Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.     

EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer

The incidence of brain metastasis (BM) is high in patients with non-small-cell lung cancer. Available standard therapeutic options, such as whole-brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. Novel agents, such as EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), have now been included in standard non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by a response rate of 70–80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. However, since most of the larger studies on these agents have excluded BM patients from their series, few prospective data are available on the efficacy of these agents in this setting. In recent years, however, several authors have reported a growing number of cases of partial and complete response in BM patients treated with EGFR TKIs. Data from retrospective series and Phase II studies also suggest that a response can be obtained using EGFR TKI treatment for patients with BM, especially those harboring EGFR mutations.     

晚期NSCLC吉非替尼治疗失败后的再次治疗(病例报告及文献复习)

目的:对吉非替尼治疗失败后的晚期NSCLC患者再次使用吉非替尼治疗,分析其疗效及安全性。方法:复习1例吉非替尼治疗失败后的晚期NSCLC患者再次使用吉非替尼治疗及临床资料,结合相关文献探讨其临床特征、治疗及预后。结果:该患者首次使用吉非替尼约8月后耐药,停药5月后再次使用吉非替尼,1月后复查肺部CT提示肺部病灶明显缩小,2个月后再次失效,最终总生存期达21月,使用吉非替尼期间不良反应轻微。结论:曾使用吉非替尼有效的晚期NSCLC患者,再次使用吉非替尼仍有可能延长其生存时间且不良反应轻微。     

Personalized medicine for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is a heterogeneous illness associated with a high mortality rate. Personalized therapy may improve treatment outcomes by identification of a specific genotypic anomaly and target-specific therapy. The most significant development in recent years was the discovery of activated EGF receptor (EGFR) mutations at exons 19 and 21. Patients with EGFR mutations respond dramatically to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib, resulting in longer progression-free survival. Multiple randomized studies, including the Iressa Pan-Asia Study and WJTOG3405, have confirmed the role of EGFR tyrosine kinase inhibitors as standard first-line therapy for patients with the EGFR mutation. In this article, we summarize the current nonpersonalized therapies and examine the available and investigational personalized therapies for patients with resectable early-stage, unresectable locally advanced, or metastatic disease.     

苦参对耐吉非替尼人肺腺癌PC9/ZD细胞上皮间质转化及吉非替尼药物敏感性的影响

目的探讨苦参对耐吉非替尼人肺腺癌PC9/ZD细胞上皮间质转化及吉非替尼药物敏感性的影响。方法选取对细胞无毒性作用的苦参浓度,采用体外苦参作用于耐吉非替尼人肺腺癌PC9/ZD细胞;分为对照组、吉非替尼组、苦参联合吉非替尼组。分别通过MTT法、Transwell实验检测各组人肺腺癌PC9/ZD细胞增殖及侵袭能力,Western blot实验检测EMT相关蛋白表达,流式细胞术检测细胞凋亡率。结果 MTT法检测结果显示,苦参联合吉非替尼组人肺腺癌PC9/ZD细胞增殖抑制率(74.59±3.21)%,明显高于吉非替尼组(33.46±0.84)%(P0.05);Western blot实验结果显示,在苦参作用下,吉非替尼诱导的人肺腺癌PC9/ZD细胞波形蛋白及N钙黏蛋白表达下调,E钙黏附分子表达上调;Transwell实验检测结果显示,苦参联合吉非替尼组人肺腺癌PC9/ZD细胞侵袭率(48.59±7.26)%,较吉非替尼组(64.23±8.04)%和对照组(91.03±11.02)%明显降低(P均0.05);流式细胞术检测结果显示,对照组人肺腺癌PC9/ZD细胞凋亡率(31.14±5.26)%,吉非替尼组(56.48±8.77)%,苦参联合吉非替尼组(76.25±10.28)%,三组间人肺腺癌PC9/ZD细胞凋亡率比较,差异均有统计学意义(P均0.05)。结论苦参可逆转人肺腺癌PC9/ZD细胞上皮间质转化,增加对吉非替尼药物敏感性。     

白花蛇舌草乙醇提取物联合吉非替尼对TGF-β1诱导的肺腺癌细胞H358上皮间质化的干预作用

目的 研究白花蛇舌草乙醇提取物(ethanol extract of Hedyotis diffusa,EEHD)联合吉非替尼对TGF-β₁诱导的肺腺癌细胞H358上皮间质化的干预作用。方法 以上皮表型人肺腺癌细胞H358为研究对象,TGF-β₁诱导构建细胞上皮间质化模型,按EEHD、吉非替尼及两药3种不同顺序联合作用分为6组：A组,EEHD作用48 h;B组,吉非替尼作用48 h;A24B24组,先EEHD作用24 h,后吉非替尼作用24 h;B24A24组,先吉非替尼作用24 h,后EEHD作用24 h;AB48组,同时加入吉非替尼和EEHD作用48 h;对照组。CCK-8法测定各组细胞坏死率,Western-blot检测各组细胞中E-cadherin、Vimentin、EGFR蛋白表达情况,流式细胞仪检测各组细胞凋亡情况,比较组间差异。结果 各组药物作用均能不同程度抑制上皮间质化肺腺癌细胞H358增殖,E-cadherin表达呈上升趋势,Vimentin表达下降。其中EEHD联合吉非替尼组的细胞生长抑制率和细胞凋亡率显著高于吉非替尼单用组,E-cadherin蛋白表达率则显著高于吉非替尼单用组,而EGFR、Vimentin蛋白表达率显著低于吉非替尼单用组(P<0.05),EEHD与吉非替尼先后顺序作用组间差异无统计学意义。结论 EEHD与吉非替尼对上皮间质化的H358细胞具有联合抑制作用,白花蛇舌草可部分逆转H358细胞上皮间质化状态。     

