EGFR Mutations in Non-Small Cell Lung Cancer

描述（由申请人提供）：2011年美国221,130例肺癌病例中，非小细胞肺癌（NSCLC）约占85%。化疗和靶向单克隆抗体化疗对非小细胞肺癌患者仍然适度有效。因此，需要更有效的靶向药物来全身治疗不同的非小细胞肺癌，以及与治疗获益相关的生物标志物。2004年发现表皮生长因子受体（EGFR）体细胞突变与EGFR酪氨酸激酶抑制剂吉非替尼和厄洛替尼的临床疗效之间存在关联。随后在日本、中国、东亚和欧洲进行的临床研究显示，与以铂为基础的全身化疗相比，用吉非替尼或厄洛替尼治疗EGFR突变的NSCLC患者的反应和无进展生存期高2-3倍，毒性更小。在美国、欧洲和世界各地，需要更多的NSCLC和EGFR突变患者使用不同的EGFR抑制剂治疗的信息。此外，还需要确定耐药机制，确定克服对EGFR抑制剂耐药的方法，并改进抑制剂。该研究的目的是前瞻性地验证晚期NSCLC患者获得性耐药突变和基因组变化的频率和类型，以及EGFR抑制剂治疗的EGFR体致敏突变。在世界范围内对EGFR抑制剂治疗的NSCLC患者的EGFR突变的研究将确定EGFR突变、治疗反应、无进展生存和欧洲种族背景和东亚种族背景的接受厄洛替尼和吉非替尼治疗的NSCLC患者生存之间的关系。肺癌细胞系不同治疗方法的实验和对EGFR抑制剂获得性耐药模型将通过研究从对EGFR酪氨酸激酶抑制剂有临床耐药的患者身上采集或建立的肿瘤和肿瘤细胞系来完成。这将有助于开发更有效的EGFR抑制剂，无论是单独使用还是联合使用

DESCRIPTION (provided by applicant): Non-small cell lung (NSCLC) cancer is responsible for approximately 85% of the 221,130 lung cancer cases in the US in 2011. Chemotherapy and chemotherapy with targeted monoclonal antibodies for patients with NSCLC remain modestly effective. Therefore, more effective targeted agents are needed for systemic therapy of different NSCLCs as well as the biomarkers associated with treatment benefit. The association between somatic mutations in the epidermal growth factor receptor (EGFR) and the clinical efficacy of the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, was discovered in 2004. Subsequent clinical studies done in Japan, China, East Asia, and Europe showed NSCLC patients with EGFR mutations treated with gefitinib or erlotinib have a 2-3 fold greater response and progression-free survival with less toxicity than those treated with platinum-based systemic chemotherapy. Further information is needed about patients with NSCLC and EGFR mutations treated with the different EGFR inhibitors in the US, Europe, and around the world. In addition, defining the mechanisms of resistance, identifying means of overcoming resistance to EGFR inhibitors, and improvements in the inhibitors are needed. The aims of the study are to prospectively validate the frequency and type of acquired resistance mutations and genomic changes arising in subjects with advanced NSCLC and somatic sensitizing mutations of EGFR treated with EGFR inhibitors. Studies of EGFR mutations in NSCLC patients treated with EGFR inhibitors around the world will define the relationship between EGFR mutations, response to treatment, progression-free survival, and survival in subjects with NSCLC treated with erlotinib and gefitinib in subjects with European ethnic background and those from East Asia. The experiments on different therapeutic approaches in lung cancer cell lines and models of acquired resistance to EGFR inhibitors will be done by studying tumors and tumor cell lines harvested or established from patients with clinical resistance to EGFR tyrosine kinase inhibitors. This will facilitate the development of more effective EGFR inhibitors either alone, or with other tyrosine kinase inhibitors and additional targeted agents.