DataSheet_1_Progression-Free Survival and Time to Progression as Potential Surrogate Endpoints for Overall Survival in Chemoradiotherapy Trials in Limited-Stage Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.docx

PurposeTo investigate whether progression-free survival (PFS) or time to progression (TTP) could be a valid surrogate endpoint for overall survival (OS) in patients with limited-stage small-cell lung cancer (LS-SCLC) receiving combined chemoradiotherapy.
MethodsLiterature searching was performed in PubMed, Embase, and The Cochrane Library up to 2021. Prediction models were firstly established using data from phase III randomized controlled trials (RCTs) and then externally validated in phase II and retrospective studies. Correlation analysis was evaluated by a weighted linear regression model at both trial and arm levels. Cross-validation was performed to assess the consistency and robustness of the established models.
Results37 studies, including 15 phase III RCTs, 12 phase II studies, and 10 retrospective studies, were selected in the final analysis. In trial-level surrogacy, a very good correlation was observed between hazard ratios (HRs) of PFS/TTP and OS (R2 = 0.783, 95% CI 0.771–0.794). In arm-level surrogacy, very good correlations were also observed between 2-year (R2 = 0.823, 95% CI 0.814–0.832), 3-year (R2 = 0.843, 95% CI 0.833–0.850), 5-year (R2 = 0.852, 95% CI 0.843–0.859) PFS/TTP, and 5-year OS. An excellent correlation was observed between 4-year PFS/TTP and 5-year OS (R2 = 0.906, 95% CI 0.901–0.910). Cross-validation demonstrated reasonable overall consistency. External validation in phase II and retrospective studies showed good agreement (R2, 0.728–0.824).
ConclusionsPFS/TTP was a valid surrogate endpoint for OS in patients with LS-SCLC receiving combined chemoradiotherapy. The finding provides high-level evidence to support PFS/TTP as the primary endpoint in clinical trials so as to speed up introducing novel agents to the treatment of LS-SCLC.

目的：探讨无进展生存期（progression-free survival, PFS）或疾病进展时间（time to progression, TTP）能否作为接受放化疗联合治疗的局限期小细胞肺癌（limited-stage small-cell lung cancer, LS-SCLC）患者总生存期（overall survival, OS）的合格替代终点。方法：检索截至2021年的PubMed、Embase及Cochrane Library数据库文献。首先利用Ⅲ期随机对照试验（randomized controlled trials, RCTs）数据构建预测模型，随后在Ⅱ期研究及回顾性研究中开展外部验证。在试验水平与研究臂水平均采用加权线性回归模型进行相关性分析。通过交叉验证评估所构建模型的一致性与稳健性。结果：最终共纳入37项研究，其中包含15项Ⅲ期随机对照试验、12项Ⅱ期研究及10项回顾性研究。在试验水平替代终点分析中，PFS/TTP的风险比（hazard ratios, HRs）与OS的风险比呈现极强相关性（R²=0.783，95%置信区间0.771~0.794）。在研究臂水平替代终点分析中，2年PFS/TTP（R²=0.823，95%置信区间0.814~0.832）、3年PFS/TTP（R²=0.843，95%置信区间0.833~0.850）、5年PFS/TTP（R²=0.852，95%置信区间0.843~0.859）与5年OS均呈现极强相关性；4年PFS/TTP与5年OS则呈现极佳相关性（R²=0.906，95%置信区间0.901~0.910）。交叉验证结果显示模型整体一致性良好。Ⅱ期研究及回顾性研究的外部验证结果显示一致性较好（R²=0.728~0.824）。结论：对于接受放化疗联合治疗的局限期小细胞肺癌患者，PFS/TTP可作为OS的合格替代终点。本研究结论可为将PFS/TTP作为临床试验主要终点提供高级别证据支持，从而加速新型治疗药物应用于局限期小细胞肺癌的临床治疗进程。