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1.
The epidermal growth factor receptor (EGFR) is a promising target in the treatment of advanced stage non-small-cell lung cancer
(NSCLC). Currently erlotinib and gefitinib are approved by the US Food and Drug Administration, whereas cetuximab is being
studied for use in NSCLC. Erlotinib has shown a survival advantage in patients with advanced NSCLC. Further studies have identified
female sex, nonsmokers, Asian race, good performance status, and adenocarcinoma histology as predictors of patient response
to these agents. A genetic mutation in EGFR has also been correlated with an increase in response. 相似文献
2.
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. 相似文献
3.
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. 相似文献
4.
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. 相似文献
5.
The epidermal growth factor receptor (EGFR) is a cellular transmembrane receptor with tyrosine kinase enzymatic activity which plays a key role in human cancer. EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. Several anti-EGFR drugs are in Phase III clinical development as single agent or in combination with other anticancer modalities. Cetuximab (Erbitux), a chimeric human-mouse monoclonal immunoglobin (Ig)G1 antibody, which blocks ligand binding and functional activation of the EGFR, is currently registered in the USA, Switzerland and the European Union for the treatment of advanced, irinotecan-refractory colorectal cancer. Gefitinib, (Iressa), a small molecule EGFR-selective inhibitor of tyrosine kinase activity which blocks EGF autophosphorylation and activation, has been the first EGFR-targeting drug to be registered in 28 countries worldwide, including the USA, for the third-line treatment of chemoresistant non-small cell lung cancer patients. This review will focus on the preclinical background and on the clinical data with the anti-EGFR drugs in most advanced clinical development. Furthermore, a series of open clinical issues for the development of optimal strategies of using EGFR-targeting agents will be discussed. 相似文献
6.
After many years of uncertainty regarding the role of immunotherapy in cancer, we finally have vaccines approved for the treatment of some malignancies (e.g., prostate cancer and melanoma). In non-small-cell lung cancer, several vaccines are being studied in randomized Phase III clinical trials due to their promising results seen in the clinic, such as BLP-25 and melanoma-associated antigen A3. Traditionally, non-small-cell lung cancer has not been considered a good target for immunotherapy due to lack of immunogenicity and the strong presence of regulatory T cells, which do not allow an adequate immune response in the host. EGF vaccination is a novel area of immunotherapy for this disease. Thus far, there has been success in generating immune and clinical responses with this vaccine in several clinical trials, and we will review in depth the efficacy and toxicity of this novel agent. 相似文献
7.
BACKGROUND: North American and Japanese non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activation via tyrosine kinase (TK) mutations respond dramatically to gefitinib treatment. To date, however, the frequency and effect of EGFR TK mutations have not been examined in European patients. PATIENTS AND METHODS: Eighty-three Spanish advanced NSCLC patients who had progressed after chemotherapy, were treated with compassionate use of gefitinib. Patients were selected on the basis of available tumor tissue. Tumor genomic DNA was retrieved from paraffin-embedded tissue obtained by laser capture microdissection. EGFR mutations in exons 19 and 21 were examined by direct sequencing. RESULTS: EGFR mutations were found in 10 of 83 (12%) of patients. All mutations were found in adenocarcinomas, more frequently in females (P=0.007) and non-smokers (P=0.01). Response was observed in 60% of patients with mutations and 8.8% of patients with wild-type EGFR (P=0.001). Time to progression for patients with mutations was 12.3 months, compared with 3.6 months for patients with wild-type EGFR (P=0.002). Median survival was 13 months for patients with mutations and 4.9 months for those with wild-type EGFR (P=0.02). CONCLUSIONS: EGFR TK mutational analysis is a novel predictive test for selecting lung adenocarcinoma patients for targeted therapy with EGFR TK inhibitors. 相似文献
8.
The epidermal growth factor receptor (EGFR) has emerged as an attractive therapeutic target for patients with non-small-cell lung cancer (NSCLC). However, despite its almost universal presence in NSCLC tumors, therapeutic inhibition of EGFR has resulted in significant tumor regressions in only 10% to 20% of patients. Several investigations over the last 12 months have uncovered somatic mutations in EGFR that underlie the sensitivity to EGFR inhibitors. NSCLC tumors and cell lines with EGFR mutations are exquisitely sensitive to the EGFR tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, and are biologically distinct from other forms of NSCLC. Somatic mutations in EGFR are found more frequently in patients with adenocarcinomas, nonsmokers, patients of Asian ethnicity, and in females. EGFR mutation detection is now becoming clinically available and is being incorporated into clinical treatment decisions and into the design of future clinical trials. Mutations in K-ras, a mediator of EGFR signaling, are mutually exclusive with EGFR mutations, and are associated with resistance to EGFR TKIs. In addition, secondary mutations, conferring resistance to EGFR TKIs, in patients with primary EGFR mutations once sensitive to EGFR TKIs, are beginning to be identified. The frequency of EGFR mutations, their impact on NSCLC biology, clinical treatment, and clinical trial design, as well as methods and limitations for mutation detection, will be reviewed. 相似文献
9.
Chemotherapy continues to play an essential role in the treatment of most stages of non-small-cell lung cancer (NSCLC). In fact, within the past 5 years, this role has greatly expanded into adjuvant therapy for early-stage resected disease. Likewise, agents targeting the epidermal growth factor receptor (EGFR), particularly the tyrosine kinase inhibitors gefitinib and erlotinib, have proven to be clinically active in patients with advanced-stage NSCLC. Because of these findings, it is logical to expect that combinations of these 2 classes of antineoplastic agents would prove more efficacious than either one alone. Yet 4 large randomized phase III trials of chemotherapy with or without an EGFR tyrosine kinase inhibitor in unselected patients with advanced-stage NSCLC, altogether totaling > 4000 patients, did not demonstrate improvement in clinical outcomes with the combination. Whether these negative results will be reproduced in ongoing combination studies of chemotherapy plus monoclonal antibodies directed against EGFR remain to be determined. Herein, we review recent preclinical and clinical data addressing this topic and explore the biologic rationale for developing new combination strategies based on patient selection by molecular and clinical factors, or by pharmacodynamic parameters. 相似文献
11.
Introduction: Epidermal growth factor receptor ( EGFR) mutations are well-described drivers of non-small cell lung cancer (NSCLC) and EGFR tyrosine kinase inhibitors (TKIs) have become key components of the NSCLC front-line treatment landscape. Tumors inevitably develop resistance to these agents, and development efforts continue to focus on identifying mechanisms of resistance and drugs to target these mechanisms. Areas covered: With several EGFR TKIs approved for use in the first-line or in later-line settings, an understanding of the efficacy and safety of these inhibitors in various populations is warranted. Furthermore, given the frequent emergence of drug resistance in NSCLC, examination of tumor tissue throughout the disease course provides the opportunity to select treatments based on the tumor’s mutation profile. Here, we discuss: key efficacy and safety findings for approved and investigational EGFR TKIs; known mechanisms of resistance, particularly the T790M acquired EGFR mutation; and recent advances in EGFR mutational testing that may facilitate less invasive tissue testing and guide treatment selection. Expert commentary: The expanding armamentarium of EGFR TKIs, improvements in the understanding of resistance mechanisms and technological developments in the molecular analysis of tumors may help render EGFR mutation-positive NSCLC a chronic disease in many patients by facilitating optimal sequential therapy. 相似文献
13.
The majority of patients with ovarian cancer, especially those who present with stages IIIC and IV, will relapse soon after completion of platinum-based induction treatment. It is imperative to find ways to improve and/or enhance the efficacy of induction and to prolong the duration of the first remission. The epidermal growth factor receptor (EGFR) family has been exploited, and currently, three agents that directly target this group of receptors are in use in the treatment of colorectal, non-small-cell lung and breast cancers. EGFR and HER2/neu are overexpressed in a significant percentage of epithelial ovarian cancers. Thus, it would be reasonable to explore directly targeted therapy in ovarian cancer. Numerous investigational trials involving a variety of EGFR inhibitors in ovarian cancer are ongoing. Our institution has an active phase II clinical study that seeks to define the role of erlotinib (Tarceva) in potentiating first-line chemotherapy, and to determine whether the drug offers a significant contribution as maintenance therapy. It is hoped that data from these and other studies will help investigators to understand more clearly the biology of ovarian cancer and to delineate the role of EGFR inhibitors in the management of ovarian cancer. 相似文献
14.
First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs. 相似文献
15.
The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers. 相似文献
16.
特异性阻断肿瘤生长的表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌(NSCLC)的治疗中具有极大潜力。目前,有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例,综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。 相似文献
17.
PURPOSE: Gefitinib and erlotinib are small molecules that selectively inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. When these drugs were introduced into the clinic, the specific targets affected in human tumors were unknown. In April 2004, two groups reported that mutations in the tyrosine kinase domain of EGFR are strongly associated with gefitinib sensitivity in patients with non-small-cell lung cancer (NSCLC). We subsequently extended these findings and showed that such mutations are also associated with sensitivity to erlotinib. Here, we present current knowledge about EGFR mutations in the context of clinical trials involving gefitinib and erlotinib in NSCLC. DESIGN: This article reviews the rationale for targeting EGFR, the development of gefitinib and erlotinib, the discovery of EGFR mutations, and subsequent studies to define the incidence, spectrum, and functions of EGFR mutations. RESULTS: The discovery of EGFR mutations promises to alter the ways in which we consider and treat NSCLC. CONCLUSION: This information can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC. 相似文献
18.
特异性阻断肿瘤生长的表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌(NSCLC)的治疗中具有极大潜力。目前,有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例,综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。 相似文献
19.
Despite advances in chemotherapeutics, overall survival for advanced lung cancer patients remains poor. Consequently, efforts have focused on the use of targeted therapies to improve response rates and survival. The epidermal growth factor receptor (EGFR) is overexpressed in a variety of cancers, including lung, and may play a critical role in the pathogenesis of disease. Small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa(R)), have response rates of between 10 and 27% in Phase II trials, and anecdotal reports of dramatic and sustained responses. Two recent studies published simultaneously, identified mutations in the ATP-binding cleft of the EGFR that are associated with clinical response to gefitinib. This finding has extraordinary implications and serves as a critical step toward individualized, patient-specific treatment plans based on the molecular constitution of the tumor of each individual. 相似文献
20.
BACKGROUND: We designed a prospective study to test epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) in resected stage I-IIIA non-small-cell lung cancer (NSCLC) and to correlate overexpression with survival. PATIENTS AND METHODS: EGFR expression was evaluated in 130 consecutive NSCLC patients after radical surgery (60 squamous cell carcinomas, 48 adenocarcinomas, 22 large cell carcinomas: stage I, 41 (31%); stage II, 37 (29%) and stage IIIA, 52 (40%). RESULTS: Overall, 101 of 130 (78%) specimens expressed EGFR, and with a cut-off value of 10% positive cells 48 cases (37%) were classified as positive. At univariate analysis, EGFR was significantly more expressed in stage III (50%) than stage I (20%) and stage II (25%) (P <0.03). No correlation with histotype was found. After a median follow-up of 84 months, both median survival time (18 versus 50 months), 2-year (43% versus 70%) and 5-year (31% versus 46%) survival rates of positive cases were significantly lower than negative ones [P <0.001; hazard ratio 1.96; 95% confidence interval (CI) 1.16-3.30]. At the multivariate analysis, EGFR overexpression and stage emerged as independent factors for cancer-related mortality. CONCLUSION: In patients with radically resected stage I-IIIA NSCLC, EGFR overexpression predicts shorter survival, thus representing a valuable prognostic factor. 相似文献
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