Surrogate endpoints for overall survival in randomized clinical trials testing immune checkpoint inhibitors: a systematic review and meta-analysis

Abstract

Introduction: There is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors (ICIs).

Methods: We systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS.

Results: 61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HR_PFS and HR_mPFS both had a strong surrogacy value (R² = 0.74 and R² = 0.81, respectively). In comparisons testing ICI as monotherapy, HR_PFS was the best surrogate, although having a moderate correlation (R² = 0.58). In comparisons testing ICI plus other treatment(s), the associations were very weak for all the surrogate endpoints and treatment effect measures, with R² ranging from 0.01 to 0.22.

Conclusion: In RCTs testing ICIs, the value of potential surrogates for HR_OS was strongly affected by the type of treatment(s) tested. The evidence available supports HR_PFS as the best surrogate, and disproves the use of alternative endpoints, such as the mPFS, or treatment effect measures, such as the RMST.

Keywords: immune check inhibitor (ICI); immunotherapy; methodology; randomized clinical trial; surrogate.