Correlation of EGFR Mutations and Response to Gefitinib

描述（由申请人提供）：吉非替尼是一种EGFR TKI，在美国未选择的晚期NSCLC患者中应答率为10%。然而，非吸烟者或具有细支气管肺泡肺癌特征的NSCLC患者应答率为25-50%。目前，这种“靶向”治疗被用于晚期NSCLC患者，而不管EGFR信号是否是肿瘤生长的关键驱动因素。最近的数据表明，在对晚期NSCLC患者进行的小型回顾性研究中，EGFR酪氨酸激酶结构域的突变与疗效相关。这是一项前瞻性研究，研究对象为I期和II期NSCLC患者，这些患者具有与对吉非替尼“丰富”反应相关的特征（从不或很少吸烟和BAG特征）。本研究将对50例手术候选者进行治疗；我们将在吉非替尼治疗前通过核心活检获得新鲜的冷冻组织，之后患者将在术前接受至少21天的吉非替尼治疗。患者将在吉非替尼治疗后通过重复CT扫描评估疗效，随后进行手术切除；额外的新鲜冷冻组织将在手术中获得。对吉非替尼治疗有反应的患者和/或从核心活检中发现EGFR突变的患者将在术后继续“维持”吉非替尼2年。本研究的主要终点是：(1)在I/II期NSCLC患者中，EGFR基因酪氨酸激酶结构域突变的存在与放射学反应的前瞻性关联；(2)通过瞬时转染试验中磷酸酪氨酸活性和EGFR的自磷酸化来评估特定突变的激酶活性，并与野生型EGFR相比，对吉非替尼的敏感性。次要终点是(1)鉴定吉非替尼治疗前后基因表达变化的基因或基因簇，利用微阵列分析鉴定敏感和耐药肿瘤之间基因表达的显著差异；(2)确定接受“维存性”吉非替尼治疗的l/ll期NSCLC患者的复发时间和生存期。进一步表征含有这些突变的肿瘤，可能对非小细胞肺癌患者具有重要的治疗意义，并改变我们治疗非小细胞肺癌患者的模式。

DESCRIPTION (provided by applicant): Gefitinib is an EGFR TKI with a response rate of 10% in unselected patients with advanced NSCLC in the U.S. However, patients with NSCLC who are never smokers or have features of bronchioloalveolar lung cancer have response rates of 25-50%. At present, this "targeted" therapy is given to patients with advanced NSCLC regardless of whether EGFR signaling is a critical driver of their tumor's growth. Recent data would suggest that mutations in the EGFR tyrosine kinase domain correlate with response in small retrospective studies conducted in patients with advanced NSCLC. This is a prospective study in patients with Stage I and II NSCLC who have features that correlate with response (never or minimal smokers and features of BAG) to "enrich" for response to gefitinib. Fifty patients who are candidates for surgery will be treated on this study; we will obtain fresh frozen tissue by core biopsy before treatment with gefitinib after which patients will be treated with at least 21 days of gefitinib pre-operatively. Patients will be assessed for response by repeat CT scan after gefitinib therapy and subsequently undergo surgical resection; additional fresh frozen tissue will be procured at surgery. Patients with a response to gefitinib therapy and/or patients with EGFR mutations identified from core biopsy will continue "maintenance" gefitinib for 2 years after surgery. The primary endpoints of this study are (1) Correlate the presence of mutations in the tyrosine kinase domain of EGFR gene and radiographic response prospectively in patients with Stage I/II NSCLC patients; (2) Determine kinase activity of specific mutations as assessed by phosphotyrosine activity and autophosphorylation of EGFR in transient transfection assays and sensitivity to gefitinib as compared to wild-type EGFR. Secondary Endpoints are (1) Identify gene(s) or gene clusters that exhibit changes in gene expression before and after treatment with gefitinib, and identify significant differences in gene expression between sensitive and resistant tumor, using microarray analysis; (2) Determine time to recurrence and survival in patients with Stage l/ll NSCLC patients treated with "maintenance" gefitinib. Further characterization of tumors harboring these mutations, may have significant therapeutic implications for patients with NSCLC and change the paradigm whereby we treat patients with NSCLC.