Yin Jun, Shen Shihao, Shi Qian
Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.
Dermbiont, Inc., Boston, MA, USA.
Ann Transl Med. 2022 Sep;10(18):1038. doi: 10.21037/atm-22-356.
In the era of precision oncology, improved understanding of tumor heterogeneity, particularly at the molecular level, has caused a shift from traditionally histology based cancer drug development to molecularly targeted drug development. The shift to the molecular view of cancer leads to increasingly small cancer populations for clinical trials which may be underpowered using traditional statistical designs. This paradigm shift lead to the recent developments of innovative clinical trial designs to address the challenges from precision oncology clinical trials. Hence, this paper reviewed and described innovative trial designs for precision oncology. Different strategies were discussed to account patient and treatment effect heterogeneity, including precision dose-finding designs that tailor the optimal dose to different patients at different time points, master protocol designs that match patients' molecular alterations with specific targeted agents, and adaptive enrichment designs that dynamically modify eligibility criteria and enroll patients that are most likely to benefit from the novel agents. Despite their superior performance, better understanding of practical barriers is needed to widen their implementation for precision oncology trials. Therefore, this paper also reviewed the practical challenges regarding the implementation of precision oncology clinical trials, along with the strength and weakness of various approaches of precision oncology clinical trial designs.
在精准肿瘤学时代，对肿瘤异质性（尤其是分子水平的异质性）的深入理解，使得癌症药物研发从传统的基于组织学的模式转向分子靶向药物研发。向癌症分子视角的转变导致用于临床试验的癌症群体越来越小，使用传统统计设计可能无法提供足够的效力。这种范式转变促使了创新临床试验设计的最新发展，以应对精准肿瘤学临床试验带来的挑战。因此，本文回顾并描述了精准肿瘤学的创新试验设计。讨论了不同的策略以应对患者和治疗效果的异质性，包括在不同时间点为不同患者量身定制最佳剂量的精准剂量探索设计、将患者的分子改变与特定靶向药物相匹配的主方案设计，以及动态修改入选标准并招募最有可能从新型药物中获益的患者的适应性富集设计。尽管它们具有卓越的性能，但仍需要更好地理解实际障碍，以扩大其在精准肿瘤学试验中的应用。因此，本文还回顾了精准肿瘤学临床试验实施方面的实际挑战，以及精准肿瘤学临床试验设计各种方法的优缺点。
