探讨晚期黑色素瘤患者的总生存期（OS）、无进展生存期（PFS）和客观缓解率（ORR）之间的关系。
Exploring the relationship between Overall Survival (OS), Progression Free Survival (PFS) and Objective Response Rate (ORR) in patients with advanced melanoma.
机构信息
U.S. Food and Drug Administration.
出版信息
Cancer Treat Res Commun. 2021;26:100272. doi: 10.1016/j.ctarc.2020.100272. Epub 2020 Dec 10.
PURPOSE
From 2011 to 2016, 13 randomized clinical trials with active controls were submitted to U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma. While regular approval is generally granted due to a substantial improvement in overall survival (OS), or a large, clinically meaningful improvement in progression-free survival (PFS), accelerated approval can be granted based on incremental change in a surrogate end point reasonably likely to predict clinical benefit, such as objective response (ORR) of large magnitude and long duration. However, the relationship between objective response rate and progression free survival or objective response rate and overall survival in advanced melanoma has not been established.
PATIENTS AND METHODS
We conducted analyses to assess the correlation of objective response rate with progression free survival as well as overall survival by examining all advanced melanoma trials submitted to the FDA between 2011 and 2016. In order to examine these relationships, associations between trial-level hazard ratio (HR) of progression free survival, hazard ration of survival and odds ratio of objective response rate were analyzed using a weighted linear regression model. Patient-level responder analyses comparing progression free survival and overall survival between patients with and without an objective response were performed using pooled data from all studies.
RESULTS
In the trial-level analysis, the linear relationships between progression free survival and objective response rate, and overall survival and objective response rate were weak (R² = 0.019 and 0.093, respectively). The linear relationship between overall survival and progression free survival (R² = 0.075) was also weak. In the patient-level responder analyses, patients who achieved a response had better progression free survival and overall survival compared with non-responders in both the control drug treatment and the experimental drug treatment.
CONCLUSION
Based on this analysis, use of objective response rate as a surrogate endpoint for overall survival or progression free survival in this population appears not appropriate. However, due to the nature of heterogeneity, interpretation needs to be cautious.
目的
从 2011 年到 2016 年，有 13 项针对晚期黑色素瘤的积极对照随机临床试验提交给了美国食品和药物管理局（FDA）。虽然通常由于总生存期（OS）的显著改善，或者无进展生存期（PFS）的大幅且有临床意义的改善而给予常规批准，但也可以基于替代终点的增量变化来加速批准，这些变化合理地预示着临床获益，例如大而持久的客观缓解率（ORR）。然而，晚期黑色素瘤中的客观缓解率与无进展生存期或客观缓解率与总生存期之间的关系尚未确定。
患者和方法
我们通过检查 2011 年至 2016 年期间提交给 FDA 的所有晚期黑色素瘤试验，进行了分析以评估客观缓解率与无进展生存期以及总生存期之间的相关性。为了研究这些关系，使用加权线性回归模型分析了试验水平的无进展生存风险比（HR）、生存风险比和客观缓解率的比值之间的关联。使用来自所有研究的汇总数据，对有和无客观缓解的患者之间的无进展生存期和总生存期进行了患者水平的应答者分析。
结果
在试验水平的分析中，无进展生存期和客观缓解率之间以及总生存期和客观缓解率之间的线性关系较弱（R²分别为 0.019 和 0.093）。总生存期和无进展生存期之间的线性关系也较弱（R²为 0.075）。在患者水平的应答者分析中，与非应答者相比，在对照药物治疗和实验药物治疗中，达到缓解的患者的无进展生存期和总生存期均更好。
结论
基于这项分析，在该人群中，将客观缓解率用作总生存期或无进展生存期的替代终点似乎并不合适。然而，由于异质性的性质，解释需要谨慎。
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