Tislelizumab combined with radiotherapy for unresectable locally advanced esophageal squamous cell carcinoma: A prospective, single-arm, phase II study (TREC)

Background: Treatment options for unresectable locally advanced esophageal squamous cell carcinoma (ESCC) that cannot tolerate concurrent chemoradiotherapy (CCRT) are exceedingly limited. This study aimed to evaluate the efficacy and safety of tislelizumab, a programmed cell death protein 1 (PD-1) inhibitor, in combination with definitive radiotherapy as a novel chemotherapy-free first-line treatment for patients with unresectable, locally advanced ESCC who are ineligible for standard CCRT. Methods: This prospective, single-arm, phase II clinical trial (ChiCTR2100053182) recruited treatment-naïve patients diagnosed with unresectable, locally advanced ESCC at Binzhou Medical University Hospital. Eligibility was limited to patients considered ineligible for standard CCRT due to medical contraindications or patient preference. The investigational regimen consisted of tislelizumab (200 mg intravenously) administered on a three-week cycle, initiated concurrently with the first fraction of radiotherapy. The primary endpoint was progression-free survival (PFS). Additionally, the protocol included a prespecified exploratory analysis of tumor immune microenvironment markers using high-throughput multiplex immunofluorescence. Results:From May 2021 to October 2022, 32 eligible patients were enrolled. The mPFS was 23.5 months (95% CI 18.2–not reached), the 1-, 2-, and 3-year PFS rates were 75.0%, 57.1% and 42.9% respectively. The median overall survival (mOS) was not reached, with a 3-year OS rate of 53.6%. The regimen demonstrated substantial efficacy, achieving an objective response rate (ORR) of 82.1% and a pathological complete response (pCR) rate of 64.3%. Treatment was well-tolerated; the most frequent grade ≥3 treatment-related adverse event (TRAE) was lymphopenia (53.6%). Exploratory biomarker analysis revealed that high densities of T-cell exhaustion markers (e.g., intratumoral PD-1+ cells) were significantly associated with poorer PFS and OS, whereas high expression of stromal CD68+PD-L1+ cells was a strong favorable prognostic factor. Conclusion: This phase II study demonstrates that the combination of tislelizumab and definitive radiotherapy yields promising efficacy and manageable toxicity in patients with unresectable, locally advanced ESCC who are ineligible for standard CCRT. Moreover, the observed associations between immune cell signatures and treatment outcomes highlight the potential for biomarker-driven patient selection in future trials.