Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China.
J Natl Cancer Inst. 2023 Sep 7;115(9):1085-1091. doi: 10.1093/jnci/djad125.
Relapse-free survival (RFS) has been considered a primary endpoint to assess the effects of immunotherapy in the adjuvant setting among patients with early-stage disease. However, it is not clear whether RFS is a valid surrogate endpoint for overall survival (OS) in this clinical context.
Phase II or III clinical trials of adjuvant immunotherapy that reported hazard ratios on OS and RFS were identified. We used a weighted regression analysis at the arm and trial levels to assess the efficacy of RFS as a surrogate for OS, quantified by the weighted coefficient of determination (R2). Strong correlations (R2 ≥ 0.7) at the arm and trial levels indicated valid surrogacy. The surrogate threshold effect was also evaluated.
Fifteen high-quality randomized clinical trials involving 13 715 patients were included. At the arm level, moderate and strong associations were observed between RFS2-year and OS3-year (R2 = 0.58, 95% confidence interval [CI] = 0.25 to 0.92) and RFS3-year and OS5-year (R2 = 0.72, 95% CI = 0.38 to 1.00), respectively. At the trial level, a moderate association was observed between effect of treatment on RFS and OS (R2 = 0.63, 95% CI = 0.33 to 0.94). The surrogate threshold effect for RFS was 0.86. Consistent results were confirmed in several sensitivity analyses based on different trial phases, experimental arms, cancer types, and treatment strategies.
Our meta-analysis failed to find a clinically strong association between RFS and OS in randomized clinical trials of adjuvant immunotherapy. Our findings challenge the use of RFS as the primary efficacy endpoint and suggest the use of OS in this clinical context.
在早期疾病患者的辅助治疗环境中，无复发生存 (RFS) 已被认为是评估免疫疗法效果的主要终点。然而，在这种临床情况下，RFS 是否是总生存 (OS) 的有效替代终点尚不清楚。
确定了报告 OS 和 RFS 风险比的辅助免疫治疗的 II 期或 III 期临床试验。我们在手臂和试验水平上使用加权回归分析来评估 RFS 作为 OS 的替代终点的功效，通过加权决定系数 (R2) 来量化。手臂和试验水平上的强相关性 (R2≥0.7) 表明具有有效的替代关系。还评估了替代终点的阈值效应。
纳入了 15 项涉及 13715 例患者的高质量随机临床试验。在手臂水平，RFS2 年与 OS3 年之间存在中度至强相关性 (R2=0.58，95%置信区间 [CI] = 0.25 至 0.92)，RFS3 年与 OS5 年之间存在中度至强相关性 (R2=0.72，95% CI = 0.38 至 1.00)。在试验水平，观察到治疗对 RFS 和 OS 的影响之间存在中度相关性 (R2=0.63，95% CI = 0.33 至 0.94)。RFS 的替代终点阈值为 0.86。基于不同的试验阶段、实验手臂、癌症类型和治疗策略的几种敏感性分析结果均证实了一致的结果。
我们的荟萃分析未能在辅助免疫治疗的随机临床试验中发现 RFS 和 OS 之间具有临床强相关性。我们的研究结果对 RFS 作为主要疗效终点的使用提出了挑战，并建议在这种临床情况下使用 OS。
