Toripalimab plus chemotherapy and radiotherapy for treatment-naïve advanced esophageal squamous cell carcinoma: Long-term survival and recurrence patterns.

4064 Background: Concurrent chemoradiotherapy plus PD-1 blockade is standard for locally advanced esophageal squamous cell carcinoma (ESCC), but its role in advanced disease remains undefined. We investigated the safety and efficacy of Toripalimab combined with chemotherapy and radiotherapy (RCIT) as first-line treatment for advanced ESCC, analyzing long-term survival, recurrence patterns, and immune biomarkers. Methods: This single-arm, phase II trial enrolled treatment-naïve patients with stage IV ESCC (N3 nodal or oligometastases; 5 lesions in 3 organs). Treatment comprised induction chemoimmunotherapy (2 cycles) followed by concurrent radiotherapy (Cycles 3-4) and maintenance immunotherapy. Patients received Paclitaxel (135-175 mg/m2) and Carboplatin (AUC 4-6) plus Toripalimab (240 mg) on day 1 (Q3W). Intensity-modulated radiotherapy (50-50. 4 Gy/25-28f) targeted primary/regional lesions, while SBRT (30-40 Gy/3-5f) targeted oligometastases. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), recurrence patterns, health-related quality of life (HRQOL), and biomarker analysis via multiplex immunofluorescence (mIF). Results: Thirty-three patients were enrolled. At a median follow-up of 33. 4 months, the 2-year PFS and OS rates were 30. 3% (95% CI: 18. 1-50. 8) and 48. 5% (95% CI: 34. 1-68. 9), respectively. In the efficacy-evaluable population completing radiotherapy (n = 26), outcomes were significantly superior to those who did not, with a median OS of 27. 4 months and a 2-year OS of 61. 5% (HR = 0. 26, p = 0. 004). Recurrence occurred in 26 (78. 8%) patients, comprising locoregional only (27. 3%), distant only (18. 2%), and combined failure (33. 3%). Notably, among patients completing RT, in-field recurrence (57. 7%) remained a predominant failure pattern despite multimodal therapy. HRQOL analysis demonstrated significant post-induction improvement in pain and social functioning scores, whereas radiotherapy transiently worsened dysphagia at 3 months post-RT (p = 0. 041). Translational analysis revealed that high baseline tumor infiltration of CD8+ T cells, PD-L1+ dendritic cells, and PD-L1+ macrophages, alongside elevated serum IL-4, IL-17, and IFN-γ, were significantly associated with long-term survival (OS ≥24 months; p < 0. 05). Conclusions: First-line RCIT yields promising long-term survival in advanced oligometastatic ESCC, particularly in patients completing the full radiotherapeutic course, achieving a 2-year OS of 61. 5%. However, high rates of in-field recurrence suggest a need for further optimization of local control strategies. Baseline immune infiltrates and cytokine profiles offer potential predictive value for patient stratification. Randomized trials are warranted to validate these findings. Clinical trial information: ChiCTR2100046715.