Wickenstones Ltd, Oxford, UK.
Augmentium Pharma Consulting Inc., Toronto, Canada.
Pharmacoeconomics. 2017 Dec;35(12):1257-1270. doi: 10.1007/s40273-017-0558-5.
New immuno-oncology (I-O) therapies that harness the immune system to fight cancer call for a re-examination of the traditional parametric techniques used to model survival from clinical trial data. More flexible approaches are needed to capture the characteristic I-O pattern of delayed treatment effects and, for a subset of patients, the plateau of long-term survival.
Using a systematic approach to data management and analysis, the study assessed the applicability of traditional and flexible approaches and, as a test case of flexible methods, investigated the suitability of restricted cubic splines (RCS) to model progression-free survival (PFS) in I-O therapy.
The goodness of fit of each survival function was tested on data from the CheckMate 067 trial of monotherapy versus combination therapy (nivolumab/ipilimumab) in metastatic melanoma using visual inspection and statistical tests. Extrapolations were validated using long-term data for ipilimumab.
Modelled PFS estimates using traditional methods did not provide a good fit to the Kaplan-Meier (K-M) curve. RCS estimates fit the K-M curves well, particularly for the plateau phase. RCS with six knots provided the best overall fit, but RCS with one knot performed best at the plateau phase and was preferred on the grounds of parsimony.
RCS models represent a valuable addition to the range of flexible approaches available to model survival when assessing the effectiveness and cost-effectiveness of I-O therapy. A systematic approach to data analysis is recommended to compare the suitability of different approaches for different diseases and treatment regimens.
利用免疫系统对抗癌症的新型免疫肿瘤学（I-O）疗法要求重新检查用于对临床试验数据进行生存建模的传统参数技术。需要更灵活的方法来捕捉 I-O 治疗效果延迟的特征，以及对于一部分患者长期生存的平台期。
本研究通过系统的数据管理和分析方法，评估了传统和灵活方法的适用性，并作为灵活方法的测试案例，研究了限制立方样条（RCS）在 I-O 治疗中对无进展生存期（PFS）建模的适用性。
使用视觉检查和统计检验，对转移性黑色素瘤单药治疗与联合治疗（nivolumab/ipilimumab）的 CheckMate 067 试验数据，检验了每种生存函数的拟合优度。使用伊匹单抗的长期数据验证了外推的有效性。
传统方法建模的 PFS 估计值与 Kaplan-Meier（K-M）曲线拟合不佳。RCS 估计值与 K-M 曲线拟合良好，特别是在平台期。六结 RCS 提供了最佳的整体拟合，但单结 RCS 在平台期表现最佳，并且基于简约性而被优先选择。
RCS 模型代表了在评估 I-O 疗法的有效性和成本效益时，对用于生存建模的一系列灵活方法的有价值的补充。建议采用系统的数据分析方法，比较不同方法对不同疾病和治疗方案的适用性。
