Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.

中文翻译：

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肿瘤学临床试验中事件发生时间终点分析的统计注意事项：CAR-T 免疫疗法研究插图

嵌合抗原受体 T 细胞 (CAR-T) 疗法是癌症免疫学领域令人兴奋的发展，近年来引起了广泛关注。CAR-T 研究中分析了许多与复发、疾病进展和缓解相关的事件发生时间 (TTE) 终点，以评估治疗效果。这些 TTE 终点的定义并不总是一致的，即使对于相同的结果（例如，无进展生存期）也是如此，这通常源于关于将哪些事件视为复合终点的一部分、分析中的审查或竞争风险的分析选择。造血干细胞移植等后续疗法很常见，但不同研究中的治疗方法并不相同。标准生存分析方法通常应用于 TTE 分析，但通常没有充分考虑所选分析中固有的假设。我们强调了 CAR-T 研究以及肿瘤学其他环境中出现的 TTE 分析的两个重要问题：竞争风险的处理以及评估时变（输注后）暴露与 TTE 结果之间的关联。我们回顾了现有的分析方法，包括用于分析竞争风险的累积发生函数和回归模型，以及用于分析输注后暴露的里程碑和时变协变量分析。我们阐明了不同分析方法所解决的科学问题，并使用多项已发表的 CAR-T 研究的数据说明了应用不适当的方法如何导致不同的结果。提供了在标准统计软件中实施这些方法的代码。