PD-1 inhibitors + chemo improve OS, PFS, ORR in first-line advanced ESCC; benefit limited in PD-L1 CPS <1Who benefits most from new esophageal cancer treatment? Most patients do, except one group

BACKGROUND: Esophageal cancer exhibits peak incidence in Asia and Africa, representing the sixth most common malignancy and seventh leading cause of global cancer mortality. Esophageal squamous cell carcinoma (ESCC) constitutes 90% of esophageal cancer cases. The European Medicines Agency approved programmed death 1 (PD-1) inhibitors plus chemotherapy as a first-line treatment for high PD-1-expressing ESCC. METHODS: We systematically searched randomized controlled trials of PD-1 or PD-L1 inhibitors as first-line treatment from PubMed, Embase, and Cochrane Library. The following outcomes were combined: overall survival, progression-free survival, objective response rate, and treatment-related adverse events (TRAEs). Bias risk was rigorously evaluated using the Cochrane Risk of Bias Tool. RevMan 5.3 and R Studio (Boston) were utilized for data synthesis in this meta-analysis, with sensitivity analyses comparing fixed- and random-effects models to reinforce findings. RESULTS: A total of 4702 patients (PD-1 inhibitors plus chemotherapy: 2529; chemotherapy: 2173) were enrolled in 8 randomized controlled trials. Compared with conventional chemotherapy, first-line PD-1 inhibitors plus chemotherapy significantly improved the overall survival (hazard ratio = 0.68, 95% confidence interval (CI): 0.63-0.74; P < .00001) and objective response rate (relative risk [RR] = 2.03, 95% CI: 1.80-2.29; P < .00001) of advanced ESCC patients. Moreover, PD-1 inhibitor-based therapy provided benefits in progression-free survival (hazard ratio = 0.62, 95% CI: 0.58-0.66; P < .00001). But PD-1 inhibitors were not associated with statistically lower incidences of TRAEs and grade 3 to 5 TRAEs. In subgroup analyses, except the limited benefit observed in the programmed death-ligand 1 (PD-L1) combined positive score < 1 subgroup, none of the following factors significantly influenced the efficacy of PD-1 inhibitor therapy: advanced age, metastatic status, number of metastatic organs, or presence of liver metastases. CONCLUSION: The combination of PD-1 inhibitors with chemotherapy demonstrates superior efficacy as first-line therapy for advanced esophageal squamous cell carcinoma. Both elderly patients and those with metastatic involvement derive universal benefit without increased adverse risks. However, patients with PD-L1 combined positive score < 1 may experience restricted clinical benefits. Thus, more precise predictive markers are required to stratify potential responders, enabling broader patient populations to derive benefits from PD-1 inhibitor-chemotherapy regimens.