Neoadjuvant Therapy as a Platform for Drug Development and Approval in Breast Cancer
Neoadjuvant Therapy as a Platform for Drug Development and Approval in Breast Cancer
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DOI：
10.1158/1078-0432.ccr-13-0916
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发表时间：
2013-12-01
影响因子：
11.5
通讯作者：
Baselga, Jose
中科院分区：
文献类型：
--
作者：
Bardia, Aditya;Baselga, Jose
基于大型III期研究的传统乳腺癌药物开发过程具有严重的局限性，需要进行重大改革。寻找新的方法，在术前（新辅助）设置方法中测试新药物提供了一种潜在的快速和有效的策略，用于药物开发，利用病理完全缓解（路径CR），生存的替代标志物，作为主要终点。此外，新辅助研究允许评估药物对靶点的影响（药效学反应）和开发反应的预测性生物标志物。手术标本中残留肿瘤的分子特征也可以提供对耐药机制的见解。认识到新辅助治疗试验对药物开发的潜力，美国卫生部。S.美国食品和药物管理局（FDA）最近宣布考虑新辅助试验，以加速早期乳腺癌的药物批准，特别是对于复发风险高和预后不良的肿瘤，并于2013年9月提供了新辅助帕妥珠单抗的加速批准。FDA强调，虽然路径CR的改善可以用于“加速”批准，但生存率的改善仍需要证明才能获得“常规”批准。进行此类新辅助药物开发试验的关键考虑因素包括（i）研究设计，例如利用生物标志物分层设计来评价可丰富缓解的生物标志物，（ii）路径CR的定义，（iii）影响治疗组之间路径CR的因素分布，（iv）预先指定的随访计划，以获得生存数据，以及（v）安全性，因为它涉及具有可治愈疾病的患者群体。在未来的几年里，我们预计新辅助治疗试验的数量会增加，这些新辅助治疗试验有望为乳腺癌患者带来有效的新疗法开辟一条新的道路。临床癌症研究; 19（23）; 6360-70。(C)2013年AACR。
The traditional drug development process in breast cancer based on large phase III studies has serious limitations and needs a major overhaul. Searching for new approaches, the testing of novel agents in the preoperative (neoadjuvant) setting approach offers a potentially rapid and efficient strategy for drug development utilizing pathologic complete response (path CR), a surrogate marker for survival, as the primary endpoint. In addition, neoadjuvant studies allow the assessment of drug effects on the target (pharmacodynamic response) and the development of predictive biomarkers of response. Molecular profiling of the residual tumor in the surgical specimen may also provide insights into actionable mechanisms of resistance. Recognizing the potential of neoadjuvant trials for drug development, the U. S. Food and Drug Administration (FDA) recently announced consideration of neoadjuvant trials for accelerated drug approval in early breast cancer, particularly for tumors with high risk of recurrence and unfavorable prognosis, and provided accelerated approval to neoadjuvant pertuzumab in September 2013. The FDA has emphasized that while improvement in path CR could be utilized for "accelerated" approval, improvement in survival will still need to be demonstrated for "regular" approval. Key considerations in conduct of such neoadjuvant drug development trials include (i) study design such as utilization of biomarker stratified design to evaluate a biomarker that could enrich response, (ii) definition of path CR, (iii) distribution of factors that influence path CR between the treatment arms, (iv) prespecified plan for follow-up to obtain data on survival, and (v) safety as it involves a patient population with curable disease. In the years to come, we anticipate an increase in the number of neoadjuvant trials testing novel therapies that hopefully will open a new path in bringing efficacious new therapies to patients with breast cancer. Clin Cancer Res; 19(23); 6360-70. (C) 2013 AACR.