Correlation of EGFR Mutations and Response to Gefitinib

描述（由申请方提供）：吉非替尼是一种EGFR TKI，在美国晚期NSCLC的NSCLC患者中的缓解率为10%。然而，从不吸烟或具有细支气管肺泡肺癌特征的NSCLC患者的缓解率为25- 50%。目前，这种“靶向”治疗用于晚期NSCLC患者，无论EGFR信号是否是肿瘤生长的关键驱动因素。最近的数据表明，在晚期NSCLC患者中进行的小型回顾性研究中，EGFR酪氨酸激酶结构域突变与缓解相关。这是一项在I期和II期NSCLC患者中进行的前瞻性研究，这些患者具有与吉非替尼“富集”应答相关的特征（从不吸烟或最少吸烟者和BAG特征）。本研究将对50名手术候选患者进行治疗;在吉非替尼治疗前，我们将通过芯活检获得新鲜冷冻组织，之后患者将在术前接受至少21天的吉非替尼治疗。在吉非替尼治疗后，将通过重复CT扫描评估患者的反应，随后进行手术切除;手术时将获得额外的新鲜冷冻组织。对吉非替尼治疗有反应的患者和/或从核心活检中鉴定出EGFR突变的患者将在手术后继续“维持”吉非替尼2年。本研究的主要终点是（1）在I/II期NSCLC患者中前瞻性地将EGFR基因酪氨酸激酶结构域突变的存在与放射学缓解相关联;（2）通过瞬时转染试验中EGFR的磷酸酪氨酸活性和自磷酸化评估确定特定突变的激酶活性，以及与野生型EGFR相比对吉非替尼的敏感性。次要终点是（1）使用微阵列分析鉴定在用吉非替尼治疗之前和之后表现出基因表达变化的基因或基因簇，并鉴定敏感性和抗性肿瘤之间基因表达的显著差异;（2）确定用“维持”吉非替尼治疗的I/II期NSCLC患者的复发时间和存活率。进一步表征携带这些突变的肿瘤，可能对NSCLC患者具有重要的治疗意义，并改变我们治疗NSCLC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.