Identification on surrogating overall survival with progression-free survival of first-line immunochemotherapy in advanced esophageal squamous cell carcinoma—an exploration of surrogate endpoint

BACKGROUND: Overall survival (OS) is the gold standard to assess novel therapeutics to treat cancer. However, to identify early efficacy and speed up drug approval, trials have used progression-free survival (PFS) as a surrogate endpoint (SE). Herein, we aimed to examine if PFS could function as an OS surrogate in advanced Esophageal Squamous Cell Carcinoma (ESCC) treated with first-line immunochemotherapy. METHODS: Two hundred ninety-two advanced ESCC patients treated using inhibitors of PD-1/PD-L1 + chemotherapy or chemotherapy alone were collected. In addition, six phase III randomized clinical trials were eligible for inclusion. Bayesian normal-induced-copula-estimation model in retrospective patient data and regression analysis in the published trial data were used to determine the PFS-OS correlation. RESULTS: PFS correlated moderately with OS in the retrospective cohort (Kendall’s Tau = 0.684, τ = 0.436). In trial-level, treatments effects for PFS correlated weakly with those for OS in intention-to-treat population (R(2) = 0.436, adj.R(2) = 0.249, P > 0.05) and in PD-L1-enriched population (R(2) = 0.072). In arm-level, median PFS also correlated weakly with median OS. Moreover, analysis of the retrospective cohort demonstrated that the annual death risk after progression in the continued immunotherapy group was considerably lower than that in the discontinued group. CONCLUSION: In trials of anti-PD-1 agents to treat advanced ESCC, the current results provide only weak support for PFS as an OS surrogate; OS cannot be substituted completely by PFS in these cases. The results also suggest that qualified patients with advanced ESCC might benefit from continuous immunotherapy beyond progression to achieve a decreased risk of death. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-023-10613-y.