female, non-smoker, smoker, adenocarcinoma, and previous stable to induction chemotherapy. Severe adverse events were not frequent. Main limitations of this analysis are that it is not based on individual patient data, and not all studies provided detailed subgroups analysis.

Conclusions

The results show that maintenance therapy with erlotinib or gefitinib produces a significant PFS and OS benefit for unselected patients with advanced NSCLC compared with placebo or observation. Given the less toxicity of TKIs than chemotherapy and simple oral administration, this treatment strategy seems to be of important clinical value.     

Efficacy and Safety Profile of Combining Vandetanib with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

Objective

To evaluate the efficacy and safety profile of combining vandetanib with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).

Methods

MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts, ESMO Abstracts, Wanfang Database, CNKI were searched. Eligible studies were the randomized clinical trials (RCTs) that compared the efficacy and safety profile of adding vandetanib to chemotherapy with single chemotherapy in patients with advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. All meta-analysis were performed using Review Manager 5.1. The fixed-effect model weighted by the Mantel-Haenszel method was used. When considerable heterogeneity was found (p<0.1, or I²>50%), further analysis (subgroup analysis, sensitivity analysis or random-effect model) was performed to identify potential cause.

Results

Results reported from 5 RCTs involving 2284 patients were included in the analysis. Compared to chemotherapy alone, the addition of vandetanib resulted in a significant longer PFS (HR 0.79 [0.72–0.87], p<0.00001) and a higher ORR (RR 1.75 [1.43–2.15], p<0.00001), but failed to show advantage on OS (HR 0.96 [0.87–1.06], p = 0.44).

Conclusion

Vandetanib has activity in NSCLC. Identification of predictive biomarkers is warranted in future trials to select a subset of patients with advanced NSCLC who may benefit from vandetanib.     

A simple HPLC-UV method for the simultaneous quantification of gefitinib and erlotinib in human plasma

Gefitinib and erlotinib are two oral tyrosine kinase inhibitors (TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Published methods for simultaneous analysis of erlotinib and gefitinib in plasma are exclusively based on mass spectrometry. The purpose of this study was to develop a simple and sensitive HPLC-UV method to simultaneously quantify these two TKI in plasma. Following liquid-liquid extraction, gefitinib, erlotinib and sorafenib (internal standard), were separated with gradient elution (on a C8+ Satisfaction(?) using a mobile phase of acetonitrile/20mM ammonium acetate pH 4.5). Samples were eluted at a flow rate of 0.4 ml/min throughout the 15-min run. Dual UV wavelength mode was used, with gefitinib and erlotinib monitored at 331 nm, and sorafenib at 249 nm. The calibration was linear in the range 20-1000 ng/ml and 80-4000 ng/ml for gefitinib and erlotinib, respectively. Inter- and intra-day imprecision were less than 7.2% and 7.6% for gefitinib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure to these TKI in NSCLC patients. This simple, sensitive, accurate and cost-effective method can be used in routine clinical practice to monitor gefitinib or erlotinib concentrations in plasma from NSCLC patients.     

外周血CTC、VEGF的水平与晚期非小细胞肺癌临床特征及化疗疗效关系的研究

摘要 目的：探讨外周血循环肿瘤细胞（CTC）、血管内皮生长因子（VEGF）的水平与晚期非小细胞肺癌临床特征及化疗疗效的关系。方法：选取我院2017年1月到2020年1月收治的80例晚期非小细胞肺癌患者作为研究对象,所有患者均采取一线方案化疗,分析外周血CTC、VEGF的水平与患者的年龄、性别等的关系,并对晚期非小细胞肺癌化疗疗效进行单因素与多因素COX分析。结果：CTC、VEGF与不同性别、年龄患者和TNM分期无明显关系（P＞0.05）,与淋巴结转移、肿瘤分化程度、肿瘤大小有关（P＜0.05）;80例患者中,客观缓解率（ORR）为51.25 %（41/80）,疾病控制率（DCR）为71.25 %（57/80）;淋巴结转移、肿瘤分化程度、CTC和血清VEGF水平为晚期非小细胞肺癌患者ORR、DCR的影响因素（P＜0.05）;COX分析分析表明：肿瘤中、低分化、CTC阴性、VEGF降低为晚期非小细胞肺癌化疗ORR和DCR提升的独立影响因素（P＜0.05）。结论：外周血CTC、VEGF检测对于晚期非小细胞肺癌化疗近远期疗效评估具有重要价值,属于预后独立影响因素。因此,CTC、VEGF可作为晚期非小细胞肺癌的预后及疗效判断的指标。     

