Abstract: Objective To evaluate the efficacy and safety of combining immune checkpoint inhibitor (ICI) with chemotherapy， as opposed to administering second⁃line chemotherapy alone， in patients with progressive or metastatic esophageal squamous cell carcinoma (ESCC) who have experienced failure of first⁃line immunotherapy. Methods The study included patients with advanced ESCC who were treated at the Department of Oncology， Renmin Hospital of Wuhan University， from September 2019 to December 2023. Patients who received only second⁃line chemotherapy following progression on first⁃line immunotherapy were designated as the chemotherapy⁃alone group， whereas those who received a combination of ICI and chemotherapy were classified as the ICI combined with chemotherapy group. The study compared overall survival (OS)， progression⁃free survival (PFS)， objective response rate (ORR)， disease control rate (DCR)， and safety outcomes between the two groups. Results A total of 112 eligible patients were screened， comprising 31 individuals in the chemotherapy⁃ alone group and 81 in the ICI combined with chemotherapy group. Survival analysis demonstrated that the ICI combined with chemotherapy group indicated a significantly longer OS compared to the chemotherapy⁃alone group (10.8 months vs 6.9 months; HR=0.56， 95%CI: 0.35-0.89; P=0.013) and a higher DCR (80.2% vs 58.1%; OR=0.35， 95%CI: 0.15-0.81; P=0.016). However， PFS was not significantly extended (5.0 months vs 3.7 months; HR=0.79， 95%CI : 0.50-1.23; P=0.293)， nor was the ORR (33.3% vs 16.1%; OR=0.38， 95%CI: 0.15-1.14; P=0.071). Subgroup analysis revealed that male patients with primary tumor located in the middle esophagus， stage Ⅲ-Ⅳ， distant metastasis， or PD⁃L1 combined positive score (CPS)  ≥10 derived greater benefit from the chemotherapy combined with ICI treatment， regardless of first⁃line PFS duration. The overall incidence of any grade treatment⁃related adverse events (TRAEs) was 93.5% in the chemotherapy⁃alone group and 98.8% in the ICI combined with chemotherapy group (P=0.126)， while the incidence of TRAEs of grade 3 or higher was 29.0% and 34.6% (P=0.577)， respectively; all grade 3 or higher TRAEs were resolved with symptomatic treatment.结论In patients with advanced ESCC who had previously failed first⁃line immunotherapy， the combination of chemotherapy and ICI treatment exhibited significant survival benefits and an acceptable safety profile compared to chemotherapy alone.

Key words: Esophageal squamous cell carcinoma, Immune checkpoint inhibitor, Chemotherapy, Second?line treatment, Efficacy, Safety