Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced NonSmall Cell Lung Cancer
Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced NonSmall Cell Lung Cancer
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DOI：
10.1016/j.jval.2017.07.011
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发表时间：
2018-01-01
期刊：
影响因子：
4.5
通讯作者：
Heeg, Bart
中科院分区：
文献类型：
--
作者：
Hashim, Mahmoud;Pfeiffer, Boris M.;Heeg, Bart
背景 在之前的研究中，晚期非小细胞肺癌（NSCLC）的总生存期（OS）与客观缓解率（ORR）或无进展生存期（PFS）等替代终点之间的相关性较差。这可能会因交叉和进展后治疗而产生偏差。 目的 在不允许交叉或报告平衡的进展后治疗的晚期 NSCLC 研究中评估这两个替代终点与 OS 之间的关系。 方法 对接受二线和进一步治疗的晚期 NSCLC 患者进行系统评价。使用相关系数 (R) 和加权回归模型评估 ORR 或中位 PFS (mPFS) 的绝对差异与中位 OS (mOS) 的绝对差异之间的关系。根据进展后治疗的交叉和平衡，在预定义的数据切割中重复进行分析。当Rs 95%置信区间（CI）上限大于0.7时，估计替代阈值效应（STE）。结果 总共纳入146项随机临床试验（43,061名患者）。平均 ORR、mPFS 和 mOS 分别为 12.2% +/- 11.2%、3.2 +/- 1.3 个月和 9.6 +/- 4.1 个月。 ORR 和 mPFS 与 mOS 的相关系数分别为 0.181 (95% CI 0.0160.337) 和 0.254 (95% CI 0.0740.418)。然而，在不允许交叉并报告平衡进展后治疗的试验中，ORR 和 mPFS 与 mOS 的相关系数分别为 0.528 (95% CI 0.0810.798) 和 0.778 (95% CI 0.4750.916)。根据 STE 估计，在显示显着治疗效果大小为 41.0% 或以上 ORR 或 4.15 或以上 mPFS 个月的试验中，可以充分确定地预期 OS 获益。 结论 交叉和进展后治疗可能会导致替代终点与 OS 之间的关系产生偏差。当用作主要终点时，所提出的 STE 计算可用于解释对 ORR 或 PFS 的治疗效果。
Background In previous studies, correlation between overall survival (OS) and surrogate endpoints like objective response rate (ORR) or progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) was poor. This can be biased by crossover and postprogression treatments.Objectives To evaluate the relationship between these two surrogate endpoints and OS in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments.Methods A systematic review in patients with advanced NSCLC receiving second- and further-line therapy was performed. The relationship between the absolute difference in ORR or median PFS (mPFS) and the absolute difference in median OS (mOS) was assessed using the correlation coefficient (R) and weighted regression models. The analysis was repeated in predefined data cuts based on crossover and balance of postprogression treatments. When the upper limit of Rs 95% confidence interval (CI) was more than 0.7, the surrogate threshold effect (STE) was estimated.Results In total, 146 randomized clinical trials (43,061 patients) were included. The mean ORR, mPFS, and mOS were 12.2% +/- 11.2%, 3.2 +/- 1.3 months, and 9.6 +/- 4.1 months, respectively. The correlation coefficients of ORR and mPFS were 0.181 (95% CI 0.0160.337) and 0.254 (95% CI 0.0740.418), respectively, with mOS. Nevertheless, in trials that did not allow crossover and reported balanced postprogression treatments, the correlation coefficients of ORR and mPFS were 0.528 (95% CI 0.0810.798) and 0.778 (95% CI 0.4750.916), respectively, with mOS. On the basis of STE estimation, in trials showing significant treatment effect size of 41.0% or more ORR or 4.15 or more mPFS months, OS benefit can be expected with sufficient certainty.Conclusions Crossover and postprogression treatments may bias the relationship between surrogate endpoints and OS. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints.