A Review of Overall Survival Extrapolations of Immune-Checkpoint Inhibitors Used in Health Technology Assessments by the French Health Authorities

Abstract

Objectives Extrapolation is often required to inform cost-effectiveness (CE) evaluations of immune-checkpoint inhibitors (ICIs) since survival data from pivotal clinical trials are seldom complete. The objectives of this study were to evaluate the accuracy of estimates of long-term overall survival (OS) predicted in French CE assessment reports of ICIs, and to identify models presenting the best fit to the observed long-term survival data. Methods A systematic review of French assessment reports of ICIs in the metastatic setting since inception until May 2020 was performed. A targeted literature review was conducted to collect associated extended follow-up of randomized controlled trials (RCTs) used in the CE assessment reports. Difference between projected and observed OS was calculated. A range of standard parametric and spline-based models were applied to the extended follow-up data from the RCT to determine the best-fitting survival models. Results Of the 121 CE assessment reports published, 11 reports met the inclusion criteria. OS was underestimated in 73 percent of the CE assessment reports. The mean relative difference between each source was −13 percent (median: −15 percent; IQR: −0.4 to 26 percent). Models providing the best fit were those that could reflect nonmonotonic hazards. Conclusions Based on the available data at the time of submission, longer-term survival of ICIs was not fully captured by the extrapolation models used in CE assessments. Standard and flexible parametric models which can capture nonmonotonic hazard functions provided the best fit to the extended follow-up data. However, these models may still have performed poorly if fitted to survival data available at the time of submission to the French National Authority for Health.

Clinical benefit of anti-PD-(L)1 immunotherapies in advanced cancer in France: a population-based estimate from 2014 to 2021

“…To limit the risk of misestimation, we used only the economic evaluations validated by the HAS leading to the exclusion of some IT indications and tested the results in sensitivity analyses. Moreover, a previous study indicated that extrapolation tends to underestimate long-term OS in patients treated with ICIs 25 suggesting that we present here a minimal estimation of the benefit. In addition, extrapolations were carried out using data from results of phase III studies (as these data have the highest internal validity), whereas a large difference may exist between the trial population and treated population with reimbursement, especially regarding performance status and comorbidity indexes.…”

Impact of Extrapolation Model Choices on the Structural Uncertainty in Economic Evaluations for Cancer Immunotherapy: A Case Study of Checkmate 067

“…Although using flexible techniques can be helpful in reducing the uncertainty of capturing complex survival hazards, few studies take a full model choice into consideration. A recent systematic review of French health technology assessment (HTA) reports indicated that only one study applied a flexible technique among 11 assessed targeted cancer immunotherapies [ 36 ]. Although using external evidence could be helpful when dealing with immature data [ 17 , 19 ], results generated from the immature data should be carefully considered for decision making because of unaddressed uncertainties.…”

A Review of Overall Survival Extrapolations of Immune-Checkpoint Inhibitors Used in Health Technology Assessments by the French Health Authorities – Erratum

“…In the original publication of Grumberg et al (2022) a typesetting error occurred in Table 2. The correct Table 2 is reproduced below.…”