• 【RELAY研究的治疗依据和研究设计:厄洛替尼联合雷莫昔单抗或安慰剂对表皮生长因子受体突变阳性转移性非小细胞肺癌患者的多中心,随机,双盲研究。】 复制标题 收藏 收藏
    DOI:10.1016/j.cllc.2016.05.023 复制DOI
    作者列表:Garon EB,Reck M,Paz-Ares L,Ponce S,Jaime JC,Juan O,Nadal E,Lee P,Dalal R,Liu J,He S,Treat J,Nakagawa K
    BACKGROUND & AIMS: INTRODUCTION:We present the treatment rationale and study design for the RELAY study (NCT02411448 ). This phase Ib/III study will assess safety, tolerability, and efficacy of the combination of ramucirumab with erlotinib in previously untreated stage IV non-small-cell lung cancer patients with an activating epidermal growth factor receptor (EGFR) mutation. PATIENTS AND METHODS:The study is being conducted in approximately 120 sites in North America, Europe, and Asia and is currently open for enrollment. In part A (phase Ib), approximately 12 patients will receive ramucirumab (10 mg/kg) every 2 weeks with erlotinib (150 mg) every day. Dose-limiting toxicity will be assessed during 2 cycles (4 weeks) of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every 2 weeks with erlotinib daily until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary end point is progression-free survival, on the basis of investigator assessment. Secondary end points include overall survival, objective response rate, disease control rate, duration of response, safety, and quality of life. CONCLUSION:Erlotinib with ramucirumab combination was chosen because the addition of an antiangiogenic agent, such as ramucirumab, would further improve the efficacy of erlotinib, which is a standard of care in the first-line treatment of patients with activating EGFR mutations.
    背景与目标: 简介:我们介绍了RELAY研究(NCT02411448)的治疗原理和研究设计。这项Ib / III期研究将评估ramucirumab与厄洛替尼联合使用在先前未经治疗的IV期非小细胞肺癌患者中的活化表皮生长因子受体(EGFR)突变的安全性,耐受性和疗效。
    患者与方法:这项研究正在北美,欧洲和亚洲的大约120个地点进行,目前正在接受研究。在A部分(Ib期)中,每天约有12名患者每2周接受拉莫昔单抗(10 mg / kg)和厄洛替尼(150 mg)的治疗。在2个疗程(4周)内评估剂量限制毒性。在B部分(III期)中,约有450名患者将以1:1的比例随机分配,每2周接受厄洛替尼治疗,每2周接受雷莫昔单抗或安慰剂治疗,直至疾病进展,不可接受的毒性或其他戒断标准得到满足。根据研究人员的评估,主要终点是无进展生存期。次要终点包括总体生存率,客观缓解率,疾病控制率,缓解持续时间,安全性和生活质量。
    结论:选择厄洛替尼联合雷莫昔单抗治疗是因为添加抗血管生成剂,如雷莫昔单抗,将进一步提高厄洛替尼的疗效,这是一线治疗EGFR活化突变患者的标准治疗方法。
  • 【厄洛替尼可通过调节ERK1 / 2,STAT3,p53和凋亡途径来阻止腺嘌呤对小鼠的肾毒性。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-020-68480-7 复制DOI
    作者列表:Awad AM,Saleh MA,Abu-Elsaad NM,Ibrahim TM
    BACKGROUND & AIMS: :Renal fibrosis is a failed regenerative process that facilitates chronic kidney disease progression. The current study was designed to study the effect of erlotinib, a receptor tyrosine kinase inhibitor, on the progression of renal fibrosis. The study included four groups of mice: control group; adenine group: received adenine (0.2% w/w) daily with food for 4 weeks; erlotinib group: received 80 mg/kg/day erlotinib orally (6 ml/kg/day, 1.3% w/v suspension in normal saline 0.9%) for 4 weeks; adenine + erlotinib group: received adenine and erlotinib concurrently. Kidney function and antioxidant biomarkers were measured. Renal expression of Bcl2 and p53 and histopathological changes (tubular injury and renal fibrosis) were scored. Renal tissue levels of transforming growth factor-β1, p-ERK1/2 and p-STAT3 were measured. Results obtained showed significant decrease (P < 0.001) in serum creatinine, urea and uric acid in erlotinib + adenine group. Level of malondialdehyde was decreased significantly (P < 0.001) while reduced glutathione and catalase levels were increased (P < 0.01) by erlotinib concurrent administration. Erlotinib markedly reduced fibrosis and tubular injury and decreased TGF-β1, p-ERK1/2 and p-STAT3 (P < 0.5). In addition, expression level of Bcl-2 was elevated (P < 0.001) while that of p53-was reduced compared to adenine alone. Erlotinib can attenuate renal fibrosis development and progression through anti-fibrotic, antioxidant and anti-apoptotic pathways.
