Therapeutic advances in oncology in the 21st century have contributed to significant declines in cancer mortality. Notably, targeted therapies comprised the largest proportion of oncology drugs approved by the United States (US) Food and Drug Administration (FDA) over the past 25 years and have become the standard of care for the treatment of many cancers. However, despite the metamorphosis of the therapeutic landscape, some aspects of cancer drug development have remained essentially unchanged. In particular, the dose-finding methodology originally developed for cytotoxic chemotherapy drugs continues to be implemented, even though this approach no longer represents the most appropriate strategy for modern cancer therapies. In recognition of the need to reconsider assumptions, adapt the dose selection process for newer drugs, and design alternative strategies, the FDA has undertaken several initiatives in recent years to address these concerns. These actions include the launch of Project Optimus in 2021 and the issuance of draft guidance for industry on dose optimization of oncology drugs in 2023. Amid this evolving regulatory environment, the present manuscript reviews case studies for six different targeted cancer therapies, highlighting how dose-finding challenges have been managed to date by oncologists, sponsors, and regulators.
21世纪肿瘤治疗领域的进展显著降低了癌症死亡率。值得注意的是，在过去25年间，靶向治疗药物占美国食品药品监督管理局批准的抗肿瘤药物最大比例，并已成为多种癌症治疗的标准方案。然而，尽管治疗格局发生深刻变革，癌症药物研发的某些环节仍基本沿袭传统模式。特别是最初为细胞毒性化疗药物设计的剂量探索方法至今仍在沿用，尽管该策略已不适用于现代肿瘤治疗。为重新评估传统假设、优化新型药物剂量选择流程并设计替代策略，美国食品药品监督管理局近年来已采取多项举措应对这些问题，包括2021年启动的"Optimus计划"及2023年发布的《肿瘤药物剂量优化行业指南草案》。在此监管环境变革背景下，本文通过六种不同靶向癌症疗法的案例研究，系统阐述临床肿瘤学家、申办方与监管机构迄今应对剂量探索挑战的策略与实践。
Dose Optimization of Targeted Therapies for Oncologic Indications
肿瘤(癌症)患者之家