Immune checkpoint inhibitors plus chemotherapy versus chemotherapy alone as first-line treatment for unresectable or metastatic esophageal carcinoma: A systematic review and meta-analysis of randomized trials.

e16083 Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy are standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC); however, their benefit in esophageal adenocarcinoma (EAC) and across programmed death-ligand 1 (PD-L1) subgroups remains uncertain. Given substantial histologic heterogeneity, we performed a systematic review and meta-analysis to critically assess the efficacy and safety of first-line ICI-chemotherapy in advanced esophageal carcinoma. Methods: PubMed, Embase, Cochrane Central, and major oncology conference proceedings were searched through April 2024 for phase II/III randomized trials comparing anti–PD-1/PD-L1–based ICI plus platinum/fluoropyrimidine chemotherapy versus chemotherapy alone in treatment-naïve patients with unresectable or metastatic esophageal carcinoma. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and grade ≥3 treatment-related adverse events (TRAEs). Random-effects models were used to estimate pooled hazard ratios (HRs) and odds ratios (ORs). Prespecified subgroup and interaction analyses were conducted by histology, PD-L1 combined positive score (CPS), and liver metastases. Risk of bias was assessed using the Cochrane RoB 2 tool. Results: Seven trials comprising 4,812 patients were included. ICI-chemotherapy significantly improved OS (HR 0.68, 95% CI 0.63–0.74) and PFS (HR 0.62, 95% CI 0.57–0.67) versus chemotherapy alone. OS benefit was robust in ESCC (HR 0.68, 95% CI 0.62–0.74) but not statistically significant in EAC (HR 0.74, 95% CI 0.54–1.02). OS benefit was observed in PD-L1 CPS ≥10 and CPS < 10 subgroups without significant interaction (p = 0.09). Patients with liver metastases derived significantly less OS benefit (p-interaction = 0.04). ORR favored ICI-chemotherapy (OR 1.82, 95% CI 1.52–2.17), with higher grade ≥3 TRAEs (OR 1.32, 95% CI 1.12–1.56). Most trials were ESCC-dominant. Conclusions: First-line ICI-chemotherapy confers a meaningful survival advantage in advanced esophageal carcinoma, driven primarily by ESCC. Evidence in EAC remains inconclusive and underpowered. Apparent benefit across PD-L1 CPS strata and reduced efficacy in liver metastases emphasize the need for histology-specific and biomarker-refined strategies.