3029 - First-Line Low-Dose Radiotherapy with Immunochemotherapy Followed by Conventionally Fractionated Radiotherapy and Immunotherapy in Metastatic Esophageal Squamous Cell Carcinoma: A Phase Ib Trial

L. Lin¹, W. Yu¹, S. Zhao², Y. Li¹, W. Feng¹, X. Zhu¹, and X. Fu¹; ¹Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, ²Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

Purpose/Objective(s): Immunochemotherapy (ICT) has emerged as the first-line treatment for metastatic esophageal squamous cell carcinoma (ESCC), yet its efficacy in improving progression-free survival (PFS) and overall survival (OS) remains limited. While radiotherapy is typically used to alleviate symptoms in metastatic ESCC, our retrospective findings indicated a favorable outcome when radiotherapy was delivered if an objective response to first line ICT was observed. Low-dose radiotherapy (LDRT) has been shown to enhance immune cell infiltration and modulate tumor microenvironment, potentially overcoming immunotherapy resistance. Here, we investigated the incorporation of LDRT with ICT, followed by conventionally fractionated radiotherapy (CFRT) and immunotherapy as the first-line treatment for metastatic ESCC, evaluating its efficacy and safety. Materials/

Methods: Patients aged over 18 with treatment-naïve metastatic ESCC were recruited and underwent two steps of treatment. In Step 1, patients received four 3-week cycles of LDRT (2Gy/2Fx over 2 days) immediately followed by ICT (paclitaxel 150mg/m² d1 + carboplatin AUC=5 d1 + PD-1 inhibitor 200mg d1). The gross target volume (GTV) of LDRT covered all visible lesions identified on baseline imaging. In Step 2, patients underwent CFRT (40-50Gy/20-25Fx) and PD-1 inhibitor maintenance Q3W for up to 24 months. The GTV of CFRT covered the residual tumor and metastatic regional lymph nodes identified by PET/CT and endoscopy after Step 1. Primary endpoint was median PFS, and secondary endpoints comprised median OS and grade 3 or higher treatment-related adverse events (TRAEs) assessed by Common Terminology Criteria for Adverse Events (CTCAE) 5.0. OS and PFS were estimated using the Kaplan-Meier method.
Results: From October 2022 to October 2023, 24 eligible patients (median age: 67.5; 83.3% male) from two institutions were enrolled, 21 (87.5%) completing Step 1 and proceeding to Step 2. Nineteen patients (79.2%) completed CFRT and continued with immunotherapy. Evaluation after Step 1 revealed an objective response rate (ORR) of 65.2%, which increased to 71.4% after Step 2. With a median follow-up of 6 months, the median PFS was 9.3 months (95%CI, 8.7-NA months), and the median OS was 11.6 months (95%CI, 9.8-NA months). Most common grade 3 or higher TRAEs included leukopenia (33.3%), neutropenia (20.8%), anemia (16.7%) and dermatitis (8.3%). One patient died from immune-related colitis.
Conclusion: Preliminary findings of the trial showed promising efficacy and relatively mild toxicity, which deserves further follow-up. Larger randomized controlled trials are needed to illustrate the benefit of the combination of radiotherapy and ICT over ICT alone in metastatic ESCC.