Association of immune-related adverse events with survival outcomes in esophageal squamous cell carcinoma following neoadjuvant chemoimmunotherapy: a national multicenter retrospective cohort study in China

Although immune-related adverse events (irAEs) are increasingly recognized as biomarkers of response to immunotherapy in advanced cancers, their prognostic role in the neoadjuvant setting for esophageal squamous cell carcinoma (ESCC) remains unclear. This retrospective multicenter cohort study aimed to evaluate the associations between irAEs, pathological response, and 2-year survival outcomes in patients with locally advanced ESCC treated with neoadjuvant chemoimmunotherapy (NCIT) followed by esophagectomy. A total of 1076 patients with cT1bN1-3 M0 or cT2-4aN0-3 M0 ESCC who received NCIT and surgery between January 2019 and March 2023 across 26 tertiary centers in China were included. IrAEs, defined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, were observed in 181 patients (16.8%), with rash/pruritus being the most common. Patients who developed irAEs completed fewer NCIT cycles and had longer treatment-to-surgery intervals, both of which were independently associated with worse disease-free survival (DFS). Although the occurrence of irAEs correlated with inferior overall survival (OS)-particularly pneumonitis and rash/pruritus-multivariable analysis revealed that irAEs were not independent predictors of either OS or DFS. The strongest independent predictors of survival were pathological nodal status (ypN3) and poor tumor regression (TRG4). In conclusion, despite being linked to prolonged treatment-to-surgery intervals, irAEs were not significantly associated with pathological response or long-term survival outcomes in this cohort of ESCC patients treated with NCIT and surgery, underscoring the importance of effective management of irAEs during neoadjuvant therapy.