Over the past two decades, targeted therapies have become cornerstone treatments for numerous cancers with oncogene addiction. Unfortunately, their effectiveness reduces over time and most patients who receive targeted therapies relapse within 12 months. The emergence of drug-resistance mechanisms in tumours paved the way for next-generation inhibitors. However, insufficient concentration of targeted therapy is a frequent but poorly explored mechanism of treatment failure. Additionally, the maximum tolerated dose (MTD) is not always reached in phase studies, and the recommended phase 2 dose is mostly based on benefit–risk ratio and pharmacokinetic considerations, which could result in a suboptimal dose. This scenario has led us to propose a new concept in clinical drug development: the late phase 1 study. The primary goal of this type of trial is to define an alternative MTD of a drug in patients who are chronically exposed and had an initial benefit from targeted therapy but subsequently progressed without an identified resistance alteration. Intrapatient dose escalation might increase drug concentration and restore drug activity or efficacy.

在过去的二十年中，靶向治疗已成为许多致癌基因成瘾癌症的基石治疗方法。不幸的是，它们的有效性会随着时间的推移而降低，大多数接受靶向治疗的患者会在 12 个月内复发。肿瘤耐药机制的出现为下一代抑制剂铺平了道路。然而，靶向治疗浓度不足是治疗失败的常见但探索不足的机制。此外，在阶段研究中并不总能达到最大耐受剂量 (MTD)，推荐的 2 期剂量主要基于获益风险比和药代动力学考虑，这可能会导致次优剂量。这种情况导致我们提出了临床药物开发的新概念：后期 1 期研究。此类试验的主要目标是为长期暴露并从靶向治疗中获得初始益处但随后进展而没有确定耐药性改变的患者定义一种药物的替代 MTD。患者体内剂量递增可能会增加药物浓度并恢复药物活性或疗效。