Immune Checkpoint Inhibitor Therapy for Advanced, Unresectable Esophageal Squamous Cell Carcinoma: A Series of Patient-level Meta-analyses From Phase III Trials

AimThis study reconstructed patient-level data to provide updated evidence on survival outcomes across PD-L1 expression subgroups.Materials and MethodsA systematic search was conducted on March 2, 2025, using PubMed, Embase, Web of Science, Cochrane, and Scopus for RCTs comparing ICIs to chemotherapy in advanced ESCC. Kaplan-Meier curves were reconstructed using a time-to-event algorithm for all patients and for PD-L1 subgroups. KMSubtraction was used to retrieve unpublished survival data. A patient-level meta-analysis was performed using a stratified Cox model.ResultsThirteen phase III trials (6,672 patients) were included. In the first-line setting, patients with TPS <1% (from CheckMate-648 and ESCORT-1st) showed no overall survival (OS) benefit (HR: 0.88, p = 0.187), whereas those with TPS ≥1% from the same trials showed a significant benefit (HR: 0.61, p < 0.001).For a combined positive score (CPS) ≥10, pooled data from ASTRUM-007, KEYNOTE-590, ORIENT-15, and GEMSTONE-304 showed significant OS benefit (HR: 0.60, p < 0.001). CPS <10 (KEYNOTE-590, ORIENT-15, and GEMSTONE-304) also showed benefit (HR: 0.81, p = 0.02), but no survival benefit was seen in CPS 1–9 (ASTRUM-007 and GEMSTONE-304) (HR: 0.82, p = 0.117).ConclusionPD-L1 appears to be a useful biomarker in advanced ESCC. Patients with PD-L1 levels of 10 or higher consistently showed survival benefits. For PD-L1 <10, treatment decisions may be less clear; further research on combining PD-L1 with other biomarkers is needed. Patients with PD-L1 <1 showed minimal benefit and should be informed about the limited efficacy of ICIs.