Chemotherapy and anti-EGFR Antibody C225 in Lung Cancer

有强有力的实验证据表明，表皮生长因子受体（EGFR）的信号转导途径起着重要的作用，作为一种细胞的生存机制，并维持某些上皮恶性肿瘤的生长。 EGFR在约60%的非小细胞肺癌（NSCLC）肿瘤中过表达。C225是一种人源化单克隆抗体，通过与EGF竞争结合EGFR特异性抑制EGFR功能，从而导致细胞生长抑制。 在体内实验系统中，已显示C225可使表达EGFR的肿瘤对多种细胞毒性剂的作用特异性敏感。现在还有新的临床证据表明，C225可以使顺铂耐药的头颈部肿瘤对顺铂敏感。在三项独立的随机试验中，手术切除后的新辅助化疗已被证明可改善IIIA期NSCLC患者的生存率。 然而，所用方案的病理完全缓解率在5%至11%之间。 可以合理地假设，新辅助治疗方案将导致更高的病理学完全缓解率，从而进一步改善这些患者的生存率。在这个提议中，我们将测试C225与紫杉烷类和铂类药物在具有激活的EGFR信号转导通路的NSCLC肿瘤中协同作用的假设。 为此目的：1）我们将在裸鼠中研究紫杉烷/铂+/- C225在一系列人NSCLC异源移植物中的抗肿瘤活性，并将鉴定协同作用的分子决定因素; 2）我们将在IIIA期NSCLC肿瘤患者中进行紫杉烷/铂+ C225新辅助治疗的II期临床研究，使用20%的病理学完全缓解作为主要终点。 临床研究的入选标准将包括表达协同作用的分子决定簇的肿瘤，如编号1所示。 在临床研究的背景下，我们将病理学反应的程度与治疗前和治疗后肿瘤的EGFR活化状态相关联。拟定研究的结果将表明该联合治疗NSCLC的潜力，确定更可能对该联合治疗产生反应的特定肿瘤亚组，并最终证明在随机临床试验中对假设进行明确检验的合理性。

There is strong experimental evidence that the epidermal growth factor receptor (EGFR) signal transduction pathway plays an important role as a cell survival mechanism and to sustain the growth of certain epithelial malignancies. EGFR is overexpressed in about 60 percent of non-small cell lung cancer (NSCLC) tumors. C225 is a humanized monoclonal antibody that specifically inhibits EGFR function by competing with EGF for binding to EGFR, thus resulting in cell growth inhibition. C225 has been shown to specifically sensitize tumors expressing EGFR to the effects of a variety of cytotoxic agents in in vivo experimental systems. There is also now emerging clinical evidence that C225 can sensitize cisplatin-resistant head and neck tumors to cisplatin. Neoadjuvant chemotherapy followed by surgical resection has been shown to improve the survival of patients with stage IIIA NSCLC in three separate randomized trials. However, the pathological complete remission rate with the regimens used ranges between 5 and 11 percent. It is reasonable to assume that a neoadjuvant regimen that would result in a higher rate of pathological complete response would further improve the survival of these patients. In this proposal, we will test the hypothesis that C225 synergizes with taxanes and platinum drugs in NSCLC tumors that have an activated EGFR signal transduction pathway. For that purpose: 1) we will study the antitumor activity of taxane/platinum +/- C225 in a series of human NSCLC heterotransplants in nude mice and will identify the molecular, determinants of synergism; and 2) we will conduct a Phase II clinical study of neoadjuvant taxane/platinum + C225 in patients with stage IIIA NSCLC tumors using a 20 percent pathological complete response as primary endpoint. Entry criteria for the clinical study will include tumors expressing the molecular determinants of synergism identified under number 1. In the context of the clinical study, we will correlate the degree of pathological response with the pre- and post-therapy EGFR activation status of the tumors. The results of the studies proposed will indicate the potential of this combination in the treatment of NSCLC, identify the specific subsets of tumors that are more likely to respond to this combination, and eventually justify the definitive testing of the hypothesis in a randomized clinical trial.