Zhang Jianrong, Liang Wenhua, Liang Hengrui, Wang Xiaofei, He Jianxing
Brown School at Washington University in St. Louis, St. Louis, USA.
Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, USA.
Ann Transl Med. 2019 Jun;7(11):244. doi: 10.21037/atm.2019.04.72.
Few cancer drugs or their indications achieved survival benefit in subsequent trials during postmarket period after approval based on surrogate endpoints. This causes a concern of using surrogate endpoints instead of overall survival (OS) as the primary endpoint for trial design, implementation and regulation approval. We conducted a systematic review to summarize the findings from published meta-analyses which have evaluated endpoint surrogacy for OS in oncological randomized controlled trials (RCTs) with immunotherapies. After searching articles indexed in PubMed prior to 24 February 2019, we identified a total of 11 meta-analyses for advanced multiple tumors, non-small cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma, melanoma; most (91%; 10/11) focused on immune checkpoint inhibitors. Although the evaluation criteria adopted by these meta-analyses for validating endpoint surrogacy were not consistent (ranging from R ≥0.60 to R ≥0.80), the results were consistent. Few studies show an association between OS and progression-free survival (PFS)/objective response rate (ORR) that met the lowest evaluation criteria (R ≥0.60), based on treatment effects (8%; 2/26 indications) or absolute results from experimental arm (0%; 0/11 indications). However, the association between OS and 1-year survival rate met the lowest criteria based on both the trial-level results (4/4 indications) and the arm-level results (5/5 indications). In lieu of this finding, we are supportive of an alternative endpoint, e.g., 1-year survival rate, rather than the more conventional choices PFS and ORR, as promising surrogate endpoint for OS in immunotherapy RCTs. We encourage further investigation on endpoint surrogacy based on the same or different settings, especially an assessment on survival rate at milestone time (e.g., 1-year), which has been demonstrated valuable for predicting OS in meta-analyses.
在基于替代终点获批后的上市后时期，很少有癌症药物或其适应证在后续试验中实现生存获益。这引发了对于在试验设计、实施及监管批准中使用替代终点而非总生存期（OS）作为主要终点的担忧。我们进行了一项系统评价，以总结已发表的荟萃分析的结果，这些荟萃分析评估了免疫疗法用于肿瘤学随机对照试验（RCT）中OS的终点替代指标。在检索2019年2月24日前PubMed收录的文章后，我们共识别出11项针对晚期多种肿瘤、非小细胞肺癌（NSCLC）、尿路上皮癌、肾细胞癌、黑色素瘤的荟萃分析；其中大多数（91%；11项中的10项）聚焦于免疫检查点抑制剂。尽管这些荟萃分析用于验证终点替代指标所采用的评估标准不一致（范围从R≥0.60至R≥0.80），但其结果是一致的。基于治疗效果（8%；26项适应证中的2项）或试验组的绝对结果（0%；11项适应证中的0项），很少有研究显示OS与无进展生存期（PFS）/客观缓解率（ORR）之间的关联符合最低评估标准（R≥0.60）。然而，基于试验水平结果（4/4项适应证）和组水平结果（5/5项适应证），OS与1年生存率之间的关联均符合最低标准。鉴于这一发现，我们支持将替代终点，例如1年生存率，而非更传统的PFS和ORR，作为免疫疗法RCT中OS有前景的替代终点。我们鼓励基于相同或不同背景对终点替代指标进行进一步研究，尤其是对里程碑时间（例如1年）生存率的评估，这在荟萃分析中已被证明对预测OS有价值。
