Progression-free survival as a surrogate for overall survival in gastro-esophageal cancer trials with immunotherapy: A meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs)-based regimens are the first-line standard of care for most patients with advanced gastroesophageal adenocarcinoma (GEA) and esophageal squamous cell carcinoma (ESCC). The efficacy of these treatments often depend on PD-L1 expression levels. Overall survival (OS) has traditionally been the primary endpoint for evaluating treatment efficacy. Through a meta-analysis, we investigated whether progression-free survival (PFS) is a valid surrogate for OS in the ICIs-era, overall and across different PD-L1 subgroups. METHODS: A systematic literature review was conducted to identify eligible randomized controlled trials (RCTs) published by 30/06/2025. Trial-level surrogacy of PFS for OS was assessed using Spearman rank correlation coefficient (R) and weighted linear regression, calculating the coefficient of determination (R2). RESULTS: Eighteen eligible RCTs were evaluated. Regarding GEA, the correlation between treatment effects on PFS and on OS was moderate in the overall population (R=0.82; R2=0.52) and in the CPS≥ 1 subgroup (R=0.81; R2=0.66), moderate yet non-significant in the CPS< 1 subgroup (R=0.67; R2=0.51), and strong in the CPS≥ 5 subgroup (R=0.77; R2=0.85). In ESCC, the correlation in the overall population was weak (R=0.64; R2=0.47). No improvement of the correlation was found in the subgroup of patients with CPS≥ 10 (R=0.33; R2=0.16) or TPS≥ 1 % (R=0.40, R2=0.005). CONCLUSIONS: While the correlation between treatment effects on PFS and OS was weak in ESCC, it was moderate in PD-L1-low GEA, and good in PD-L1-high GEA. Therefore, PFS is an adequate co-primary endpoint in future trials investigating novel ICIs-based regimens in GEA, especially if the analyses are pre-planned in PD-L1-high subgroups.