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。     

埃罗替尼治疗吉非替尼耐药的晚期非小细胞肺癌有效1例

晚期非小细胞肺癌(NSCLC)预后差,以化疗为主的联合治疗只能降低死亡风险26%-32%[1].近年来,非小细胞肺癌的靶向治疗成为研究热点,其中尤以表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)进展最快,其代表药物吉非替尼(gefitinib、iressa)和埃罗替尼(erlotinib、tarceva).我科用埃罗替尼治疗吉非替尼耐药的晚期非小细胞肺癌(NSCLC)一例取得了较好疗效,现报告如下.     

EGFR-TKI在非小细胞肺癌中的研究进展

摘 要：肺癌是引起人类恶性肿瘤相关性死亡的主要原因,也是世界范围内发病率最高的恶性肿瘤,其中非小细胞肺癌（NSCLC）是其主要类型。近年来,NSCLC的治疗取得重要突破,已由传统的手术、化疗和放疗,发展到精准分子靶向治疗时代和免疫治疗时代。NSCLC分子靶向治疗中,又以表皮生长因子酪氨酸激酶抑制剂（EGFR-TKI）研究最透彻,已广泛应用于EGFR突变人群中。一代EGFR-TKI已是EGFR突变晚期NSCLC患者的标准一线治疗。一代EGFR-TKIs药物间疗效无显著性差异,不良反应发生率上厄洛替尼相对更低。二代EGFR-TKI疗效不亚于一代EGFR-TKI,对少见突变患者具有一定疗效。三代EGFR-TKIs作为后起之秀,对EGFR突变患者（包括T790M突变）疗效显著,对脑转移患者亦有作用。新时代下EGFR-TKI联合化疗、放疗、免疫及抗肿瘤血管治疗等其他治疗模式的探索初现成果,TKI联合其他抗肿瘤治疗给患者治疗带来新的选择和方向。EGFR-TKI治疗NSCLC在挑战与机遇中砥砺前行。     

培美曲塞单药或联合吉非替尼治疗EGFR-TKI耐药后晚期非小细胞肺癌临床观察

背景与目的:生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)获得性耐药后尚无标准的治疗方案,亟待探寻有效的后续治疗方法.为临床应用提供指导,该研究旨在比较后续治疗采用培美曲塞单药或联合吉非替尼治疗EGFR-TKI获得性耐药的晚期NSCLC的临床疗效及安全性.方法:入组既往接受过EGFR-TKI治疗后进展的晚期NSCLC患者62例.其中32接受培美曲塞联合吉非替尼治疗,设为联合组;30例单用培美曲塞治疗,设为化疗组.评价临床疗效及不良反应.结果:联合组客观有效率(objective response rate,ORR)为46.9%,高于化疗组的20%,差异有统计学意义(χ2=4.933,P<0.05);两组疾病控制率(disease control rate,DCR)差异无统计学意义(P>0.05);联合组的中位无病生存期(progression-free survival,PFS)为8.0个月,化疗组中位PFS为6.3个月,差异有统计学意义(χ2=8.063,P<0.05),两组总生存期(overall survival,OS)差异无统计学意义(P>0.05).联合组中性粒细胞减少、皮疹的发生率高于化疗组,差异有统计学意义(P<0.05),Ⅲ~Ⅳ不良反应两组差异无统计学意义(P>0.05).结论:晚期NSCLC患者EGFR-TKI获得性耐药后,采用培美曲塞联合吉非替尼较单用培美曲塞显示出更优势临床有效率和中位PFS,不良反应可耐受,值得临床推广运用.     

吉非替尼治疗化疗无效的晚期非小细胞肺癌疗效观察

吉非替尼(gefitinib)是一种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),治疗化疗失败的晚期肺癌安全有效。研究结果显示,吉非替尼治疗含铂化疗失败的晚期NSCLC疗效不低于标准的二线治疗药物泰索帝[1],我们使用吉非替尼治疗化疗无效的晚期NSCLC患者28例,现将结果进行总结和讨论。     

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。     

EGFR L858R突变型晚期非小细胞肺癌的分子生物学特性及治疗策略

表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变是非小细胞肺癌发生率最高的驱动基因突变类型,其中以外显子19缺失突变和L858R突变最常见。相比外显子19缺失突变,L858R突变型NSCLC具有独特的分子生物学特性,如肿瘤侵袭性更强、更易发生伴随突变、对EGFR-酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitor,EGFR-TKI)药物敏感性更差。因此,L858R突变被视为与外显子19缺失突变完全不同的另一种亚型。针对L858R突变型晚期NSCLC治疗方法包括EGFR-TKI单药及其联合化疗、抗血管药物以及免疫治疗等。其中,仅第二代EGFR-TKI达科替尼获得无进展生存期(10.9个月)与总生存期(25.0个月)的生存优势,TKI联合化疗取得无进展生存时间优势但无总生存时间获益,而厄洛替尼联合贝伐珠单抗的无进展生存时间最高(19.5个月)。总之,与外显子19缺失突变相比,L858R突变型NSCLC需要采取不同的治疗策略,厄洛替尼联合贝伐珠单抗可作为首选方案,而免疫治疗仅作为EGFR-TKI治疗失败的后线方案。     

