Pharma Mar S.A, Avda. de los Reyes, 1, Polígono Industrial "La Mina", 28770, Colmenar Viejo (Madrid, Spain.
Healthcotrials, Madrid, Spain.
Cancer Chemother Pharmacol. 2022 Oct;90(4):285-299. doi: 10.1007/s00280-022-04467-7. Epub 2022 Aug 27.
During the last decade, the treatment for many cancer indications has evolved due to intensive clinical research into anti-tumor agents' combination. In most instances, new combination treatments consist of an add-on to the standard of care (SOC), which then demonstrate a substantial gain in efficacy and no detrimental effect in tolerability. In the era of targeted therapies, for which maximum tolerated dose (MTD)-based dosing strategies are no longer applicable, early stage studies exploring new combinations are often conducted in the population of interest, expediting the collection of preliminary safety data, to be promptly expanded to collect preliminary efficacy data. Nevertheless, rule-based dose-finding studies are still a prevailing approach for early stage cancer, especially for chemotherapy (CT)-containing combinations. Pharmacokinetic (PK) assessments play a key role throughout the clinical development of drug combinations, informing potential PK interactions. But most importantly, they allow the development of innovative exposure-response (E-R) models aimed at exploring the contribution of each agent to the overall effect of the combination therapy. This review identifies 81 new drug combinations approved by the United States Food and Drug Administration (FDA) for hemato-oncology during the 2011-2021 period and summarizes the main design features of clinical trials and the role of PK assessments.
在过去的十年中，由于对抗肿瘤药物联合治疗的深入临床研究，许多癌症适应症的治疗方法发生了变化。在大多数情况下，新的联合治疗方案是在标准治疗（SOC）的基础上增加一种药物，从而在疗效上有显著提高，且在耐受性方面没有不良影响。在靶向治疗时代，最大耐受剂量（MTD）为基础的剂量策略不再适用，因此，在目标人群中进行探索新联合治疗的早期研究通常可以更快地收集初步安全性数据，并及时扩展以收集初步疗效数据。然而，基于规则的剂量探索研究仍然是早期癌症的主要方法，尤其是含有化疗药物（CT）的联合治疗。药代动力学（PK）评估在药物联合开发的整个过程中起着关键作用，为潜在的 PK 相互作用提供信息。但最重要的是，它们允许开发创新的暴露-反应（E-R）模型，旨在探索每个药物对联合治疗总体效果的贡献。本文确定了 2011 年至 2021 年期间美国食品和药物管理局（FDA）批准用于血液肿瘤学的 81 种新的药物联合治疗，并总结了临床试验的主要设计特点和 PK 评估的作用。
