Antibody–drug conjugates (ADC) are targeted agents that have shown promise in treating cancer. A central challenge in development of ADCs is the relatively narrow therapeutic index observed in clinical studies. Patient selection strategies based on expression of the target in tumors have the potential to maximize benefit and provide the best chance of clinical success; however, implementation of biomarker-driven trials can be difficult both practically and scientifically. We conducted a survey of recent clinical experience from early-phase ADC trials completed between 2000 and 2019 to evaluate the different approaches to patient selection currently being used and assess whether there is evidence that target expression is associated with clinical activity. Our analysis of patient selection strategies indicates that optimal trial design for early-stage trials should be based on multiple factors, including prevalence and heterogeneity of target expression among intent-to-treat patients, as well as biological factors influencing expression of cell surface and soluble target. To ensure a high probability of success, early implementation of patient selection strategies centered around target expression are pivotal to development of ADCs. In this review, we propose a strategic approach that can be applied for optimization of trial design.

中文翻译：

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最大化抗体药物偶联物治疗指数的患者选择策略：先前的方法和未来的方向

抗体-药物偶联物 (ADC) 是在治疗癌症方面显示出前景的靶向药物。ADC 开发的一个核心挑战是临床研究中观察到的相对狭窄的治疗指数。基于肿瘤中靶标表达的患者选择策略有可能使获益最大化并提供临床成功的最佳机会；然而，生物标志物驱动试验的实施在实践和科学上都可能很困难。我们对 2000 年至 2019 年期间完成的早期 ADC 试验的近期临床经验进行了调查，以评估目前使用的不同患者选择方法，并评估是否有证据表明靶标表达与临床活动相关。我们对患者选择策略的分析表明，早期试验的最佳试验设计应基于多种因素，包括意向治疗患者中靶点表达的普遍性和异质性，以及影响细胞表面和可溶性表达的生物学因素。目标。为确保成功的高概率，早期实施以靶标表达为中心的患者选择策略对于 ADC 的开发至关重要。在这篇综述中，我们提出了一种可用于优化试验设计的战略方法。以目标表达为中心的患者选择策略的早期实施对于 ADC 的开发至关重要。在这篇综述中，我们提出了一种可用于优化试验设计的战略方法。以目标表达为中心的患者选择策略的早期实施对于 ADC 的开发至关重要。在这篇综述中，我们提出了一种可用于优化试验设计的战略方法。