Molecular Analysis-Directed Individualised Therapy in Ad

描述（由申请人提供）：非小细胞肺癌（NSCLC）患者的临床管理进展缓慢，5年生存率仅为14%，5年生存率被用作该疾病假定治愈的基准。原因是大多数患者处于疾病的晚期，此时对化疗的反应率（25-35%）较低，尽管有几种较新的药物可用，但完全缓解和长期部分缓解罕见。显然，需要一种创新和新颖的治疗策略来提高这种疾病的生存率。最近在确定NSCLC不良结局的分子决定因素方面取得的进展为基于个体患者肿瘤分子谱的治疗决策提供了希望。我们假设，根据患者肿瘤的分子特征选择化疗方案，可以提高晚期NSCLC患者的缓解率、中位生存率和1年生存率。我们和其他人的研究结果表明，肺癌患者的预后与ERCC 1和RRMI基因的表达密切相关。ERCC 1和RRM 1基因的高表达分别预示着对铂类药物和吉西他滨的耐药性。使用ERCC 1和RRM 1作为化疗反应和生存的预测标志物，我们设计了一项II期临床研究。目的是确定新诊断的晚期NSCLC患者的缓解率（RR），这些患者接受基于ERCC 1表达和RRM 1表达分配的化疗方案治疗。在治疗之前，我们将测量患者肿瘤中ERCC 1和RRM 1的表达水平，在此基础上，患者将被分配特定的双重化疗。治疗后，缓解率将作为主要终点进行评估。治疗疗效的其他指标是使用这种合理算法方法治疗的晚期NSCLC患者的无进展生存期（PFS）、中位生存期（MS）和1年生存期（1年S）。将对患者进行随访直至死亡，并生成生存曲线。

DESCRIPTION (provided by applicant): Advances in the clinical management of patients with non-small-cell lung cancer (NSCLC) have been slow, and the 5-year survival, which is used as a benchmark for putative cure from this disease, is only 14%. Reasons are that most patients present in advanced stages of the disease when response rates (25-35%) to chemotherapy are low and complete and prolonged partial remissions rare, despite the availability of several newer agents. Clearly an innovative and novel therapeutic strategy is needed to improve survival in this disease. Recent advances in the identification of molecular determinants of poor outcome from NSCLC hold the promise for therapeutic decisions based on individual patients' tumor's molecular profile. We hypothesize that we will improve response rates, median, and 1-year survival in patients with advanced NSCLC by treating with chemotherapy selected on the basis of the patient's tumor's molecular profile. Results generated by us and others suggest that the outcome of patients with lung cancer is closely associated with expression of the genes ERCC1 and RRMI. High ERCC1 and RRM1 gene expression predicts for resistance to platinum agents and gemcitabine, respectively. Using ERCC1 and RRM1 as predictive markers for chemotherapy response and survival we designed a phase II clinical study. The goal is to determine the response rates (RR) in newly diagnosed patients with advanced NSCLC who are treated with a chemotherapeutic regimen assigned to them on the basis of ERCC1 expression and RRM1 expression. Prior to treatment we will measure the level of ERCC1 and RRM1 expression in the patient's tumor, on the basis of which the patient will be assigned specific doublet chemotherapy. After treatment, response rates will be assessed as primary endpoint. Additional measures of treatment efficacy are progression free survival (PFS), median survival MS), and 1-yr survival(1-yr S) in patients with advanced NSCLC treated using this rational algorithmic approach. Patients will be followed till death and survival curves will be generated.