埃克替尼联合化疗治疗EGFR突变型晚期非小细胞肺癌的疗效及对生活质量和血清肿瘤标志物的影响

目的:观察表皮生长因子受体(EGFR)突变型晚期非小细胞肺癌(NSCLC)经化疗联合埃克替尼治疗后的临床效果。方法:122例研究对象均为我院于2015年3月~2019年3月期间收治的晚期NSCLC患者且为EGFR突变型。采用随机数字表法将患者分为对照组(单药埃克替尼靶向药物治疗)和实验组(埃克替尼联合化疗),各61例。观察两组疗效、生活质量、血清肿瘤标志物、毒副反应的变化,比较两组患者的无进展生存期(PFS)和总生存期(OS)。结果:实验组治疗后的客观缓解率、疾病控制率均高于对照组(P<0.05)。实验组治疗后整体生活质量和健康状况总得分高于对照组,功能及症状总得分低于对照组(P<0.05)。实验组治疗后癌胚抗原(CEA)、癌抗原125(CA125)与角蛋白19片段(CYFRA21-1)低于对照组(P<0.05)。实验组毒副反应总发生率高于对照组(P<0.05)。两组间PFS、OS生存率比较均有统计学差异(P<0.05)。结论:埃克替尼联合化疗治疗EGFR突变型晚期NSCLC患者疗效较好,可有效阻止疾病进展,提高患者生活质量,改善患者预后。     

重组人血管内皮抑素联合化放疗治疗晚期恶性肿瘤的临床观察

目的:探讨重组人血管内皮抑素(recombinant human endostatin,rh-ES)联合化放疗治疗晚期恶性肿瘤的疗效及安全性。方法:回顾性分析我科2010年1月至2013年8月收治的27例晚期恶性肿瘤患者病例,27例患者均接受rh-ES联合化疗±放疗的综合治疗,rh-ES用药1周期后评价生活质量变化及不良反应,2周期后评价疗效。结果:23例可评价近期疗效的患者客观有效率30.4%,疾病控制率78.3%。18例非小细胞肺癌(non-small cell lung cancer,NSCLC)中位无进展生存期5.5月,中位总生存期12.0月,1年生存率50.0%,2年生存率28.6%。全组患者生活质量改善或稳定23例(85.2%),Ⅲ~Ⅳ度不良反应8例次。结论:Rh-ES联合化放疗治疗晚期恶性肿瘤的疗效及安全性良好,可改善或稳定患者生活质量。与其他单纯化疗研究结果比较,晚期NSCLC的中位无进展生存期及1年生存率较高,值得临床推广。     

Recent advances of novel targeted therapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths world-wide. Recent advances in cancer biology have led to the identification of new targets in neoplastic cells and the development of novel targeted therapies. At this time, two targeted agents are approved by the FDA in advanced non-small cell lung cancer (NSCLC): the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, and the anitangiogenic bevacizumab. A third agent, cetuximab, which was recently shown to enhance survival when used with cisplatin and vinorelbine as first line therapy for advanced NSCLC, will likely be approved by regulatory agencies. With more than 500 molecularly targeted agents under development, the prospects of identifying novel therapies that benefit individual patients with lung cancer are bright.     

Percutaneous Fine-Needle 5% Ethanol-Cisplatin Intratumoral Injection Combined with Second-Line Chemotherapy Improves On the Standard of Care in Patients with Platinum-Pretreated Stage IV Non–Small Cell Lung Cancer

BACKGROUND: Efficacy of second-line chemotherapy in platinum-pretreated non–small cell lung cancer (NSCLC) is poor. This study investigated efficacy of computed tomography–guided percutaneous fine-needle 5% ethanol-cisplatin intratumoral injection (CT-PFNECII) combined with second-line chemotherapy in patients with platinum-pretreated stage IV NSCLC. PATIENTS: Between October 2011 and July 2013, 34 eligible patients were randomly assigned to receive either CT-PFNECII combined with second-line chemotherapy (combination group, n = 17) or second-line chemotherapy alone (chemotherapy group, n = 17). The primary end points were the proportions of patients who achieved an overall response rate (ORR) and disease control rate (DCR). Secondary end points were median survival and progression-free survival (PFS). RESULTS: The ORR and DCR in the combination group were significantly higher than in the chemotherapy group (23.53% vs 11.76% for ORR, P < .01; and 58.82% vs 35.29% for DCR, P < .01). Compared with patients in the chemotherapy group, patients in the combination group had significantly longer PFS (5.4 months vs 3.0 months, P < .01) and median survival (9.5 months vs 5.3 months, P < .01). CONCLUSIONS: CT-PFNECII combined with second-line chemotherapy provided a higher response rate and improved survival than second-line chemotherapy for patients with platinum-pretreated stage IV NSCLC.     

