Medical Oncology Department Clinica Universidad de Navarra, Madrid, Spain; Interdisciplinary Teragnosis and Radiosomics (INTRA) Network Universidad of Navarre, Madrid, Spain.
Interdisciplinary Teragnosis and Radiosomics (INTRA) Network Universidad of Navarre, Madrid, Spain.
Eur J Cancer. 2022 Jan;161:79-89. doi: 10.1016/j.ejca.2021.11.002. Epub 2021 Dec 18.
The mechanism of action of immune checkpoints inhibitors hinders the writing of rational statistical analysis plans for phase III randomised clinical trials (RCTs) because of their unpredictable dynamic effects. The purpose is to illustrate the advantages of Bayesian reporting of treatment efficacy analysis in immunotherapy RCTs, in contrast to frequentist reporting.
Fourteen RCTs (one with two pairwise comparisons) that failed to achieve their primary objective (overall survival, OS) were selected. These RCTs were reanalysed using Bayesian Cox models with dynamic covariate coefficients and time-invariant models.
The RCTs that met inclusion criteria were 7 lung cancer trials, various other tumours, with antiPD1, antiPDL1 or antiCTLA4 therapies. The minimum detectable effect (δ) was superior to the true benefit observed in all cases, in conditions of non-proportional hazards. Schoenfeld tests indicated the existence of PH assumption violations (p<0.05) in 6/15 cases. The Bayesian Cox models revealed a probability of benefit >79% in all the RCTs, with the therapeutic equivalence hypothesis unlikely. The OS curves diverged after a median of 9.1 months. Since the divergency, no non-proportionality was evinced in 13/15, while the Wald tests achieved p<0.05 in 12/15 datasets. In all cases, the Bayesian Cox models with dynamic coefficients detected fluctuations of the hazard ratio, and increased 2-year OS was the most likely hypothesis.
We recommend progressively implementing Bayesian and dynamic analyses in all RCTs of immunotherapy to interpret and assess the credibility of frequentist results.
免疫检查点抑制剂的作用机制阻碍了 III 期随机临床试验（RCT）的合理统计分析计划的制定，因为它们具有不可预测的动态效应。目的是说明贝叶斯报告免疫治疗 RCT 治疗效果分析的优势，与频率派报告相比。
选择了 14 项未能达到主要终点（总生存期，OS）的 RCT 进行分析。这些 RCT 使用具有动态协变量系数的贝叶斯 Cox 模型和时不变模型进行重新分析。
符合纳入标准的 RCT 为 7 项肺癌试验和其他各种肿瘤，使用抗 PD1、抗 PDL1 或抗 CTLA4 治疗。在非比例风险的情况下，最小可检测效应（δ）优于所有情况下观察到的真实获益。Schoenfeld 检验表明，在 6/15 例中存在 PH 假设违反（p<0.05）。贝叶斯 Cox 模型显示所有 RCT 中获益的可能性>79%，治疗等效性假设不太可能。OS 曲线在中位数为 9.1 个月后出现分歧。自分歧以来，在 13/15 例中没有出现非比例性，而 Wald 检验在 12/15 个数据集达到 p<0.05。在所有情况下，具有动态系数的贝叶斯 Cox 模型都检测到了风险比的波动，并且增加的 2 年 OS 是最有可能的假设。
我们建议在所有免疫治疗 RCT 中逐步实施贝叶斯和动态分析，以解释和评估频率派结果的可信度。
