Surrogacy of Time to Progression for Overall Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Time to progression (TTP) is widely used as the endpoint in early-phase trials of advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. The PubMed database and ASCO Meeting Library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. The correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and postprogression survival (PPS), defined as the period obtained by subtracting the median TTP from the median OS, were also evaluated. The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. The correlation between median OS and median TTP was not so strong (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). In advanced HCC, the OS HR can be predicted from the TTP HR, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. TTP may be a better endpoint than OS for evaluating a novel agent in a pivotal trial, because an improvement in antitumor effect cannot fully reflect an improvement in OS due to the strong impact of PPS on OS.