BresMed Health Solutions, Sheffield, UK; Delta Hat, Nottingham, UK.
School of Health and Related Research, University of Sheffield, Sheffield, UK.
Value Health. 2019 Mar;22(3):276-283. doi: 10.1016/j.jval.2018.10.007. Epub 2018 Dec 13.
Immune-checkpoint inhibitors may provide long-term survival benefits via a cured proportion, yet data are usually insufficient to prove this upon submission to health technology assessment bodies.
We revisited the National Institute for Health and Care Excellence assessment of ipilimumab in melanoma (TA319). We used updated data from the pivotal trial to assess the accuracy of the extrapolation methods used and compared these to previously unused techniques to establish whether an alternative extrapolation may have provided more accurate survival projections.
We compared projections from the piecewise survival model used in TA319 and those produced by alternative models (fit to trial data with minimum follow-up of 3 years) to a longer-term data cut (5-year follow-up). We also compared projections to external data to help assess validity. Alternative approaches considered were parametric, spline-based, mixture, and mixture-cure models.
Only the survival model used in TA319 and a mixture-cure model provided 5-year survival predictions close to those observed in the 5-year follow-up data set. Standard parametric, spline, and non-curative-mixture models substantially underestimated 5-year survival. Survival estimates from the TA319 model and the mixture-cure model diverge considerably after 5 years and remain unvalidated.
In our case study, only models that incorporated an element of external information (through a cure fraction combined with background mortality rates or using registry data) provided accurate estimates of 5-year survival. Flexible models that were able to capture the complex hazard functions observed during the trial, but which did not incorporate external information, extrapolated poorly.
免疫检查点抑制剂可能通过治愈比例提供长期生存获益，但在提交给卫生技术评估机构时，数据通常不足以证明这一点。
我们重新评估了国家卫生与保健优化研究所（NICE）对黑色素瘤免疫检查点抑制剂伊匹单抗（ipilimumab）的评估（TA319）。我们使用关键性试验的最新数据来评估所使用外推方法的准确性，并将这些方法与之前未使用的技术进行比较，以确定替代外推方法是否可以提供更准确的生存预测。
我们将 TA319 中使用的分段生存模型的预测结果与其他替代模型（拟合具有至少 3 年随访的试验数据）的预测结果进行了比较，并将这些预测结果与更长期的数据（5 年随访）进行了比较。我们还将预测结果与外部数据进行了比较，以帮助评估有效性。考虑的替代方法包括参数、样条、混合和混合治愈模型。
只有 TA319 中使用的生存模型和混合治愈模型提供的 5 年生存率预测结果接近 5 年随访数据集观察到的结果。标准参数、样条和非治愈混合模型大大低估了 5 年生存率。TA319 模型和混合治愈模型的生存估计在 5 年后差异很大，且仍未得到验证。
在我们的案例研究中，只有那些纳入了外部信息（通过治愈分数与背景死亡率相结合或使用登记数据）的模型才能提供 5 年生存率的准确估计。能够捕捉到试验中观察到的复杂风险函数的灵活模型，但没有纳入外部信息，外推效果不佳。
