Kite, a Gilead Company, Stockley Park, Uxbridge, England, UK; Department of Medicine, University College London, England, UK.
Delta Hat Ltd, Nottingham, England, UK.
Value Health. 2022 Jun;25(6):1010-1017. doi: 10.1016/j.jval.2021.10.015. Epub 2022 Jan 31.
Survival extrapolation for chimeric antigen receptor T-cell therapies is challenging, owing to their unique mechanistic properties that translate to complex hazard functions. Axicabtagene ciloleucel is indicated for the treatment of relapse or refractory diffuse large B-cell lymphoma after 2 or more lines of therapy based on the ZUMA-1 trial. Four data snapshots are available, with minimum follow-up of 12, 24, 36, and 48 months. This analysis explores how survival extrapolations for axicabtagene ciloleucel using ZUMA-1 data can be validated and compared.
Three different parametric modeling approaches were applied: standard parametric, spline-based, and cure-based models. Models were compared using a range of metrics, across the 4 data snapshot, including visual fit, plausibility of long-term estimates, statistical goodness of fit, inspection of hazard plots, point-estimate accuracy, and conditional survival estimates.
Standard and spline-based parametric extrapolations were generally incapable of fitting the ZUMA-1 data well. Cure-based models provided the best fit based on the earliest data snapshot, with extrapolations remaining consistent as data matured. At 48 months, the maximum survival overestimate was 8.3% (Gompertz mixture-cure model) versus the maximum underestimate of 33.5% (Weibull standard parametric model).
Where a plateau in the survival curve is clinically plausible, cure-based models may be helpful in making accurate predictions based on immature data. The ability to reliably extrapolate from maturing data may reduce delays in patient access to potentially lifesaving treatments. Additional research is required to understand how models compare in broader contexts, including different treatments and therapeutic areas.
由于嵌合抗原受体 T 细胞疗法具有独特的作用机制，转化为复杂的风险函数，因此其生存外推具有挑战性。Axicabtagene ciloleucel 基于 ZUMA-1 试验，被批准用于治疗二线或以上治疗后复发或难治性弥漫性大 B 细胞淋巴瘤。目前有 4 个数据快照，随访时间至少为 12、24、36 和 48 个月。本分析探讨了如何使用 ZUMA-1 数据验证和比较 axicabtagene ciloleucel 的生存外推。
应用了三种不同的参数建模方法：标准参数、基于样条的和基于治愈的模型。使用一系列指标在 4 个数据快照中比较了模型，包括视觉拟合、长期估计的合理性、统计拟合优度、风险图检查、点估计准确性和条件生存估计。
标准和基于样条的参数外推通常无法很好地拟合 ZUMA-1 数据。基于治愈的模型基于最早的数据快照提供了最佳拟合，随着数据成熟，外推保持一致。在 48 个月时，最大生存高估为 8.3%（Gompertz 混合治愈模型），最大低估为 33.5%（Weibull 标准参数模型）。
在生存曲线出现平台的情况下，治愈模型可能有助于根据不成熟的数据做出准确预测。从成熟数据中可靠外推的能力可能会减少患者获得潜在救生治疗的延迟。需要进一步研究来了解模型在更广泛的背景下如何比较，包括不同的治疗方法和治疗领域。
