Real-world evidence on definitive chemoradiotherapy following neoadjuvant chemoimmunotherapy in locally advanced head and neck squamous cell carcinoma.

6094 Background: Real-world evidence regarding the efficacy and safety of neoadjuvant chemoimmunotherapy (NACI) in the treatment of curable head and neck squamous cell carcinoma (HNSCC) is currently limited. This multi-center study aimed to evaluate the outcomes of NACI in China. Methods: This retrospective study examined stage II-IVB HNSCC patients who underwent NACI followed by radical surgery (Group A) or definitive concurrent chemoradiotherapy (CCRT) (Group B) at four medical centers in China from 2019 to 2025. Propensity score matching was employed to balance baseline covariates between the groups. The primary endpoint was progression-free survival (PFS), while key secondary endpoints included complete pathological response (pCR), major pathological response (MPR), overall survival (OS), and treatment-related adverse events (TRAEs), which were graded according to the CTCAE v5.0 criteria. Survival analyses were conducted using Kaplan-Meier/log-rank tests and Cox proportional hazards models. Results: After matching (n=756), baseline characteristics were well-balanced (|SMD|<0.1). Group A (NACI + surgery, n=457) showed a 67% radiological response and MPR rate, with a 38% pCR, while Group B (NACI + CCRT, n=299) achieved a higher 76% radiological response rate. Regimens were similar (taxane-platinum-immunotherapy), but Group A received fewer chemotherapy cycles (3-4 cycles: 66% vs. 90%). Post-NACI progression was lower in Group B (0.7%). Group B demonstrated significantly longer PFS (hazard ratio [HR] 0.68; p=0.036) and markedly improved OS (HR 0.20; p<0.001). Multivariate analysis confirmed NACI + CCRT (Group B) as a significant independent predictor of improved OS (HR=0.20, 95% CI 0.07–0.59; p=0.003), considering factors such as betel nut use, tumor location, and T and N staging. Common grade 3-4 TRAEs were neutropenia and transaminase elevations; among grade 3 immune-related AEs, thyroid dysfunction predominated. Conclusions: This multicenter real-world study highlights that the combination of NACI and CCRT (Group B) results in significantly better PFS and OS outcomes compared to the NACI and surgical intervention (Group A), despite a pCR rate of 38% in Group A. These findings support the potential benefit of concurrent chemoradiotherapy as a consolidative approach following NACI. However, it is important to recognize that the observational nature of this study prevents definitive conclusions about causality. Therefore, prospective randomized controlled trials are essential to confirm these findings and to ascertain the optimal consolidative strategy. Additionally, further investigation into biomarker-driven patient selection is vital for enhancing treatment precision and effectiveness.