Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Faculty of Medical Sciences, Sun Yat-Sen University, Guangzhou, China.
JAMA Netw Open. 2019 May 3;2(5):e193433. doi: 10.1001/jamanetworkopen.2019.3433.
Immune checkpoint inhibitors (ICIs) have unique patterns of response and survival that differ from conventional chemotherapies. Novel intermediate end points are urgently required to detect the early signals of ICI activity.
To evaluate milestone rate (Kaplan-Meier estimates of survival probabilities at given time points) and milestone restricted mean survival time (RMST, the area under survival curves up to given time points) as potential intermediate end points for ICI trials.
Electronic databases (pre-MEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) were searched for randomized clinical trials published between January 1, 2000, and December 31, 2017.
Phase 2 and phase 3 randomized clinical trials evaluating ICIs in advanced solid tumors.
Two investigators extracted the data and reconstructed individual patient data to estimate the milestone rate or milestone RMST from the published Kaplan-Meier curves.
Trial-level milestone rates or milestone RMSTs were estimated for 6-month and 9-month progression-free survival (PFS) and 9-month and 12-month overall survival (OS). A weighted linear regression model evaluated the correlations of ratios of milestone rates or milestone RMSTs with OS hazard ratios (HRs).
Twenty-six trials examining 8 different tumor types were identified, including 12 892 patients. Overall survival HR was correlated with the ratio of 9-month OS milestone rate (R2 = 0.45; 95% CI, 0.27-0.74), and with the ratio of 12-month OS milestone rate (R2 = 0.40; 95% CI, 0.22-0.70). The ratio of 9-month OS milestone RMST (R2 = 0.60; 95% CI, 0.28-0.74) and ratio of 12-month OS milestone RMST were correlated with OS HR (R2 = 0.64; 95% CI, 0.42-0.78). No correlations were observed between OS HR and the ratio of 6-month or 9-month PFS milestone rates or milestone RMSTs.
Ratios of OS milestone RMSTs had a stronger correlation with OS HRs than ratios of OS milestone rates, whereas ratios of PFS milestone rates and ratios of PFS milestone RMSTs were not correlated with OS HRs. The OS milestone RMST could be further studied as an intermediate end point in future ICI trials.
免疫检查点抑制剂（ICIs）的反应和生存模式与传统化疗不同。迫切需要新的中间终点来检测 ICI 活性的早期信号。
评估里程碑率（生存概率的 Kaplan-Meier 估计值在给定时间点）和里程碑限制平均生存时间（RMST，直至给定时间点的生存曲线下面积）作为 ICI 试验的潜在中间终点。
电子数据库（预 MEDLINE、MEDLINE、Embase 和 Cochrane 对照试验中心注册库）搜索了 2000 年 1 月 1 日至 2017 年 12 月 31 日期间发表的随机临床试验。
评估晚期实体瘤中 ICI 的 2 期和 3 期随机临床试验。
两名研究人员提取数据并重建个体患者数据，以从已发表的 Kaplan-Meier 曲线中估计里程碑率或里程碑 RMST。
为 6 个月和 9 个月无进展生存期（PFS）和 9 个月和 12 个月总生存期（OS）估计了试验水平的里程碑率或里程碑 RMST。加权线性回归模型评估了里程碑率或里程碑 RMST 比值与 OS 风险比（HR）的相关性。
确定了 26 项研究，涵盖了 8 种不同的肿瘤类型，共纳入 12892 名患者。OS 风险比与 9 个月 OS 里程碑率的比值（R2=0.45；95%CI，0.27-0.74）相关，与 12 个月 OS 里程碑率的比值（R2=0.40；95%CI，0.22-0.70）相关。9 个月 OS 里程碑 RMST 的比值（R2=0.60；95%CI，0.28-0.74）和 12 个月 OS 里程碑 RMST 的比值与 OS HR 相关（R2=0.64；95%CI，0.42-0.78）。9 个月或 12 个月 PFS 里程碑率或里程碑 RMST 的比值与 OS HR 之间没有观察到相关性。
OS 里程碑 RMST 比值与 OS HR 的相关性强于 OS 里程碑率比值，而 PFS 里程碑率比值和 PFS 里程碑 RMST 比值与 OS HR 不相关。OS 里程碑 RMST 可作为未来 ICI 试验的中间终点进一步研究。
