Optimal Sequencing of First-Line Immune Checkpoint Inhibitors With Definitive Chemoradiotherapy: A Multicenter Real-World Cohort Study Comparing Induction, Concurrent, and Consolidation Strategies for Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma.

While first-line immune checkpoint inhibitors (ICIs) combined with chemoradiotherapy (CRT) represent a crucial advancement for unresectable locally advanced esophageal squamous cell carcinoma (ESCC), the optimal sequencing of these modalities remains unresolved. To evaluate the efficacy and safety of induction, concurrent, and consolidation ICI strategies, this multicenter real-world cohort study enrolled 662 patients with Stage II-IVA unresectable ESCC across 12 cancer centers. Patients were categorized into induction (IC-CRT), concurrent (ICRT), and consolidation (CRT-IC) groups, with inverse probability of treatment weighting (IPTW) applied to balance baseline characteristics. Following IPTW adjustment, the median overall survival (OS) in the IC-CRT, ICRT, and CRT-IC groups was 34.7 months, not reached, and 23.1 months, respectively (p = 0.016), while the corresponding median progression-free survival (PFS) times were 20.1, 25.3, and 12.9 months, respectively (p = 0.014). Among the three sequencing strategies, ICRT achieved the most favorable survival outcomes, followed by IC-CRT and CRT-IC. Multivariable Cox regression confirmed that ICRT was associated with a significantly reduced risk of mortality compared with IC-CRT (HR = 0.71, p = 0.046) and CRT-IC (HR = 0.53, adjusted p < 0.001). Safety profiles indicated that ICRT carried the highest burden of Grade 3-4 treatment-related pneumonitis (7.7%). In conclusion, ICRT as a first-line treatment for locally advanced ESCC showed the most favorable survival profile compared with induction or consolidation sequencing, although its higher toxicity profile necessitates careful patient selection and proactive clinical management. In contrast, the CRT-IC strategy exhibited the best tolerability but the least favorable survival outcome.