Department of Medical Oncology, Peter McCallum Cancer Centre, Melbourne, Victoria, Australia.
Department of Medical Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.
J Natl Cancer Inst. 2023 Dec 6;115(12):1475-1482. doi: 10.1093/jnci/djad152.
Overall survival is the optimal marker of treatment efficacy in randomized clinical trials (RCTs) but can take considerable time to mature. Progression-free survival (PFS) has served as an early surrogate of overall survival but is imperfect. Time to deterioration in quality of life (QOL) measures could be a surrogate for overall survival.
Phase 3 RCTs in solid malignancies that reported overall survival, PFS, and time to deterioration in QOL or physical function published between January 1, 2010, and June 30, 2022, were evaluated. Weighted regression analysis was used to assess the relationship between PFS, time to deterioration in QOL, and time to deterioration in physical function with overall survival. The coefficient of determination (R2) was used to quantify surrogacy.
In total, 138 phase 3 RCTs were included. Of these, 47 trials evaluated immune checkpoint inhibitors and 91 investigated non-immune checkpoint inhibitor agents. Time to deterioration in QOL (137 RCTs) and time to deterioration in physical function (75 RCTs) performed similarly to PFS as surrogates for overall survival (R2 = 0.18 vs R2 = 0.19 and R2 = 0.10 vs R2 = 0.09, respectively). For immune checkpoint inhibitor studies, time to deterioration in physical function had a higher association with overall survival than with PFS (R2 = 0.38 vs R2 = 0.19), and PFS and time to deterioration in physical function did not correlate with each other (R2 = 0). When time to deterioration in physical function and PFS are used together, the coefficient of determination increased (R2 = 0.57).
Time to deterioration in physical function appears to be an overall survival surrogate measure of particular importance for immune checkpoint inhibitor treatment efficacy. The combination of time to deterioration in physical function with PFS may enable better prediction of overall survival treatment benefit in RCTs of immune checkpoint inhibitors than either PFS or time to deterioration in physical function alone.
总生存期是随机临床试验（RCT）中治疗效果的最佳标志物，但需要相当长的时间才能成熟。无进展生存期（PFS）曾作为总生存期的早期替代指标，但并不完美。生活质量（QOL）指标恶化的时间可能是总生存期的替代指标。
评估了 2010 年 1 月 1 日至 2022 年 6 月 30 日期间发表的报告总生存期、PFS 以及 QOL 或身体功能恶化时间的实体恶性肿瘤的 3 期 RCT。使用加权回归分析评估 PFS、QOL 恶化时间和身体功能恶化时间与总生存期之间的关系。决定系数（R2）用于量化替代物。
共纳入 138 项 3 期 RCT。其中，47 项试验评估了免疫检查点抑制剂，91 项试验研究了非免疫检查点抑制剂药物。QOL 恶化时间（137 项 RCT）和身体功能恶化时间（75 项 RCT）作为总生存期的替代指标与 PFS 表现相似（R2=0.18 对 R2=0.19 和 R2=0.10 对 R2=0.09）。对于免疫检查点抑制剂研究，身体功能恶化时间与总生存期的相关性高于 PFS（R2=0.38 对 R2=0.19），并且 PFS 和身体功能恶化时间之间没有相关性（R2=0）。当同时使用身体功能恶化时间和 PFS 时，决定系数增加（R2=0.57）。
身体功能恶化时间似乎是免疫检查点抑制剂治疗效果的总生存替代测量指标，与单独使用 PFS 或身体功能恶化时间相比，身体功能恶化时间与 PFS 的组合可能使免疫检查点抑制剂 RCT 中对总生存期治疗获益的预测更好。
