Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research.
Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research.
复制标题
DOI：
10.1158/1078-0432.ccr-17-1355
复制
发表时间：
2018-02-15
期刊：
影响因子：
--
通讯作者：
Panageas KS
中科院分区：
文献类型：
--
作者：
Kidwell KM;Postow MA;Panageas KS
研究免疫检查点抑制剂的临床试验已导致美国食品药品监督管理局（FDA）批准抗CTLA-4（细胞毒性T淋巴细胞抗原-4），抗PD-1（程序性死亡-1）和抗PD-L1（PD-配体1）药物用于多种肿瘤类型。在转移性黑色素瘤的治疗中，检查点抑制剂的组合比单药抑制剂更有效，但组合免疫疗法与毒性的频率和严重程度增加相关。关于使用联合免疫疗法或单药抗PD-1作为初始治疗以及维持反应所需的任一方法的剂量数量存在问题。在本文中，我们描述了一种新的使用序贯多分配随机试验（SMART）设计来评估免疫检查点抑制剂，以找到基于中间反应在个体内适应的治疗方案，并导致最长的总生存期。我们为BRAF野生型转移性黑色素瘤提供了一个假设的SMART设计示例，作为研究免疫疗法治疗方案的框架。我们比较了实施SMART设计和实施多个传统的随机临床试验。我们说明了SMART相对于传统试验设计的优势，并承认SMART的复杂性。SMART设计可能是找到产生持久反应，更长生存期和更低毒性的治疗策略的最佳方法。
Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1) and anti-PD-L1 (PD-ligand 1) drugs by the United States Food & Drug Administration (FDA) for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this paper, we describe a novel use of sequential multiple assignment randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity.