Tislelizumab Combined With Induction Chemotherapy and Concurrent Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma: A Multicenter, Randomized, Phase II Trial (EC-CRT-002)

PURPOSE To evaluate the efficacy and safety of adding tislelizumab to induction chemotherapy and concurrent chemoradiotherapy (CRT), with or without maintenance immunotherapy, in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS This multicenter, randomized, open-label, phase II trial was conducted across four academic hospitals in China (ClinicalTrials.gov identifier: NCT05520619 ). Participants were adults age 18-70 years with newly diagnosed, unresectable, stage II to IVB ESCC. Patients were randomly assigned (1:1) to receive two cycles of paclitaxel/cisplatin induction chemotherapy followed by concurrent CRT in combination with tislelizumab for 16 cycles in group A (two induction, two concurrent, and 12 maintenance) or four cycles in group B (two induction and two concurrent). The primary end point was progression-free survival (PFS) in the intention-to-treat population, compared with historical control. RESULTS Between October 2022 and October 2024, 114 patients were randomly assigned to group A (n = 57) or group B (n = 57). After a median follow-up of 22.7 months (IQR, 16.2-28.2), group B demonstrated significantly better PFS versus controls (1-year: 71.9% [95% CI, 61.1 to 84.6] v 56.4% [95% CI, 44.7 to 71.1]; hazard ratio [HR], 0.54 [95% CI, 0.32 to 0.94]), while group A showed no PFS benefit (1-year: 52.6% [95% CI, 41.4 to 67.3]; HR, 1.06 [95% CI, 0.67 to 1.68]). Overall survival was also significantly better in group B (HR, 0.42 [95% CI, 0.22 to 0.82]). Grade ≥3 adverse events occurred in 86.0% of group A and 80.7% of group B, with the most common being lymphopenia (77.2% and 73.7%, respectively). Comprehensive biomarker analyses revealed that PD-L1 expression, CD8 + T-cell density, NRF2 pathway mutations, and dynamic changes in circulating tumor DNA were associated with treatment efficacy. CONCLUSION The addition of tislelizumab to induction chemotherapy and concurrent CRT without maintenance immunotherapy demonstrated superior efficacy and manageable toxicity in locally advanced ESCC.