School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Department of Biostatistics and Bioinformatics, Duke University of Medicine, Durham, NC, USA.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Chin Clin Oncol. 2022 Feb;11(1):7. doi: 10.21037/cco-21-110.
Proportional hazards (PH) assumption is often violated in cancer immunotherapy studies. Restricted mean survival time (RMST) ratio is a valid metric to quantify the size of treatment effect when non-proportional hazard (NPH) is present. This study investigated the use of RMST ratio and hazard ratio (HR) in studying progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in non-small cell lung cancer immunotherapy trials.
Trial level data were collected from 14 phase III trials published between 2012 and 2018. A weighted least-square regression (WLSR) was performed to evaluate the trial-level surrogacy. Surrogacy was evaluated via the association between RMST ratios for PFS and OS and between HRs for PFS and OS.
Using data extracted from published articles, low to moderate correlation (0.49) between PFS and OS was observed for HR while low correlation (0.35) was observed for RMST ratio. When trials violating PH in PFS were included, more consistent correlations for both HR (0.43) and RMST ratio (0.44) were observed.
In summary, the strength of PFS surrogacy for OS depends on whether HR or RMST ratio are chosen. RMST ratio and additional sensitivity analysis should be considered in addition to HR.
比例风险（PH）假设在癌症免疫疗法研究中经常被违反。当存在非比例风险（NPH）时，限制性平均生存时间（RMST）比是一种有效衡量治疗效果大小的指标。本研究探讨了在非小细胞肺癌免疫疗法试验中，使用 RMST 比和风险比（HR）来研究无进展生存期（PFS）作为总生存期（OS）的替代终点。
从 2012 年至 2018 年发表的 14 项 III 期试验中收集了试验水平的数据。通过加权最小二乘回归（WLSR）评估了试验水平的替代。通过 PFS 和 OS 的 RMST 比与 PFS 和 OS 的 HR 之间的关联来评估替代。
使用从已发表文章中提取的数据，观察到 HR 与 PFS 和 OS 之间存在低到中度相关性（0.49），而 RMST 比观察到低相关性（0.35）。当包括在 PFS 中违反 PH 的试验时，观察到 HR（0.43）和 RMST 比（0.44）都有更一致的相关性。
总之，PFS 对 OS 的替代强度取决于选择 HR 还是 RMST 比。除了 HR 之外，还应考虑 RMST 比和额外的敏感性分析。
