First-Line PD-1 Inhibitor-Based Therapy for Advanced or Metastatic Esophageal Squamous Cell Carcinoma: A Revised Systematic Review and Meta-Analysis of Phase III Trials.

BACKGROUND AND PURPOSE: Immune checkpoint blockade has changed the first-line treatment landscape for advanced esophageal squamous cell carcinoma (ESCC), but the magnitude and consistency of benefit across phase III trials require careful synthesis. METHODS: We conducted a PRISMA 2020-guided systematic review of PubMed, Embase, CENTRAL, and Web of Science (January 1, 2015 to April 30, 2025) for phase III randomized trials comparing first-line PD-1 inhibitor-based therapy with chemotherapy in advanced/metastatic ESCC. The primary endpoint was overall survival (OS). Secondary endpoints were safety and prespecified subgroup outcomes. RoB 2 was used for risk-of-bias assessment; certainty of evidence was judged with GRADE. A fixed-effect inverse-variance model was prespecified for the primary common-effect analysis, with random-effects and sensitivity analyses performed secondarily. RESULTS: Six eligible phase III trials were included in the primary analysis (KEYNOTE-590 ESCC subgroup, CheckMate-648 nivolumab-plus-chemotherapy arm, ESCORT-1st, JUPITER-06, ORIENT-15, and RATIONALE-306). Across the six parent-trial reports, 4137 patients were randomized overall; for pooling, KEYNOTE-590 was restricted to the prespecified ESCC subgroup and CheckMate-648 to the nivolumab-plus-chemotherapy comparison. PD-1 inhibitor-based therapy significantly improved OS versus chemotherapy alone (pooled HR 0.68, 95% CI: 0.63-0.74; I2 = 0%, interpreted as low statistical heterogeneity with caution because only six studies were pooled). Qualitative assessment indicated that the treatment effect was generally larger in PD-L1-high populations; however, biomarker-defined subgroup data were not sufficiently harmonized for formal pooling, and the magnitude of benefit in very low or PD-L1-negative disease remains uncertain. Grade ≥ 3 treatment-related adverse events were common in both arms, whereas immune-related toxicities were more frequent with PD-1 inhibitor-based therapy and required active monitoring. CONCLUSION: First-line PD-1 inhibitor-based therapy confers a robust OS benefit in advanced/metastatic ESCC and supports chemoimmunotherapy as a contemporary standard of care. Remaining uncertainties relate mainly to biomarker-negative disease, assay heterogeneity, and cross-trial differences in chemotherapy backbone and geographic composition.