吉非替尼进展后再治疗在EGFR罕见突变非小细胞肺癌中的临床研究

目的 探讨表皮生长因子受体(EGFR)罕见突变非小细胞肺癌患者在吉非替尼治疗进展后,接受吉非替尼再治疗的疗效和安全性.方法 选择2011年1月至2015年12月的EGFR罕见突变基因的非小细胞肺癌患者,接受吉非替尼治疗和进展后再治疗.初次疗效评价采用RECIST 1.1版,分析指标为客观缓解率(RR)和第1次无进展生存时间(PFS-1);再治疗评价根据临床医师经验,分析指标为第2次无进展生存时间(PFS-2)和总生存时间(OS).毒性评价采用NCI-CTCAE 4.0版.采用Kaplan-Meier法对PFS-1、PFS-2和OS进行生存分析.结果 6例患者的初次疗效评价为部分缓解4例,稳定2例,RR达66.7％;中位PFS-1为10个月(95％CI:6.6～13.4);再治疗后的中位PFS-2为9个月(95％CI:6.9～11.1);中位OS为28个月(95％CI:10.4～45.6).最常见的治疗相关不良反应为1～2级的皮疹、腹泻、乏力、恶心呕吐和转氨酶增高.结论 本研究EGFR罕见突变肺癌患者在吉非替尼进展后再治疗中显示了较好的疗效和安全性.     

扶正抗岩方联合吉非替尼治疗气虚血瘀型非小细胞肺癌(Ⅳ期)的前瞻性、平行随机、安慰剂对照临床研究

目的观察扶正抗岩方联合吉非替尼治疗气虚血瘀型非小细胞肺癌(Ⅳ期)的临床疗效。方法将60例气虚血瘀型非小细胞肺癌(Ⅳ期)患者随机分为对照组与治疗组,每组30例。对照组予吉非替尼+中药安慰剂,治疗组予吉非替尼+扶正抗岩方。两组均服药至肿瘤进展而终止,观察比较近期疗效、远期疗效(无进展生存期)、KPS评分变化及不良反应情况。结果①试验期间,无病例脱落。②治疗组有效率、肿瘤控制率分别为53.33%、93.33%,对照组相应分别为43.33%、90.00%;组间近期疗效比较,差异无统计学意义(P0.05)。③组间无进展生存期比较,差异有统计学意义,治疗组明显长于对照组(P0.05)。④组间治疗后比较,治疗组KPS评分明显高于对照组(P0.05)。⑤两组不良反应比较,腹泻、恶心或呕吐发生情况等级差异有统计学意义,治疗组明显轻于对照组(P0.05)。结论扶正抗岩方联合吉非替尼治疗气虚血瘀型非小细胞肺癌(Ⅳ期),可以明显延长患者的无进展生存期,改善其生活质量,减轻EGFR-TKI药物的不良反应。     

Gefitinib with or without Transarterial Infusion Chemotherapy (Cisplatin) for Large Nonsmall Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations

PurposeTo retrospectively investigate the safety and benefit of gefitinib plus transarterial infusion (TAI) therapy as a first-line treatment compared to gefitinib alone for patients with large (>7 cm) nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.Materials and MethodsBetween January 2010 and December 2013, 92 consecutive treatment-naïve patients with large NSCLC with EGFR mutations, who were treated using gefitinib plus TAI (G+T, n = 42) or gefitinib alone (G, n = 50) were reviewed. The primary endpoints were the objective response rate (ORR) and tumor reduction rate. The secondary endpoints were progression-free survival (PFS) and overall survival (OS), and safety was also assessed.ResultsThe baseline characteristics of the 2 groups were balanced, and no patients experienced treatment-related death. Toxicity outcomes did not differ between the G+T and G groups. The tumor reduction rate in the G+T group was significantly higher than that in the G group (42.9 vs 31.9%, P = .028). The ORR was 83% in the G+T group and 72% in the G group (P = .197). The median PFS was significantly longer in the G+T group than in the G group (14.0 vs 10.0 months, P = .023). The median OS was 30.0 months in the G+T group and 27.0 months in the G group (P = .235).ConclusionsThis study suggests that compared with gefitinib alone, combination therapy with gefitinib plus TAI was well tolerated and potentially improved the tumor reduction rate and PFS in patients with large NSCLC with EGFR mutations.     

吉非替尼对晚期非小细胞肺癌患者生活质量的改善

Objective  

The aim of this study was to evaluate the effect of gefitinib on improvement of quality of life (QoL) of patients with advanced non-small cell lung cancer (NSCLC).