PD-1/PD-L1 inhibitors in advanced, unresectable esophageal squamous-cell carcinoma: A meta-analysis of their effects across patient subgroups

Background: Advanced esophageal cell carcinoma (ESCC) is associated with poor survival outcomes. PD-1/PD-L1 inhibitors have been approved for the treatment of advanced ESCC. We aim to study PD-1/PD-L1 inhibitors across other variables in advanced ESCC, including data presented at the September 2024 FDA Oncologic Drugs Advisory Committee (ODAC) meeting. Methods: On February 28, 2025, we conducted a comprehensive search using PubMed, Web of Science, Scopus, and the Cochrane Library to identify randomized clinical trials evaluating PD-1/PD-L1 inhibitors in advanced ESCC. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed based on the following variables: age, gender, smoking status, ECOG performance status, liver metastasis, disease stage (locally advanced vs. metastatic), combined positive score (CPS; particularly with cutoff values of CPS 5 and CPS 1–9), and tumor area positivity (TAP). Effect sizes were estimated using the hazard ratio (HR) with random effects model. Results: Out of 5514 articles screened, only 13 papers were included, involving 6672 patients. PD-1/PD-L1 inhibitors significantly improved OS in both first- and second-line. In the first-line setting (combined with chemotherapy), they reduced the risk of death by 32 % (HR: 0.68; 95 % CI: 0.63–0.74, p < 0.001), while in the second-line setting (used as monotherapy), they reduced mortality by 27 % (HR: 0.73; 95 % CI: 0.66–0.81, p < 0.001). For PFS, a significant benefit was seen only in first-line treatment (HR: 0.62; 95 % CI: 0.58–0.67, p < 0.001) but not in second-line (HR: 0.89; 95 % CI: 0.76–1.04, p = 0.128), with a significant difference between treatment lines (p < 0.001). Most subgroups in our study demonstrated significant survival benefits, except for current smokers (HR: 0.58; 95 % CI: 0.31–1.09; p = 0.089). Finally, all CPS subgroups showed survival benefits in the first-line setting except those with CPS < 1 (PD-L1 negative). A similar pattern was observed in the second-line setting. Conclusions: PD-1/PD-L1 inhibitors significantly improve OS over chemotherapy in both first- and second-line advanced ESCC. PFS improved only in the first line. More effective therapies for the second line are still needed. Current smokers showed no survival benefit, unlike former or never smokers. OS benefit was absent in PD-L1–negative patients (CPS <1) and greatest in those with CPS ≥ 10.