Multi-Targeted Antiangiogenic Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer: Meta-Analyses of 20 Randomized Controlled Trials and Subgroup Analyses

Background

Multi-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied in many randomized controlled trials (RCTs) for treatment of advanced non-small cell lung cancer (NSCLC). We seek to summarize the most up-to-date evidences and perform a timely meta-analysis.

Methods

Electronic databases were searched for eligible studies. We defined the experimental arm as MATKI-containing group and the control arm as MATKI-free group. The extracted data on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS) and overall survival (OS) were pooled. Subgroup and sensitivity analyses were conducted.

Results

Twenty phase II/III RCTs that involved a total of 10834 participants were included. Overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, P = 0.006) and prolonged PFS (HR 0.83, 0.78 to 0.90, P = 0.005) compared to the MATKI-free group. However, no significant improvements in DCR (OR 1.08, 1.00 to 1.17, P = 0.054) or OS (HR 0.97, 0.93 to 1.01, P = 0.106) were observed. Subgroup analyses showed that the benefits were predominantly presented in pooled results of studies enrolling previously-treated patients, studies not limiting to enroll non-squamous NSCLC, and studies using MATKIs in combination with the control regimens as experimental therapies.

Conclusions

This up-to-date meta-analysis showed that MATKIs did increase ORR and prolong PFS, with no significant improvement in DCR and OS. The advantages of MATKIs were most prominent in patients who received a MATKI in combination with standard treatments and in patients who had previously experienced chemotherapy. We suggest further discussion as to the inclusion criteria of future studies on MATKIs regarding histology.     

Effectiveness and Safety of Chemotherapy Combined with Dendritic Cells Co-Cultured with Cytokine-Induced Killer Cells in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Background

Lung cancer, particularly non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality. Chemotherapy combined dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in advanced NSCLC patients'' treatment, but couldn''t provide consistent beneficial results. Therefore, it is necessary to evaluate the efficiency and safety of combination therapy to promote the application.

Methods

A literature search for randomized controlled trials of NSCLC was conducted in PubMed database. Before meta-analysis was performed, studies were evaluated heterogeneity. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed.

Results

Six eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P = 0.02) and progression free survival (PFS) (P = 0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P = 0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P = 0.21), 2-year PFS (P = 0.10), overall response rate (ORR) (P = 0.76) and partial response (PR) (P = 0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest.

Conclusions

Chemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients.     

Tailoring tyrosine kinase inhibitors to fit the lung cancer genome

Tyrosine kinase inhibitors (TKIs) have been in use as cancer therapeutics for nearly a decade, and their utility in targeting specific malignancies with defined genetic lesions has proven to be remarkably effective. Recent efforts to characterize the spectrum of genetic lesions found in non-small cell lung carcinoma (NSCLC) have provided important insights into the molecular basis of this disease and have also revealed a wide array of tyrosine kinases that might be effectively targeted for rationally designed therapies. The findings of these studies, however, also provide a cautionary tale about the limitations of single-agent therapies, which fail to account for the genetic heterogeneity and pathway redundancy that characterize advanced NSCLC. Emergence of drug resistance mechanisms to specific TKIs, such as gefitinib and erlotinib, suggests that more sophisticated chemotherapeutic paradigms that target multiple pathways at the same time will be required to effectively treat this disease.     

