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）信号转导通路作为细胞存活机制和维持某些上皮恶性肿瘤的生长起着重要作用。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竞争与EGFR结合，特异性抑制EGFR功能，从而抑制细胞生长。在体内实验系统中，C225已被证明能特异性地使表达EGFR的肿瘤对多种细胞毒性药物的作用敏感。现在也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。三个独立的随机试验表明，手术切除后的新辅助化疗可提高IIIA期非小细胞肺癌患者的生存率。然而，病理完全缓解率在5%到11%之间。我们有理由认为，新辅助治疗方案会导致更高的病理完全缓解率，从而进一步提高这些患者的生存率。在本提案中，我们将在EGFR信号转导通路激活的NSCLC肿瘤中验证C225与紫杉烷类和铂类药物协同作用的假设。为此：1)我们将研究紫杉烷/铂+/- C225在裸鼠非小细胞肺癌异源移植中的抗肿瘤活性，并确定协同作用的分子决定因素；2)我们将在IIIA期NSCLC肿瘤患者中进行一项新辅助紫杉烷/铂+ C225的II期临床研究，以20%的病理完全缓解为主要终点。临床研究的进入标准将包括表达第1条中确定的协同作用分子决定因素的肿瘤。在临床研究的背景下，我们将病理反应的程度与治疗前后肿瘤的EGFR激活状态相关联。提出的研究结果将表明这种联合治疗非小细胞肺癌的潜力，确定更有可能对这种联合治疗产生反应的特定肿瘤亚群，并最终在随机临床试验中证明该假设的明确检验是正确的。

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.