    背景与目标: :肾纤维化是一个失败的再生过程,它促进了慢性肾脏疾病的进展。当前的研究旨在研究受体酪氨酸激酶抑制剂埃洛替尼对肾纤维化进展的影响。该研究包括四组小鼠:对照组;对照组。腺嘌呤组:每天接受腺嘌呤(0.2%w / w)并连续4周进食;厄洛替尼组:口服80毫克/千克/天的厄洛替尼(6毫升/千克/天,1.3%w / v在生理盐水中的悬浮液0.9%)4周;腺嘌呤厄洛替尼组:同时接受腺嘌呤和厄洛替尼。测量肾脏功能和抗氧化剂生物标志物。对Bcl2和p53的肾脏表达以及组织病理学变化(肾小管损伤和肾纤维化)进行评分。测量了肾脏组织中转化生长因子-β1,p-ERK1 / 2和p-STAT3的水平。厄洛替尼腺嘌呤组的血清肌酐,尿素和尿酸显着下降(P <0.001)。厄洛替尼同时给药可显着降低丙二醛水平(P <0.001),同时降低谷胱甘肽和过氧化氢酶水平(P <0.01)。厄洛替尼显着减少了纤维化和肾小管损伤,并降低了TGF-β1,p-ERK1 / 2和p-STAT3(P <0.5)。另外,与单独的腺嘌呤相比,Bcl-2的表达水平升高(P <0.001),而p53-的表达水平降低。厄洛替尼可通过抗纤维化,抗氧化剂和抗凋亡途径减弱肾纤维化的发展和进程。
  • 【厄洛替尼治疗的非小细胞肺癌(NSCLC)患者中C-erbB-3的表达。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:CsToth I,Anthoine G,Berghmans T,Mascaux C,Paesmans M,Sculier JP,Meert AP
    BACKGROUND & AIMS: BACKGROUND:The clinical impact of c-erbB-3 has seldom been assessed in patients with non small cell lung cancer (NSCLC). PATIENTS AND METHODS:Forty-three NSCLC patients treated by erlotinib for c-erbB-3 and EGFR expression were investigated by immunohistochemistry analysis. RESULTS:Two partial responses, one minor response, two stable diseases and twenty progressive diseases were observed at the first evaluation. Seventeen patients died before evaluation. Median EGFR expression was 70% of the cancer cells. Forty-two percent of the tumours co-expressed c-erbB-3 and EGFR without any difference according to histology or disease stage. There was no correlation between c-erbB-3 and EGFR expression. Median survival time was 2.6 months and the six months survival rate was 21%. There was no detectable impact of EGFR (p=0.94) or c-erbB-3 (p=0.93) expression on survival. CONCLUSION:In this small particular cohort of NSCLC patients receiving salvage therapy with erlotinib, there was no correlation between c-erbB-3 expression and clinical parameters, nor between cerbB-3/EGFR expression and outcome.
    背景与目标: 背景:很少评估c-erbB-3在非小细胞肺癌(NSCLC)患者中的临床影响。
    病人和方法:对43例接受厄洛替尼治疗的NSCLC患者的c-erbB-3和EGFR表达进行了免疫组织化学分析。
    结果:首次评估时观察到两个部分反应,一个轻微反应,两个稳定疾病和二十个进行性疾病。评估前有17名患者死亡。 EGFR的中位表达为癌细胞的70%。根据组织学或疾病阶段,有42%的肿瘤共表达c-erbB-3和EGFR,没有任何差异。 c-erbB-3和EGFR表达之间没有相关性。中位生存时间为2.6个月,六个月生存率为21%。 EGFR(p = 0.94)或c-erbB-3(p = 0.93)表达对存活率无可检测的影响。
    结论:在这个小规模的非小细胞肺癌患者中,厄洛替尼进行挽救性治疗,c-erbB-3表达与临床参数之间无相关性,cerbB-3 / EGFR表达与预后之间无相关性。
  • 【一期临床试验,用于确定塞洛昔布与厄洛替尼联合用于晚期非小细胞肺癌的最佳生物剂量。】 复制标题 收藏 收藏
    DOI:10.1158/1078-0432.CCR-06-0112 复制DOI
    作者列表:Reckamp KL,Krysan K,Morrow JD,Milne GL,Newman RA,Tucker C,Elashoff RM,Dubinett SM,Figlin RA
    BACKGROUND & AIMS: PURPOSE:Overexpression of cyclooxygenase-2 (COX-2) activates extracellular signal-regulated kinase/mitogen-activated protein kinase signaling in an epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI)-resistant manner. Because preclinical data indicated that tumor COX-2 expression caused resistance to EGFR TKI, a phase I trial to establish the optimal biological dose (OBD), defined as the maximal decrease in urinary prostaglandin E-M (PGE-M), and toxicity profile of the combination of celecoxib and erlotinib in advanced non-small cell lung cancer was done. EXPERIMENTAL DESIGN:Twenty-two subjects with stage IIIB and/or IV non-small cell lung cancer received increasing doses of celecoxib from 200 to 800 mg twice daily (bid) and a fixed dose of erlotinib. Primary end points included evaluation of toxicity and determination of the OBD of celecoxib when combined with erlotinib. Secondary end points investigate exploratory biological markers and clinical response. RESULTS:Twenty-two subjects were enrolled, and 21 were evaluable for the determination of the OBD, toxicity, and response. Rash and skin-related effects were the most commonly reported toxicities and occurred in 86%. There were no dose-limiting toxicities and no cardiovascular toxicities related to study treatment. All subjects were evaluated on intent to treat. Seven patients showed partial responses (33%), and five patients developed stable disease (24%). Responses were seen in patients both with and without EGFR-activating mutations. A significant decline in urinary PGE-M was shown after 8 weeks of treatment, with an OBD of celecoxib of 600 mg bid. CONCLUSIONS:This study defines the OBD of celecoxib when combined with a fixed dose of EGFR TKI. These results show objective responses with an acceptable toxicity profile. Future trials using COX-2 inhibition strategies should use the OBD of celecoxib at 600 mg bid.
    背景与目标: 目的:环氧合酶-2(COX-2)的过表达以表皮生长因子受体(EGFR)酪氨酸激酶抑制(TKI)耐药的方式激活细胞外信号调节激酶/促分裂原激活的蛋白激酶信号传导。由于临床前数据表明肿瘤COX-2表达引起了对EGFR TKI的耐药性,因此我进行了确定最佳生物剂量(OBD)的I期试验,该剂量定义为尿中前列腺素EM(PGE-M)的最大降低,以及该药物的毒性谱图。塞来昔布和厄洛替尼联用治疗晚期非小细胞肺癌。
    实验设计:22名患有IIIB和/或IV期非小细胞肺癌的受试者接受的塞来昔布剂量从每天两次200毫克增加到800毫克(出价)和固定剂量的厄洛替尼。主要终点包括与厄洛替尼联用时的毒性评估和塞来昔布的OBD测定。次要终点研究探索性生物学标志物和临床反应。
    结果:22名受试者入选,其中21名可评估OBD,毒性和反应性。皮疹和皮肤相关的影响是最常报告的毒性,发生率达86%。没有与研究治疗有关的剂量限制性毒性和心血管毒性。对所有受试者的治疗意图进行了评估。七名患者表现出部分缓解(33%),五名患者出现疾病稳定(24%)。在有和没有EGFR激活突变的患者中均观察到反应。治疗8周后,尿中PGE-M显着下降,塞来昔布的OBD为600 mg bid。
    结论:这项研究定义了塞来昔布与固定剂量的EGFR TKI联合使用时的OBD。这些结果表明具有可接受的毒性特征的客观反应。未来使用COX-2抑制策略的试验应使用塞来昔布的OBD剂量为600 mg bid。
  • 【HCC衍生的EGFR突变体具有功能性,EGF依赖性和埃洛替尼耐药性。】 复制标题 收藏 收藏
    DOI:10.1186/s13578-020-00407-1 复制DOI
    作者列表:Sueangoen N,Tantiwetrueangdet A,Panvichian R
    BACKGROUND & AIMS: Background:Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target. Overexpression of EGFR is frequently observed in hepatocellular carcinoma (HCC) and EGFR activation has been proven to be a potential determinant of primary resistance of HCC cells to sorafenib. In our previous study, we found 13 missense mutations in EGFR exon 19-23 from hepatocellular carcinoma (HCC) tissues, but the functions of these mutations have not been determined. This study aims to determine the kinase activity and sensitivity to erlotinib, a 1st-generation EGFR-tyrosine kinase inhibitor (TKI), of seven HCC-derived mutants (K757E, N808S, R831C, V897A, P937L, T940A, and M947T). Results:Using transduction of pBabe-puro retroviral vector with or without EGFR, we constructed and determined the function of EGFRs in NIH-3T3 cells stably harboring each of the seven mutants, as well as the erlotinib-sensitive L858R-mutant, the erlotinib-resistant T790M-mutant, and EGFR wild type (WT). Our results indicate that the seven mutants are functioning, EGF-dependent, EGFRs. Cells harboring six of the seven mutants could generate some level of EGFR phosphorylation in the absence of EGF, indicating some constitutive kinase activity, but all of the seven mutants remain primarily EGF-dependent. Our results demonstrate that erlotinib induces differential degree of apoptosis and autophagy among cells harboring different EGFRs: complete apoptosis and autophagy (cleavage of both caspase-3 and PARP, and marked LC3-II increment) in L858R-mutant; partial apoptosis and autophagy (only cleavage of caspase-3, and moderate LC3-II increment) in WT and HCC-derived mutants; and no apoptosis and minimal autophagy (no cleavage of caspase-3 and PARP, and minimal LC3-II increment) in T790M-mutant. The seven HCC-derived mutants are erlotinib-resistant, as treatment with erlotinib up to high concentration could only induce partial inhibition of EGFR phosphorylation, partial or no inhibition of AKT and ERK phosphorylation, and partial apoptosis and autophagy. Conclusion:The seven HCC-derived EGFR mutants in this study are functioning, EGF-dependent, and erlotinib-resistant. Erlotinib induces differential degree of apoptosis and autophagy among cells harboring different EGFRs. The degree of inhibition of EGFR phosphorylation by erlotinib is the determining factor for the degree of apoptosis and autophagy amongst cells harboring EGFR mutants. This study paves the way for further investigation into the sensitivity of these HCC-derived mutants to the 3rd-generation irreversible EGFR-TKI, osimertinib.
    背景与目标: 背景:表皮生长因子受体(EGFR)已成为重要的治疗靶点。在肝细胞癌(HCC)中经常观察到EGFR的过表达,并且已证明EGFR激活是HCC细胞对索拉非尼原发耐药性的潜在决定因素。在我们先前的研究中,我们在肝细胞癌(HCC)组织的EGFR外显子19-23中发现了13个错义突变,但这些突变的功能尚未确定。这项研究旨在确定七个HCC衍生突变体(K757E,N808S,R831C,V897A,P937L,T940A和M947T)的激酶活性和对第一代EGFR酪氨酸激酶抑制剂(TKI)的厄洛替尼的敏感性。
    结果:通过转导含或不含EGFR的pBabe-puro逆转录病毒载体,我们构建并确定了EGFR在稳定携带7个突变体以及厄洛替尼敏感的L858R突变体,厄洛替尼-的NIH-3T3细胞中的功能。抗性的T790M突变体和EGFR野生型(WT)。我们的结果表明,这七个突变体是功能性的,依赖EGF的EGFR。携带7个突变体中的6个的细胞在没有EGF的情况下可以产生一定水平的EGFR磷酸化,表明某些组成性激酶活性,但所有7个突变体仍然主要依赖于EGF。我们的结果表明,厄洛替尼在具有不同EGFR的细胞之间诱导不同程度的凋亡和自噬:在L858R突变体中完全凋亡和自噬(裂解caspase-3和PARP,并标记LC3-II增量); WT和HCC衍生突变体中的部分细胞凋亡和自噬(仅裂解caspase-3,且LC3-II中等增加);并且在T790M突变体中没有凋亡和最小限度的自噬(不切割caspase-3和PARP,最小的LC3-II增量)。七个HCC衍生突变体均具有埃洛替尼抗性,因为高浓度的埃洛替尼治疗只能诱导EGFR磷酸化的部分抑制,AKT和ERK磷酸化的部分抑制或无抑制,部分细胞凋亡和自噬。
    结论:本研究中的七个HCC衍生的EGFR突变体具有功能性,EGF依赖性和埃洛替尼耐药性。厄洛替尼在具有不同EGFR的细胞之间诱导不同程度的凋亡和自噬。厄洛替尼对EGFR磷酸化的抑制程度是决定携带EGFR突变体的细胞凋亡和自噬程度的决定因素。这项研究为进一步研究这些HCC衍生突变体对第三代不可逆EGFR-TKI奥西替尼的敏感性铺平了道路。
  • 【小动物FDG‑PET / CT和CT对原位SCID小鼠模型的顺铂和厄洛替尼抗肺癌功效进行非侵入性监测。】 复制标题 收藏 收藏
    DOI:10.3892/or.2018.6818 复制DOI
    作者列表:Otani T,Kondo K,Takizawa H,Kajiura K,Fujino H,Otsuka H,Miyoshi H
    BACKGROUND & AIMS: :We established patient‑like models of lung cancer metastasis by orthotopically implanting human non‑small cell lung cancer cell lines into SCID mice. We evaluated the utilities of small‑animal computed tomography (CT) and positron‑emission tomography‑computed tomography (PET/CT) in these models to non‑invasively and repeatedly monitor the anticancer effects of cisplatin and erlotinib. We orthotopically implanted three non‑small cell lung cancer cell lines, A549, FT821 and PC‑9, into SCID mice. These mice were then divided into three groups: Control, cis‑diamminedichloroplatinum (II) (CDDP) (7‑mg/kg CDDP, single administration intraperitoneally), and erlotinib (25 mg/kg erlotinib/day, oral administration 5 days/week). After treatment initiation, we repeatedly performed PET/CT and CT measurements and assessed anticancer effects based on tumor volumes and FDG uptake. A549 tumors were not affected by CDDP or erlotinib. FT821 tumors were highly responsive to CDDP. PC‑9 tumors, which have an epidermal growth factor receptor mutation, were highly responsive to erlotinib. Histological results and metastatic rates correlated with the anticancer effects shown by CT. In our orthotopic SCID mouse lung cancer models, 18FDG‑PET/CT and CT imaging non‑invasively and repeatedly monitored the efficacies of cisplatin and erlotinib against not only implanted tumors, but also mediastinal lymph node metastases.
    背景与目标: :我们通过将人非小细胞肺癌细胞系原位移植到SCID小鼠中,建立了类似于肺癌的患者转移模型。我们在这些模型中评估了小动物计算机断层扫描(CT)和正电子发射断层扫描计算机断层扫描(PET / CT)的实用性,以无创且反复监测顺铂和厄洛替尼的抗癌作用。我们将三种非小细胞肺癌细胞系A549,FT821和PC‑9原位移植到SCID小鼠中。然后将这些小鼠分为三组:对照组,顺二氨二氯铂(II)(CDDP)(7‑mg / kg CDDP,腹膜内单次给药)和厄洛替尼(25 mg / kg厄洛替尼/天,口服5天/周)。治疗开始后,我们反复进行PET / CT和CT测量,并根据肿瘤体积和FDG摄取评估抗癌作用。 A549肿瘤不受CDDP或厄洛替尼的影响。 FT821肿瘤对CDDP高度敏感。具有表皮生长因子受体突变的PC‑9肿瘤对厄洛替尼具有高响应性。组织学结果和转移率与CT显示的抗癌作用相关。在我们的原位SCID小鼠肺癌模型中,18FDG‑PET / CT和CT成像无创且反复监测了顺铂和厄洛替尼不仅对植入的肿瘤,而且对纵隔淋巴结转移的疗效。
  • 【对于晚期胰腺癌患者,KRAS突变状态不能预测厄洛替尼抗EGFR治疗的客观反应。】 复制标题 收藏 收藏
    DOI:10.1007/s00535-013-0767-4 复制DOI
    作者列表:Boeck S,Jung A,Laubender RP,Neumann J,Egg R,Goritschan C,Ormanns S,Haas M,Modest DP,Kirchner T,Heinemann V
    BACKGROUND & AIMS: BACKGROUND:It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC). METHODS:AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc). RESULTS:KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (p = 0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p = 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p = 0.10) for the OSc. CONCLUSION:This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.
    背景与目标: 背景:尚未确定KRAS对厄洛替尼在晚期胰腺癌(PC)中的疗效是否具有预后价值或是否为预测性生物标志物。
    方法:AIO-PK0104是一项III期试验,在晚期PC机中比较吉西他滨/厄洛替尼,卡培他滨,卡培他滨/厄洛替尼,吉西他滨。对于此事后亚组分析,有关KRAS外显子2突变状态的生物标记数据与对一线治疗的客观反应以及与二线化疗(OSc)开始后的总体生存率相关。
    结果:在173名患者中,有121名(70%)患者的KRAS密码子12被突变。 KRAS状态显示与客观反应无关(p = 0.40),但KRAS野生型患者的OS改善(HR 1.68,p = 0.005)。在(不含厄洛替尼的)二线化疗期间也观察到生存获益的趋势,OSc的HR为1.47(p = 0.10)。
    结论:AIO-PK0104的事后分析支持以下假设:KRAS在PC中是一种预后指标,而不是预测性生物指标。
  • 【厄洛替尼和索拉非尼在原位肝细胞癌大鼠模型中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.jhep.2012.04.034 复制DOI
    作者列表:Sieghart W,Pinter M,Dauser B,Rohr-Udilova N,Piguet AC,Prager G,Hayden H,Dienes HP,Dufour JF,Peck-Radosavljevic M
    BACKGROUND & AIMS: BACKGROUND & AIMS:The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model. METHODS:The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 μM) and erlotinib (1-5 μM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay. In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10mg/kg, erlotinib 10mg/kg, and respective combinations. RESULTS:In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 μM). No additional effect was observed upon combination with erlotinib. Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib. CONCLUSIONS:Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.
    背景与目标: 背景与目的:厄洛替尼与索拉非尼的组合目前正在III期RCT中进行研究。我们在临床前模型中研究了厄洛替尼和索拉非尼对肝癌的影响。
    方法:用索拉非尼(1-10μM)和厄洛替尼(1-5μM)体外处理Morris肝癌(MH)和HepG2细胞,并评估其肿瘤细胞活力,凋亡和靶标调控。通过测量VEGF水平,内皮细胞活力,凋亡,迁移和主动脉环测定研究了抗血管生成作用。在体内,将MH细胞植入同系大鼠的肝脏中,并用溶媒,索拉非尼5-10mg / kg,厄洛替尼10mg / kg及其各自的组合进行处理。
    结果:在体外,厄洛替尼下调了p-ERK,但对MH和HEPG2细胞中的肿瘤细胞存活率没有显着影响。尽管有类似的靶标调节,索拉非尼仍通过剂量依赖性方式(11±5%; 20±10%;索拉非尼1、5、10μM为51±5%)诱导凋亡,从而显着降低HCC细胞的细胞活力。与厄洛替尼合用时未观察到其他作用。值得注意的是,厄洛替尼治疗通过诱导内皮细胞和肿瘤细胞中的VEGF mRNA和蛋白水平诱导内皮细胞迁移和主动脉环血管萌芽,而索拉非尼则阻止了该过程。在体内,厄洛替尼没有单药抗肿瘤活性,血清VEGF水平升高,与索拉非尼联合使用缺乏协同作用。
    结论:厄洛替尼在体外和体内对肝癌均无抗肿瘤作用,但可诱导VEGF,可能反映了对厄洛替尼单药治疗的耐药机制。与厄洛替尼联合使用时未观察到索拉非尼功效的改善。
  • 【在癌症治疗中靶向HER1 / EGFR:厄洛替尼的经验。】 复制标题 收藏 收藏
    DOI:10.2217/14796694.1.4.449 复制DOI
    作者列表:Giaccone G
    BACKGROUND & AIMS: :Research into the role of the human epidermal receptor growth factor receptor 1/epidermal growth factor receptor (HER1/EGFR) in tumorigenesis has generated a new class of anticancer drugs. One such agent, erlotinib (Tarceva), is a potent, selective and reversible inhibitor of HER1/EGFR tyrosine kinase activity. Erlotinib has demonstrated the clinical activity in a variety of solid tumors, and has recently demonstrated improvements in survival in large Phase III trials, in non-small-cell lung cancer and pancreatic cancer.
    背景与目标: 人表皮生长因子受体1 /表皮生长因子受体(HER1 / EGFR)在肿瘤发生中的作用研究已经产生了新的一类抗癌药物。一种这样的药物,厄洛替尼(厄洛替尼)是有效的,选择性的和可逆的HER1 / EGFR酪氨酸激酶活性抑制剂。厄洛替尼已经证明了在各种实体瘤中的临床活性,并且最近在非小细胞肺癌和胰腺癌的大型III期临床试验中证明了生存率的提高。
  • 【在先前接受化学疗法治疗的一项扩大的访问计划研究中,厄洛替尼对台湾NSCLC患者的高疗效。】 复制标题 收藏 收藏
    DOI:10.1016/j.lungcan.2008.02.023 复制DOI
    作者列表:Perng RP,Yang CH,Chen YM,Chang GC,Lin MC,Hsieh RK,Chu NM,Lai RS,Su WC,Tsao CJ,Hsia TC,Chen HC,Chen CH,Huang MS,Wang JL,Ho ML,Chung CY,Yu CJ,Chang WC,Kuo HP,Yu CT,Lin ZZ,Kao WY
    BACKGROUND & AIMS: PURPOSE:Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which has demonstrated a survival benefit in non-small-cell lung cancer (NSCLC) patients. An open label phase II study was conducted in Taiwanese patients with NSCLC to evaluate its efficacy. METHODS:Patients with proven stage IIIB/IV NSCLC who had received at least one line of standard chemotherapy or radiotherapy were enrolled into this study. All patients were given oral erlotinib, 150mg/day till disease progression. RESULTS:From May 2005 to July 2006, 300 patients were entered from 14 hospitals in Taiwan. This analysis was based on 299 patients who received at least one dose of erlotinib. The best response rates were a 29% partial response and 44% stable disease in 273 patients who had response data available. Non-smoking (p=0.033), adenocarcinoma/BAC (p=0.0027), female (p=0.0013), aged less than 65 years (p=0.0115), stage IV (p=0.0492), patients with skin rash (p=0.0216), and a higher grade of skin rash (p=0.003) were significantly correlated with response to treatment. Skin rash was a common adverse event (any grade: 84%, Gr 3-4: 16%). The median time to disease progression was 5.6 months. Cox regression model for progression free survival showed patients most at risk of early progression were males of low performance status having squamous cell carcinoma. CONCLUSIONS:This was the largest multicenter prospective clinical study of NSCLC in Taiwan. The results demonstrated the excellent response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese NSCLC patients who had been previously treated with chemotherapy or radiotherapy.