Integrin beta1 over-expression associates with resistance to tyrosine kinase inhibitor gefitinib in non-small cell lung cancer

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as gefitinib and erlotinib have been widely used in treating patients with advanced non-small cell lung cancer (NSCLC). However, acquired resistance to EGFR TKI almost occurs in every patient eventually. To identify its potential mechanism, we established a human NSCLC cell line PC9/AB2 which was 576-fold decrease in gefitinib sensitivity compared with its parental PC9 cell lines. No EGFR-T790M mutation or abnormal expression of c-Met protein was found in PC9/AB2 cells. Over-expression of integrin β1 was found, accompanied with increase of the cells' adhesion and migration. To further confirm the role of integrin β1 in gefitinib acquired resistance, we transferred its siRNA-expressing plasmid and its whole cDNA expressing plasmid into PC9/AB2 and into PC9 cells, respectively. The sensitivity of NSCLC cells to gefitinib was negatively correlated with integrin β1 expression levels. All these data suggest that up-regulation of integrin β1 might be an important factor for gefitinib resistance in NSCLC cell line PC9/AB2.     

替雷利珠单抗注射液联合白蛋白紫杉醇和卡铂对晚期NSCLC患者肠道菌群和SII、PNI的影响

摘要 目的：探讨替雷利珠单抗注射液联合白蛋白紫杉醇和卡铂对晚期非小细胞肺癌（NSCLC）患者肠道菌群和预后营养指数（PNI）、全身免疫炎症指数（SII）的影响。方法：选取2020年5月~2023年2月期间在南京市江宁医院及东南大学附属中大医院接受治疗的晚期NSCLC患者115例。根据随机数字表法将患者分为对照组和研究组,各为57例和58例。对照组接受白蛋白紫杉醇和卡铂治疗,研究组在对照组基础上接受替雷利珠单抗注射液治疗。对比两组客观缓解率（ORR）、疾病控制率（DCR）、血清肿瘤标志物[细胞角蛋白19片段（CYFRA21-1）、癌胚抗原（CEA）、糖类抗原125（CA125）]、肠道菌群（双歧杆菌、乳酸杆菌、肠球菌）和SII、PNI,同时观察两组治疗期间不良反应发生情况。结果：研究组ORR（44.83%）、DCR（77.59%）均高于对照组的24.56%、50.88%（P<0.05）。与对照组治疗后相比,研究组CYFRA21-1、CEA、CA125、肠球菌、SII更低,双歧杆菌、乳酸杆菌、PNI更高（P<0.05）。两组不良反应发生率对比未见差异（P>0.05）。结论：替雷利珠单抗注射液联合白蛋白紫杉醇和卡铂治疗晚期NSCLC患者,可提升临床疗效,改善SII、PNI和肠道菌群。     

Proliferation of Ewing sarcoma cell lines is suppressed by the receptor tyrosine kinase inhibitors gefitinib and vandetanib

Background  

Tyrosine kinase inhibitors (TKIs) have gained much attention in recent years as targeted agents for the treatment of a wide range of human cancers. We have investigated the effect of the TKIs gefitinib and vandetanib on tumor cell lines derived from Ewing sarcoma, a highly malignant tumor affecting bone and soft tissue in children and young adults. Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase activity (EGFR) and vandetanib selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2) with additional activity against VEGFR-3, EGFR and RET kinase receptors.     

Recent Development of the Second and Third Generation Irreversible Epidermal Growth Factor Receptor Inhibitors

Recent reports suggested that essential directions for new lung cancer, breast carcinoma therapies, as well as the roomier realm of targeted cancer therapies were provided through targeting the epidermal growth factor receptor (EGFR). Patients who carrying non‐small cell lung carcinoma (NSCLC) with activating mutations in EGFR initially respond well to the EGFR inhibitors erlotinib and gefitinib, which were located the active site of the EGFR kinase and designed to act as competitive inhibitors of combining with the ATP. However, patients who were treated with the erlotinib and gefitinib will relapse because of the emergence of drug‐resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. In order to overcome drug resistance, Pharmaceutical chemistry experts recently devoted great endeavors to the development of second‐generation irreversible selective inhibitors which covalently modify Cys797 or Cys773 at the ATP binding cleft. Nevertheless, these inhibitors have not reached ideal effect of experts in patients with T790M positive mutation and apparently because of the dose‐limiting toxicities associated with inhibition of wild type EGFR. A novel class of ‘third generation’ EGFR TKIs have been developed that is sensitising and T790M mutant‐specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Herein, we provides an overview of the second and third generation inhibitors currently approved, in clinical trial and also encompasses novel structures of discovery. This review mainly focuses on drug resistance, their mechanisms of action, development of structure–activity relationships and binding modes.     

EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells

Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer.