European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Gustave Roussy Cancer Campus Grand Paris, Villejuif, France; The Christie NHS Foundation Trust, Manchester, UK; University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA; Mayo Clinic Rochester, Rochester, MN; University of Tubingen, Tubingen, Germany; University of Edinburgh, Western General Hospital, Edinburgh, UK; Bristol-Myers Squibb, Wallingford, CT; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK; Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK; Universitas Brawijaya, Malang, Indonesia; IDDI, Louvain-la-Neuve, Belgium.
J Natl Cancer Inst. 2018 Jan 1;110(1). doi: 10.1093/jnci/djx133.
We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials.
Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided.
With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001).
In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.
我们通过对 5826 名接受干扰素（IFN）与观察比较的随机对照试验的个体患者数据（IPD）进行荟萃分析，评估了 II-III 期黑色素瘤患者的无复发生存率（RFS；复发/死亡时间）是否是总生存率（OS）的有效替代终点。
我们从 11 项比较 IFN 与观察的辅助治疗随机试验中收集了 5826 名患者的 RFS 和 OS 的 IPD。此外，还纳入了两项比较 IFN 与疫苗的研究的 IPD，共涉及 989 名患者。采用两级建模方法评估 Spearman 患者水平相关性（rho）、RFS 和 OS 的治疗效果的试验水平决定系数（R²）。在没有可用 IPD 的 13 项辅助研究中对结果进行了外部验证。然后，我们在欧洲癌症研究与治疗组织（EORTC）18071 号双盲试验中检验了结果，该试验比较了伊匹单抗 10mg/kg 与安慰剂的疗效，结果显示检查点抑制剂对 RFS 和 OS 有统计学意义上的影响。所有统计检验均为双侧。
中位随访 7 年后，13 项试验中有 12 项在 RFS（风险比[HR]RFS=0.88）和 OS（HR OS=0.91）方面显示 IFN 与无 IFN 差异之间具有一致性，但小试验（东部肿瘤协作组 2696 号试验）为异常值（HR RFS=0.72，HR OS=1.11）。因此，即使 rho 值较高，R² 也较低，且无法可靠估计。基于 12 项试验，rho 值仍然较高（0.89），RFS 和 OS 的风险比密切相关（R²=0.91）。RFS 的替代终点阈值效应估计为 0.77。对于 EORTC 18071 号试验，RFS 的风险比为 0.75，提示伊匹单抗对 OS 有影响。随后得到了证实（HR OS=0.72，95.1%置信区间=0.58 至 0.88，P=0.001）。
在高危 II-III 期黑色素瘤中，RFS 似乎是评估干扰素或检查点抑制剂辅助治疗的随机研究中 OS 的有效替代终点。在未来类似的辅助研究中，RFS 的风险比为 0.77 或更低将预测治疗对 OS 的影响。
