Association between hazard ratios of surrogate time-to-event endpoints and overall survival in advanced/metastatic cancers

Objectives: Surrogate endpoints can support early access to novel therapies. In trial-level endpoint validation studies, the association between treatment effect e.g., the hazard ratio (HR) on both the surrogate and hard endpoint can be estimated. We aimed to review studies reporting an association between HRs of surrogate time-to-event endpoints and overall survival (OS) in advanced/metastatic cancers. Methods: A systematic review was conducted using Medline and Embase. We included full reports assessing the association between HRs of surrogate time-to-event endpoints and OS in advanced/metastatic cancer indications. The following information was extracted: study characteristics, association measure, use of weighted analyses, logarithmic transformation of HRs, use of multivariate analysis, evaluation of crossover impact, use of IQWiG framework, estimating surrogate threshold effect (STE), and reported results and/or regression equations. Results: Forty-five studies were included. Retrieved studies were conducted in 16 different cancer indications. Different methods were used to assess associations, including Spearman's/Pearson’s correlation coefficient and linear regression analysis. Weighted analyses, logarithmic transformation of HRs and multivariate analysis were implemented in 35, 26 and 10 studies, respectively. Few studies assessed the crossover impact on the association (8 studies) and implemented IQWiG framework and STE assessment (11 studies and 3 studies, respectively). Detailed results are extracted, summarized and will be presented. Conclusions: There is inconsistency in conducting/reporting of trial-level endpoint validation studies in advanced/metastatic cancers. Future studies would benefit from building a structured data analysis checklist. Also, trial-level surrogacy was not assessed in all advanced/metastatic cancers and the strength of association varied across indications. The generalizability of results from one indication to another is limited