Pfizer Global Research and Development, La Jolla, CA, USA.
OptumInsight, Stockholm, Sweden.
Cancer Manag Res. 2014 Sep 22;6:365-71. doi: 10.2147/CMAR.S67249. eCollection 2014.
The debate surrounding the acceptance of progression-free survival (PFS) as an intermediate endpoint to overall survival (OS) has grown in recent years, due to the challenges in demonstrating an OS benefit within clinical trials today. PFS is generally a good predictor of OS for cases where survival post-progression (SPP) is short, and less so when SPP is long. SPP depends on multiple factors, including residual effect from experimental treatment and effect from crossover or other subsequent therapies, posing unique challenges into the translation of PFS benefit into OS.
The objective of this analysis was to conduct simulations investigating how increasing SPP impacts PFS translation to OS, utilizing data from the AXIS (axitinib versus sorafenib in advanced metastatic renal cell carcinoma) trial. The underlying assumption was a treatment benefit in PFS (the PFS distribution parameters were chosen to be equal to median PFS in the AXIS trial) but no treatment effect on SPP, implying that PFS improvement is directly reflected in OS improvement.
The probability of a statistically significant difference between arms for OS decreased from 54.7% to 6.1% when median SPP was increased from one to 20 months. The probability of the hazard ratio of OS being ≥0.9 was similarly increased from 24.3% to 72.6%, even though the hazard ratio for PFS was 0.69.
The present study shows that when simulated SPP is added to trial PFS data, the existing PFS benefit is diluted. Knowing that the AXIS treatment arms are well balanced with respect to post-trial treatments, we conclude that the PFS to OS benefit translation is primarily obscured by random variability largely unrelated to the true outcomes. The implications for drug development are not insignificant, as there would be a need to include more patients in studies or utilize a longer follow-up time to overcome the SPP variability issue.
近年来，由于在临床试验中证明生存获益面临挑战，围绕将无进展生存期（PFS）作为总生存期（OS）的替代终点的接受度的争论愈演愈烈。对于 PFS 后生存时间（SPP）较短的情况，PFS 通常是 OS 的良好预测指标，而对于 SPP 较长的情况则不然。SPP 取决于多个因素，包括实验性治疗的残余效应和交叉或其他后续治疗的效应，这给 PFS 获益转化为 OS 带来了独特的挑战。
本分析的目的是利用 AXIS（阿昔替尼与索拉非尼治疗晚期转移性肾细胞癌）试验的数据进行模拟研究，探讨 SPP 增加如何影响 PFS 向 OS 的转化。基本假设是 PFS 中有治疗获益（PFS 分布参数选择为 AXIS 试验中的中位 PFS），但对 SPP 无治疗作用，这意味着 PFS 改善直接反映在 OS 改善上。
当 SPP 的中位数从 1 个月增加到 20 个月时，OS 上两组之间有统计学显著差异的概率从 54.7%降至 6.1%。OS 的风险比≥0.9 的概率也从 24.3%增加到 72.6%，尽管 PFS 的风险比为 0.69。
本研究表明，当将模拟 SPP 添加到试验 PFS 数据中时，现有的 PFS 获益会被稀释。鉴于 AXIS 治疗组在试验后治疗方面是平衡的，我们得出结论，PFS 到 OS 的获益转化主要被与真实结果关系不大的随机变异性所掩盖。这对药物开发的影响不容忽视，因为需要在研究中纳入更多患者或采用更长的随访时间来克服 SPP 变异性问题。