    背景与目标: 目的:厄洛替尼是第一种表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),已证明在非小细胞肺癌(NSCLC)患者中具有生存获益。在台湾的NSCLC患者中进行了一项开放标签的II期研究,以评估其疗效。
    方法:IIIB / IV期NSCLC阶段已被证实接受过至少一线标准化疗或放疗的患者被纳入本研究。所有患者均口服厄洛替尼,剂量为150mg /天,直至疾病进展。
    结果:从2005年5月到2006年7月,来自台湾14所医院的300名患者进入了研究。该分析基于299名接受至少一剂厄洛替尼的患者。最好的缓解率是在有可用响应数据的273例患者中,部分缓解率为29%,疾病稳定率为44%。非吸烟(p = 0.033),腺癌/ BAC(p = 0.0027),女性(p = 0.0013),年龄小于65岁(p = 0.0115),IV期(p = 0.0492),皮疹患者(p = 0.0216),较高等级的皮疹(p = 0.003)与治疗反应显着相关。皮疹是常见的不良事件(任何等级:84%,Gr 3-4:16%)。疾病进展的中位时间为5.6个月。无进展生存期的Cox回归模型显示,处于早期进展风险最大的患者是表现为鳞状细胞癌的低性能男性。
    结论:这是台湾地区最大的非小细胞肺癌多中心前瞻性临床研究。结果表明,在先前接受过化学疗法或放射疗法治疗的大量台湾NSCLC患者中,厄洛替尼具有出色的缓解率,进展时间和总体生存率。
  • 【氮杂胞苷和厄洛替尼对急性髓性白血病具有协同作用。】 复制标题 收藏 收藏
    DOI:10.1038/onc.2012.469 复制DOI
    作者列表:Lainey E,Wolfromm A,Marie N,Enot D,Scoazec M,Bouteloup C,Leroy C,Micol JB,De Botton S,Galluzzi L,Fenaux P,Kroemer G
    BACKGROUND & AIMS: :The term myelodysplastic syndrome (MDS) identifies a heterogeneous group of clonal disorders originating from bone marrow stem cells that often progress to acute myeloid leukemia (AML). The reference treatments for MDS include the DNA methyltransferase inhibitors azacytidine and decitabine. Recently, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to exert antileukemic activity in vitro and in vivo, independent of the EGFR. Thanks to this feature, erlotinib is currently being tested as an antileukemic drug in clinical trials. Here, we report that azacytidine and erlotinib mediate synergistic antineoplastic effects in several primary or secondary (post-MDS) AML cell lines. The combination of azacytidine and erlotinib blocked cell-cycle progression and induced caspase-dependent apoptosis more consistently than either of the two agents alone. These effects were not a consequence of cellular differentiation and could be discriminated from each other, as the former depended on caspases whereas the latter did not. The synergy between azacitidine and erlotinib, which involved the proteasomal degradation of the anti-apoptotic Bcl-2 family members MCL-1 and BCL2L10 and the upregulation of their pro-apoptotic counterpart PUMA, was abolished when azacytidine was replaced by decitabine but persisted when erlotinib was substituted with gefitinib, another EGFR inhibitor. Of note, the intracellular accumulation of azacytidine was exacerbated by both erlotinib and gefitinib, pointing to a pharmacokinetic mechanism of synergy. In approximately half of the cases studied, marrow and circulating blasts from MDS and AML patients, respectively, exhibited hyperadditive cytotoxic responses to the combination of azacytidine and erlotinib. These results strongly suggest that the combination of azacytidine and erlotinib may exert clinically relevant antileukemic effects.
    背景与目标: :骨髓增生异常综合症(MDS)一词是由骨髓干细胞引起的一组异类克隆性疾病,通常会发展为急性髓细胞性白血病(AML)。 MDS的参考治疗方法包括DNA甲基转移酶抑制剂氮胞苷和地西他滨。最近,表皮生长因子受体(EGFR)抑制剂埃洛替尼已显示出在体内和体外发挥抗白血病作用,与EGFR无关。由于此功能,厄洛替尼目前正在临床试验中作为抗白血病药物进行测试。在这里,我们报告氮杂胞苷和厄洛替尼在几种原发性或继发性(MDS后)AML细胞系中介导协同抗肿瘤作用。氮杂胞苷和厄洛替尼的组合比单独使用两种药物中的任何一种都能更一致地阻断细胞周期进程并诱导胱天蛋白酶依赖性凋亡。这些作用不是细胞分化的结果,可以相互区分,因为前者依赖于胱天蛋白酶,而后者则不依赖于胱天蛋白酶。阿扎胞苷与厄洛替尼之间的协同作用涉及抗凋亡的Bcl-2家族成员MCL-1和BCL2L10的蛋白酶体降解以及它们的促凋亡对应物PUMA的上调,但当阿西替丁被地西他滨替代时,该协同作用被废止,但当厄洛替尼被持久化时,这种协同作用仍然存在。被另一种EGFR抑制剂吉非替尼(gefitinib)取代。值得注意的是,厄洛替尼和吉非替尼都加剧了氮杂胞苷的细胞内蓄积,这表明了协同作用的药代动力学机制。在大约一半的研究案例中,分别来自MDS和AML患者的骨髓和循环母细胞对氮杂胞苷和厄洛替尼的组合表现出高加性细胞毒性反应。这些结果强烈表明氮杂胞苷和厄洛替尼的组合可能发挥临床相关的抗白血病作用。
  • 【吉非替尼和厄洛替尼在非小细胞肺癌患者中的不良反应和疗效比较:回顾性分析。】 复制标题 收藏 收藏
    DOI:10.1007/s12032-012-0349-y 复制DOI
    作者列表:Yoshida T,Yamada K,Azuma K,Kawahara A,Abe H,Hattori S,Yamashita F,Zaizen Y,Kage M,Hoshino T
    BACKGROUND & AIMS: :Previous studies have demonstrated that both gefitinib and erlotinib are markedly effective for the treatment of non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR-mt). These agents are considered to act on EGFR through the same mechanism. However, the efficacy of these agents against EGFR wild-type (-wt) NSCLC remains unclear, and the frequency of adverse events (AEs) appears to differ between them at each approved dose. Here, we conducted a retrospective analysis of AEs and drug efficacy in patients with NSCLC whose EGFR mutation status had been confirmed and who all received 250 mg gefitinib or 150 mg erlotinib once daily. The erlotinib group (n = 35) had more AEs, including rash, fatigue, stomatitis, anorexia and constipation. On the other hand, liver dysfunction and nail change were more frequent in the gefitinib group (n = 107). AEs of ≥grade 2, including rash, fatigue and nausea, were more frequent in the erlotinib group. The erlotinib group also showed more of a tendency to require dose reduction due to AEs. With regard to treatment efficacy for patients with EGFR-wt, there was no significant difference in progression-free survival between the two drug groups. However, this study has several limitations as of the nature of retrospective design; our data suggest that gefitinib and erlotinib might have almost equal efficacy for patients with EGFR-wt NSCLC, as is the case for patients with EGFR-mt tumors, although erlotinib appears to have higher toxicity than gefitinib at each approved dose.
    背景与目标: :以前的研究表明,吉非替尼和厄洛替尼均对具有表皮生长因子受体基因(EGFR-mt)的体细胞激活突变的非小细胞肺癌(NSCLC)具有显着疗效。这些试剂被认为通过相同的机制作用于EGFR。但是,这些药物对EGFR野生型(-wt)NSCLC的疗效仍不清楚,并且在每次批准的剂量下,它们之间的不良事件(AEs)频率也有所不同。在这里,我们对NSCLC患者的AEs和药物疗效进行了回顾性分析,这些患者的EGFR突变状态已得到确认,并且均每天接受250 mg吉非替尼或150 mg厄洛替尼治疗。厄洛替尼组(n = 35)具有更多的不良事件,包括皮疹,疲劳,口腔炎,厌食和便秘。另一方面,吉非替尼组(n = 107)更常出现肝功能障碍和指甲更换。厄洛替尼组≥2级的AE,包括皮疹,疲劳和恶心。埃洛替尼组还显示出更多由于AE导致需要减少剂量的趋势。关于EGFR-wt患者的治疗效果,两组药物的无进展生存期无显着差异。然而,由于回顾性设计的性质,该研究存在一些局限性。我们的数据表明,吉非替尼和厄洛替尼对EGFR-wt NSCLC患者的疗效几乎相同,而EGFR-mt肿瘤患者也是如此,尽管在每个批准的剂量下厄洛替尼似乎比吉非替尼具有更高的毒性。
  • 【EGCG和厄洛替尼联合经典化学疗法对JAR细胞的体外评估。】 复制标题 收藏 收藏
    DOI:10.1007/s11626-017-0145-2 复制DOI
    作者列表:Telli E,Genç H,Tasa BA,Sinan Özalp S,Tansu Koparal A
    BACKGROUND & AIMS: :Gestational Trophoblastic Neoplasia (GTN) is a term used for a group of malignant gynecological tumors including choriocarcinoma. Low-risk neoplasias can be cured using single agents Methotrexate (MTX) and actinomycin-D (ACD), but in certain cases, decreased responsiveness and serious side effects occur. Therefore, researchers have been attempting to find new treatment modalities. One of the most popular way for increasing cancer patient survival rates is supporting treatment with adjuvant molecules or chemosensitizers. For this purpose, we investigated epigallocatechin-3-gallate (EGCG), a green tea cathecin, and Erlotinib, an EGFR tyrosine kinase inhibitor, as single agents and combined with MTX or ACD. In accordance with this, JAR (human placenta choriocarcinoma) cell line was used as an in vitro model and MTT, LDH, caspase-3 activation, RT-PCR, and Western Blot analyses were performed to investigate the effects of the test materials. Our studies demonstrate that combination of Erlotinib and EGCG with MTX and ACD decreases JAR cell proliferation and metastatic HER2 protein synthesis and increases caspase-3 activation compared to ACD or MTX alone. In addition, significant increase was observed in the apoptotic Bax gene, but no notable protein synthesis occurred in the Western Blot analysis, which suggests that combination of Erlotinib and EGCG with classical chemotherapeutics ACD or MTX may lead the JAR cells to apoptosis, but not by a mitochondrial pathway. All the results indicate that the synergetic effect of Erlotinib and EGCG with classical chemotherapeutics may help to increase patient survival rates of choriocarcinoma, but the detailed mechanism needs further investigation.
    背景与目标: 妊娠滋养细胞肿瘤(GTN)是一个术语,用于表示包括绒癌在内的一系列恶性妇科肿瘤。可以使用甲氨蝶呤(MTX)和放线菌素D(ACD)单一药物治愈低危的肿瘤,但在某些情况下,会降低反应性和严重的副作用。因此,研究人员一直在尝试寻找新的治疗方式。增加癌症患者存活率的最流行方法之一是支持使用辅助分子或化学增敏剂进行治疗。为此,我们研究了绿茶儿茶素表没食子儿茶素-3-没食子酸酯(EGCG)和EGFR酪氨酸激酶抑制剂厄洛替尼作为单一药物并与MTX或ACD联合使用。据此,将JAR(人胎盘绒毛膜癌)细胞系用作体外模型,并进行MTT,LDH,caspase-3激活,RT-PCR和Western Blot分析以研究测试材料的作用。我们的研究表明,与单独使用ACD或MTX相比,厄洛替尼和EGCG与MTX和ACD的组合可降低JAR细胞增殖和转移性HER2蛋白的合成,并增加caspase-3激活。此外,凋亡的Bax基因显着增加,但在Western Blot分析中未发现明显的蛋白质合成,这表明厄洛替尼和EGCG与经典化学疗法ACD或MTX的组合可能导致JAR细胞凋亡,但并非通过线粒体途径。所有结果表明,厄洛替尼和EGCG与经典化学疗法的协同作用可能有助于提高绒毛膜癌的患者生存率,但详细的机制尚需进一步研究。
  • 【转移性胰腺癌中表皮生长因子受体和胰岛素样生长因子受体-1信号的双重阻断:吉西他滨,厄洛替尼和西克斯妥单抗与吉西他滨加厄洛替尼的Ib期和随机II期试验(SWO】 复制标题 收藏 收藏
    DOI:10.1002/cncr.28744 复制DOI
    作者列表:Philip PA,Goldman B,Ramanathan RK,Lenz HJ,Lowy AM,Whitehead RP,Wakatsuki T,Iqbal S,Gaur R,Benedetti JK,Blanke CD
    BACKGROUND & AIMS: BACKGROUND:Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS:This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS:The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS:Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.
    背景与目标: 背景:针对胰腺腺癌(PC)的单一途径,不太可能影响其自然病史。我们测试了这样的假设,即表皮生长因子受体(EGFR)和胰岛素样生长因子受体1(IGF-1R)途径的同时靶向将通过废除促进耐药性的相互信号来显着改善无进展生存期(PFS)
    方法:这是一项Ib / II期研究,测试西妥木单抗联合厄洛替尼和吉西他滨(G)用于未经治疗的转移性PC患者。对照组为厄洛替尼加G。主要终点为PFS。资格包括表现状态0/1和正常的空腹血糖。还研究了参与G代谢和EGFR途径的基因的多态性
    结果:第一阶段的结果(n = 10)建立了西妥昔单抗6 mg / kg /周静脉内,厄洛替尼100 mg /天口服和G 1000 mg / m(2)在第1、8和15天静脉内的安全性28天的周期。在RP2部分(116名符合条件的患者;中位年龄为63岁)中,西妥昔单抗组的中位PFS和总生存期(OS)分别为3.6和7.0个月,对照组分别为3.6和6.7个月。西昔单抗和对照的主要3级和4级毒性分别是转氨酶升高,分别为12%和6%。疲劳分别为16%和12%;胃肠道,分别为35%和28%;中性粒细胞减少症分别为21%和10%;和血小板减少症分别为16%和7%。在16%的西妥昔单抗患者中发现3/4级高血糖。在研究的两个方面,3级或4级皮肤毒性相似(<5%)。对于任何多态性,未发现按基因型划分的PFS差异显着。
    结论:在厄洛替尼和G中加入IGF-1R抑制剂西克斯妥单抗不能导致转移性PC患者更长的PFS或OS。
  • 【比较吉非替尼和厄洛替尼作为晚期非小细胞肺癌三线治疗的疗效。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejca.2012.07.014 复制DOI
    作者列表:Shao YY,Shau WY,Lin ZZ,Chen HM,Kuo R,Yang JC,Lai MS
    BACKGROUND & AIMS: PURPOSE:The epidermal growth factor receptor inhibitors, gefitinib and erlotinib, are used as standard salvage therapy for advanced non-small-cell lung cancer (NSCLC). The aim of the present study was to compare their efficacies in this population. PATIENTS AND METHODS:The Taiwan Cancer Registry and the National Health Insurance claim databases were searched for newly diagnosed patients with NSCLC from 2004 to 2007 who received gefitinib or erlotinib as third-line therapy. Overall survival (OS) and time to treatment failure (TTF) were determined from registered parameters. Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox's proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses. RESULTS:A total of 984 patients who received gefitinib (67%) or erlotinib (33%) were included. Patients receiving gefitinib or erlotinib had similar OS (median, 10.2 versus 9.9 months, p=0.524) and TTF (median, 5.5 versus 3.4 months, p=0.103). In multivariate analyses, both treatment groups had similar risk of overall mortality (adjusted hazard ratio [HR]=1.04, p=0.629) and treatment failure (adjusted HR=0.94, p=0.417). Comparing the treatments in subgroups based on age, tumour histology and gender also revealed no differences in OS and TTF. For patients who received gefitinib or erlotinib for more than 3 or 6 months, there was no difference in TTF but patients who received erlotinib had longer OS. CONCLUSIONS:Gefitinib and erlotinib had similar efficacies as salvage therapy for advanced NSCLC in Taiwan.
    背景与目标: 目的:表皮生长因子受体抑制剂吉非替尼和厄洛替尼被用作晚期非小细胞肺癌(NSCLC)的标准挽救疗法。本研究的目的是比较他们在这一人群中的疗效。
    病人和方法:在台湾癌症登记处和国家健康保险索赔数据库中搜索2004年至2007年新诊断的接受吉非替尼或厄洛替尼作为三线治疗的非小细胞肺癌患者。根据注册参数确定总生存期(OS)和治疗失败时间(TTF)。通过对数秩检验比较总人口和具有不同临床特征的亚组的治疗效果。使用Cox比例风险模型估算多元分析中调整后的风险比率。
    结果:共纳入984例接受吉非替尼(67%)或厄洛替尼(33%)治疗的患者。接受吉非替尼或厄洛替尼的患者的OS(中位10.2对9.9个月,p = 0.524)和TTF(中位5.5对3.4个月,p = 0.103)相似。在多变量分析中,两个治疗组的总死亡率(调整后的危险比[HR] = 1.04,p = 0.629)和治疗失败(调整后的HR = 0.94,p = 0.417)的风险相似。根据年龄,肿瘤组织学和性别对亚组的治疗方法进行比较,还发现OS和TTF均无差异。对于接受吉非替尼或厄洛替尼治疗超过3或6个月的患者,TTF没有差异,但接受厄洛替尼的患者的OS更长。
    结论:吉非替尼和厄洛替尼的疗效与台湾晚期NSCLC的挽救疗法相似。

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