Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: Focus on NSCLC
Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: Focus on NSCLC
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DOI：
10.1016/j.ijrobp.2003.09.099
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发表时间：
2004-03-01
影响因子：
7
通讯作者：
Langer, CJ
中科院分区：
文献类型：
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作者：
Langer, CJ
联合化疗方案已成为晚期非小细胞肺癌的标准方法。荟萃分析表明，与最佳支持治疗相比，铂类药物治疗后的中位生存期增加了2个月，1年生存率绝对提高了10%。同样重要的是，细胞毒性疗法在症状控制和生活质量方面产生了益处。较新的药物，包括紫杉烷类、长春瑞滨、吉西他滨和伊立替康，扩大了我们治疗晚期非小细胞肺癌的选择。尽管他们的贡献，我们已经达到了一个治疗平台，反应率很少超过30-40%的合作组研究和1年生存率稳定在30%和40%之间。以各种组合用一种药物替代另一种药物是否会导致这些比率的任何进一步改善是值得怀疑的。靶向治疗是目前研究的重点，抑制表皮生长因子受体是最有前途的临床策略之一。目前正在研究的表皮生长因子受体抑制剂包括小分子吉非替尼（易瑞沙，ZD 1839）和厄洛替尼（特罗凯，OSI-774），以及单克隆抗体，如西妥昔单抗（IMC-225，爱必妥）。仅开始进行临床评价的药物包括CI-1033（一种不可逆的pan-erbB酪氨酸激酶抑制剂）和PK 1166和GW 572016（两种双重激酶抑制剂（抑制表皮生长因子受体和Her 2））。临床前模型已经证明了所有这些药物与化疗或放疗联合使用的协同作用，这使得人们对它们对肺癌治疗的最终贡献产生了极大的热情。然而，严重的临床挑战仍然存在。这些包括确定最佳剂量;将这些药物适当整合到流行的、已建立的细胞毒性方案中;以及选择测试这些化合物的最佳环境。吉非替尼和厄洛替尼在预治疗的晚期非小细胞肺癌中均显示出临床活性，但令我们懊恼的是，评估吉非替尼联合标准细胞毒性治疗的安慰剂对照随机III期研究未能证明与单独化疗相比的生存优势。(C)2004年爱思唯尔公司
Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, genicitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PK1166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds. Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone. (C) 2004 Elsevier Inc.