Division of Hematology/Oncology, Rush University Medical Center, Chicago, IL, USA.
Cancer. 2010 Mar 1;116(5):1155-64. doi: 10.1002/cncr.24815.
Many different targeted therapies with varying mechanisms of action have been added to standard first-line chemotherapy doublets in an effort to improve survival of patients with advanced nonsmall cell lung cancer (NSCLC). Only 2 targeted therapies-bevacizumab and cetuximab-have been associated with superior survival in phase 3 first-line studies. For both agents, the decision to enter phase 3 was based on results from randomized phase 2 trials, unlike other targeted therapies where the decision was made using either phase 1 or single study arm phase 2 results. There is also mounting evidence that patient selection will play a key role in the successful development of any targeted agent. Bevacizumab is indicated for patients with nonsquamous NSCLC who do not have certain comorbidities. Use of cetuximab is not restricted by safety factors, but may be focused on patients whose tumors are epidermal growth factor receptor (EGFR)-dependent; whether EGFR expression or absence of KRAS mutations are appropriate markers is still under study. By including randomized phase 2 trials in the development pathway, and by improving patient selection for individual agents (enriching trials with patients most likely to respond), it may be possible to enhance the success rate of future phase 3 clinical trials and, in turn, define future clinical practice with improved patient outcomes.
为了提高晚期非小细胞肺癌（NSCLC）患者的生存率，许多不同作用机制的靶向治疗药物已被添加到标准一线化疗双联方案中。在 3 期一线研究中，只有 2 种靶向治疗药物——贝伐珠单抗和西妥昔单抗——与生存获益相关。对于这两种药物，进入 3 期的决定是基于随机 2 期试验的结果，而其他靶向药物则是基于 1 期或单臂 2 期研究结果做出的决定。越来越多的证据表明，患者选择将在任何靶向药物的成功开发中发挥关键作用。贝伐珠单抗适用于没有某些合并症的非鳞状 NSCLC 患者。西妥昔单抗的使用不受安全性因素的限制，但可能集中在肿瘤依赖表皮生长因子受体（EGFR）的患者；EGFR 表达或 KRAS 突变缺失是否是合适的标志物仍在研究中。通过在开发途径中纳入随机 2 期试验，并通过改善对个体药物的患者选择（用最有可能有反应的患者丰富试验），有可能提高未来 3 期临床试验的成功率，并相应地通过改善患者预后来定义未来的临床实践。