晚期非小细胞肺癌患者使用EGFR-TKI治疗后长期生存的研究

目的 探索应用表皮生长因子受体酪氨酸激酶抑制剂( EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)患者长期生存的影响因素,并研究长期生存者与EGFR突变关系.方法回顾性分析2002年12月至2007年6月在北京协和医院进行EGFR-TKI治疗的292例晚期NSCLC,并收集长期生存(定义为使用吉非替尼或厄洛替尼治疗...     

奥西替尼二线治疗EGFR突变型晚期非小细胞肺癌的疗效观察

目的 评价奥西替尼二线治疗表皮生长因子受体(EGFR)突变型晚期非小细胞肺癌(NSCLC)的疗效,对治疗前转移部位、耐药后进展部位与疗效间的关系进行探讨.方法 收集2017年1月1日至2019年1月1日67例经1～2代EGFR-酪氨酸激酶抑制剂(EGFR-TKI)治疗和50例一线化疗后进展的晚期NSCLC患者.全组患者...     

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.     

挽救性化疗治疗化疗及表皮生长因子受体酪氨酸激酶抑制剂治疗失败的晚期非小细胞肺癌的疗效和安全性

目的 探讨一线含铂方案及表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败后的晚期非小细胞肺癌(NSCLC)患者接受挽救性化疗的疗效和安全性.方法 对55例一线含铂方案及后续EGFR-TKI治疗失败的晚期NSCLC患者行挽救性化疗,其中培美曲塞单药化疗24例,多西他塞单药化疗21例,其他方案化疗10例.至疾病进展或患者拒绝继续治疗.评价挽救性化疗的客观缓解率(ORR)、疾病控制率(DCR)及患者的无进展生存时间(PFS).结果 55例患者均可评价疗效,其中部分缓解(PR)7例(12.7%),稳定(SD)21例(38.2%),进展(PD)27例(49.1%),无完全缓解(CR)患者.ORR为12.7%,DCR为50.9%.全组患者的中位随访时间为5.5个月,中位PFS为2.0个月.不同性别、PS评分及化疗方案患者的近期疗效及PFS差异均无统计学意义(均P＞0.05).EGFR-TKI治疗时间≥6个月患者的ORR(21.1%)和DCR(73.7%)均明显高于EGFR-TKI治疗时间＜6个月的患者(ORR为8.3%,DCR为38.9%;均P＜0.05);EGFR-TKI治疗时间≥6个月患者与＜6个月患者的中位PFS分别为4.5月和2.0个月,差异亦有统计学意义(P=0.008).55例患者均可评价不良反应,主要表现为骨髓抑制,患者均能耐受.全组未发生治疗相关性死亡.结论 一线含铂方案及EGFR-TKI治疗失败后的晚期NSCLC患者能从挽救性化疗中获益,尤其是对EGFR-TKI治疗时间≥6个月的患者.晚期NSCLC患者对于挽救性化疗的耐受性良好.     

Erlotinib as salvage treatment after failure to first-line gefitinib in non-small cell lung cancer

Purpose

Chemotherapy is the mainstay treatment for advanced non-small cell lung cancer (NSCLC). Gefitinib, an epidermal growth factor receptor—tyrosine kinase inhibitor (EGFR-TKI), has been recently shown to be effective as a first-line treatment in Asian patients with advanced NSCLC, especially for those with favourable clinical features such as female, non-smoker and adenocarcinoma. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment. The purpose of this study is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib.

Method

Retrospective review of NSCLC patients with favourable clinical features who received gefitinib as first-line treatment and subsequent salvage treatment with erlotinib.

Results

A total of 21 patients with NSCLC were included in the study. Among them, 18 (85.7%) patients had disease control with gefitinib and 12 (57.1%) patients with salvage erlotinib. There was an association between the disease control with gefitinib and erlotinib (p = 0.031). The disease control rate of erlotinib was independent of the chemotherapy use between the two EGFR-TKIs.

Conclusion

For NSCLC patients with favourable clinical features, erlotinib was effective in those who had prior disease control with first-line gefitinib.     

Epidermal growth factor receptor tyrosine kinase inhibitors in elderly or poor performance status patients with advanced non-small cell lung cancer

Elderly and poor performance status advanced non-small cell lung cancer (NSCLC) patients often tolerate chemotherapy poorly. Special approaches are needed for these patient populations. Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), erlotinib and gefitinib, are active agents in the treatment of advanced NSCLC. Several phase II trials have been conducted utilizing EGFR TKIs in elderly or poor performance status patients with advanced NSCLC. This review will summarize the results of erlotinib or gefitinib in these subsets of patients with advanced NSCLC.     

Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors

Brain metastases (BM) is one of the most crucial distant metastases in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. There is no consensus about which EGFR tyrosine kinase inhibitor (TKI) is most effective against BM in such patients. Here, we compared prognoses of patients with EGFR-TKI naïve EGFR-positive BM treated with erlotinib or gefitinib after BM diagnosis. Of 269 patients with NSCLC treated with EGFR-TKIs at a single institution, we reviewed medical records of 205 patients with documented EGFR mutations. Eleven patients were administered erlotinib, and 52 patients were administered gefitinib as the first-line EGFR-TKI treatment after diagnosis. We used propensity score matching to balance patient backgrounds between groups, and the log-rank test to compare survival curves. Patients with BM at the induction of chemotherapy had a poorer prognosis than those without BM [median overall survival (OS) 18.5 vs. 28.0 months]. Meanwhile, there was no significant difference in OS between those with or without BM at the initiation of EGFR-TKI treatment (20.3 vs. 23.8 months). Median OS of patients treated with erlotinib was not significantly longer than that of patients treated with gefitinib (25.0 vs. 18.1 months). The presence of BM at the initiation of EGFR-TKI treatment had no apparent effect on survival. Erlotinib was deemed more effective than gefitinib in preventing intracranial lesions and prolonging survival; however, prospective studies are needed to confirm these results.     

Current views on the role of Notch signaling and the pathogenesis of human leukemia

Background

Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^nd EGFR-TKI administration.

Methods

We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.

Results

Three patients (27%) were treated with gefitinib as the 2^nd EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^nd EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^nd EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^nd EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.

Conclusions

Our results indicate that a 2^nd EGFR-TKI treatment can be an effective treatment option for gefitinib responders.     

表皮生长因子受体突变晚期非小细胞肺癌靶向治疗效果影响因素分析

目的:探讨表皮生长因子受体（EGFR）突变晚期非小细胞肺癌（NSCLC）EGFR-酪氨酸激酶抑制剂（EGFR-TKI）治疗效果的影响因素。方法:收集2015年1月至2019年10月南京医科大学附属无锡第二医院接受EGFR-TKI治疗的104例EGFR突变晚期NSCLC患者的临床资料。分析EGFR突变类型与患者的临床病理...     

EGFR-TKI一线治疗EGFR基因突变的晚期非小细胞肺癌临床观察

背景与目的研究表明,一线表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptortyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的客观缓解率及无进展生存期明显优于铂二联的化疗,且耐受性更好。本研究旨在分析EGFR-TKI一线治疗晚期EGFR突变阳性的NSCLC患者的疗效与耐受性。方法 54例晚期NSCLC患者肿瘤标本采用直接测序法证实EGFR活化突变(外显子19缺失或外显子21点突变),一线给予EGFR-TKI口服治疗直至疾病进展,观察疗效及不良反应,并进行生存随访。结果 54例患者外显子19缺失33例(61%),外显子21点突变21例(39%)。均一线接受EGFR-TKI治疗,总体缓解率为90%,中位无进展生存期(progression free survival,PFS)为8.3个月,中位生存期为19.5个月;外显子19缺失患者的中位PFS(9.0个月)较21点突变(7.0个月)时间长(P=0.002)。外显子19缺失患者的中位总生存期(overall survival,OS)(25.0个月)较21点突变(16.0个月)时间长(P=0.001);吉非替尼与厄洛替尼疗效相当,但吉非替尼组安全性更好;最常见的不良事件为皮疹和腹泻,有2例患者(4%)出现了3度皮肤毒性反应,2例患者(4%)出现了3度的转氨酶升高,1例患者(1%)出现了3度口腔炎。结论存在EGFR基因突变的晚期NSCLC患者一线接受EGFR-TKI治疗安全有效,且外显子19缺失比L858R突变疗效更优。     

Epidermal growth factor receptor-targeted agents for lung cancer.

BACKGROUND: Approximately 150,000 people were diagnosed with non-small cell lung cancer (NSCLC) in the United States in 2005. Most presented with inoperable advanced-stage disease. Although combination chemotherapy remains the standard treatment, median survival with these regimens is only 8 to 10 months. Recent advances in our understanding of lung cancer on a molecular level have led to the introduction of targeted therapies. METHODS: We reviewed the mechanism of action of gefitinib and erlotinib as well as the results of phase I, II, and III trials with these drugs. RESULTS: No survival advantage was seen with the addition of gefitinib or erlotinib to combination chemotherapy in first-line treatment of advanced NSCLC. Erlotinib has shown a survival advantage over placebo in patients with NSCLC after first- or second-line chemotherapy. Recently, mutations in the epidermal growth factor receptor-tyrosine kinase domain have been identified. Patients who express these mutations have shown a higher probability of response to gefitinib. CONCLUSIONS: Combination chemotherapy remains the first-line treatment of advanced NSCLC. The benefit of alternating drug schedules and combinations has been small. Targeted therapies such as gefitinib and erlotinib, although to date have shown no survival advantage when combined with chemotherapy in the first-line setting, remain promising. Ongoing studies of patient characteristics of responding patients and molecular studies of tumors may help to identify patients most likely to respond to these therapies.     

Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials

Gefiinib and erlotinib are two similar small molecules of selective and reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which have been approved for second-line or third-line indication in previously treated advanced Non-small-cell lung cancer (NSCLC) patients. The results of comparing the EGFR-TKI with standard platinum-based doublet chemotherapy as the first-line treatment in advanced NSCLC patients with activated EGFR mutation were still controversial. A meta-analysis was performed to derive a more precise estimation of these regimens. Finally, six eligible trials involved 1,021 patients were identified. The patients receiving EGFR-TKI as front-line therapy had a significantly longer progression-free survival (PFS) than patients treated with chemotherapy [median PFS was 9.5 versus 5.9 months; hazard ratio (HR)=0.37; 95% confidence intervals (CI)=0.27-0.52; p<0.001]. The overall response rate (ORR) of EGFR-TKI was 66.60%, whereas the ORR of chemotherapy regimen was 30.62%, which was also a statistically significant favor for EGFR-TKI [relative risk (RR)=5.68; 95% CI=3.17-10.18; p<0.001]. The overall survival (OS) was numerically longer in the patients received EGFR-TKI than patients treated by chemotherapy, although the difference did not reach a statistical significance (median OS was 30.5 vs. 23.6 months; HR=0.94; 95% CI=0.77-1.15; p=0.57). Comparing with first-line chemotherapy, treatment of EGFR-TKI achieved a statistical significantly longer PFS, higher ORR and numerically longer OS in the advanced NSCLC patients harboring activated EGFR mutations, thus, it should be the first choice in the previously untreated NSCLC patients with activated EGFR mutation.     

高剂量吉非替尼或厄洛替尼脉冲治疗继发性耐药晚期非小细胞肺癌疗效及安全性的单中心、单臂、Ⅱ期临床研究

目的 观察吉非替尼或厄洛替尼常规剂量继发性耐药的晚期非小细胞肺癌（NSCLC）患者接受高剂量相应表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）脉冲治疗的疗效及安全性。方法 收集2013年8月至2014年12月42例吉非替尼或厄洛替尼常规治疗1年后出现耐药的NSCLC患者,其中吉非替尼组29例,一次性给予相应4倍剂量的吉非替尼（1000 mg／次）,4天为1个周期;厄洛替尼组13例,一次性给予相应3倍剂量的厄洛替尼（450 mg／次）,3天为1个周期。治疗直至出现疾病进展或不可耐受的毒性反应。比较两种药物治疗的近期疗效和无进展生存期（PFS）。结果 42例初始接受吉非替尼或厄洛替尼治疗1年后出现疾病进展的患者中位PFS为30个月;其中,吉非替尼组为31个月,厄洛替尼组为24 个月,两组差异无统计学意义（P＞0.05）。经高剂量EGFR TKI脉冲治疗后,全组获PR 8例、SD 11例、PD 23例,有效率（RR）为19.0％,疾病控制率（DCR）为 45.2％,中位PFS为6个月。其中吉非替尼组获PR 6例、SD 9例、PD 14例,中位PFS为8个月;厄洛替尼组获PR 2例、SD 2例、PD 9例,中位PFS为6个月;两组比较差异均无统计学意义（P＞0.05）。按EGFR外显子突变情况分组,Exon 19突变组获PR 4例、SD 6例、PD 17例,Exon 21突变组获PR 4例、SD 5例、PD 6例;两组中位PFS分别为6个月和7个月,差异无统计学意义（P＞0.05）。毒副反应均为1～2级,主要表现为皮疹、乏力、纳差和皮肤干燥等,两组毒副反应发生率的差异无统计学意义（P＞0.05）。 结论对于吉非替尼或厄洛替尼常规剂量治疗后出现进展的晚期NSCLC患者,高剂量EGFR-TKI脉冲治疗能使部分患者再次获益,可能是一种安全有效的治疗方法。