Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain; Molecular Therapeutics Research Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Drug Development Program, Department of Medical Oncology and Haematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada.
Ann Oncol. 2018 Aug 1;29(8):1727-1740. doi: 10.1093/annonc/mdy225.
The classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-in-human trials include unusually big expansion cohorts in the search for early signs of activity and rapid regulatory approval. The fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. In this review, we discuss critical issues and caveats in immunotherapy development. A particular emphasis is put on the limitations of pre-clinical toxicology studies, where both murine models and cynomolgus monkeys have underpredicted toxicity in humans. Moreover, relevant issues surrounding dose determination during phase I trials, such as dose-escalation methods or flat versus body-weight dosing, are discussed. A proposal of how to face these different challenges is offered, in order to achieve maximum efficacy with minimum toxicity for our patients.
药物的经典开发已经逐渐式微，我们目前正处于无缝药物开发的时代，首次人体试验包括不寻常的大扩展队列，以寻找早期活动迹象和快速监管批准。不同制药公司之间的激烈竞争和对免疫联合治疗的炒作迫使我们质疑我们目前评估这些药物的方式。在这篇综述中，我们讨论了免疫治疗开发中的关键问题和注意事项。特别强调了临床前毒理学研究的局限性，其中包括小鼠模型和食蟹猴在预测人类毒性方面都存在不足。此外，还讨论了 I 期试验中确定剂量的相关问题，如剂量递增方法或固定剂量与体表面积剂量。提出了如何应对这些不同挑战的建议，以便为我们的患者实现最大疗效和最小毒性。
