Consolidation of Toripalimab and Capecitabine After Chemoradiotherapy in ESCC

Toripalimab Combined With Capecitabine as Maintenance Therapy After Definitive Chemoradiotherapy for Esophageal Squamous Cell Carcinoma: a Multicenter, Randomized Controlled, Phase III Trial (EC-CRT-008)

Definitive chemoradiotherapy (CRT) is the standard treatment for locally advanced unresectable esophageal cancer, but its efficacy remains unsatisfactory. More importantly, there is a lack of effective consolidation treatment after CRT, resulting in a high recurrence rate. Our previous prospective phase II trial (EC-CRT-001) demonstrated that the addition of toripalimab to definitive CRT improved the complete response rate in patients with locally advanced esophageal squamous cell carcinoma (ESCC), showing potential for enhanced long-term survival with a manageable safety profile. Nevertheless, the risk of recurrence requires further reduction. Metronomic capecitabine chemotherapy can modulate the tumor immune microenvironment and may synergize with PD-1 antibodies to enhance antitumor efficacy, potentially further prolonging survival in ESCC. Based on current research advances and our preliminary findings, this randomized, controlled, multicenter, phase III clinical trial aims to evaluate the efficacy and safety of toripalimab combined with capecitabine as maintenance therapy for patients with locally advanced ESCC who have not progressed after definitive CRT.

Inclusion Criteria:

1. Histologically confirmed squamous cell carcinoma of the esophagus;
2. Locally advanced esophageal cancer classified as stage I-IVA (inoperable or patient declined surgery) or stage IVB thoracic esophageal cancer with supraclavicular lymph node metastasis only (AJCC 8th edition) prior to treatment;
3. Completion of definitive concurrent chemoradiotherapy without disease progression; radiotherapy dose of 50-50.4 Gy using conventional fractionation and IMRT technique; concurrent platinum- or taxane-based doublet chemotherapy during radiotherapy; ≤4 cycles of induction chemotherapy allowed prior to radiotherapy; PD-1/PD-L1 antibody therapy permitted during induction chemotherapy and radiotherapy; no adjuvant therapy received;
4. Enrollment window: within 1-42 days after completion of chemoradiotherapy;
5. Age 18-75 years;
6. Estimated life expectancy >6 months;
7. Eastern Cooperative Oncology Group performance status ≤ 2;
8. The function of important organs meets the following requirements: a. white blood cell count (WBC) ≥3.5×109/L, absolute neutrophil count (ANC) ≥1.5×109/L; b. platelets ≥75×109/L; c. hemoglobin ≥9g/dL; d. serum albumin ≥2.8g/dL; e. total bilirubin ≤1.5×ULN, ALT, AST and/or AKP ≤2.5×ULN; f. serum creatinine ≤1.5×ULN or creatinine clearance rate >60 mL/min;
9. Ability to understand the trial details and has provided written informed consent.

Exclusion Criteria:

1. Patients who have received antitumor therapy (including adjuvant chemotherapy, surgery, immunotherapy, targeted therapy, etc.) after completion of chemoradiotherapy;
2. Stage IVb patients with metastasis to solid organs (e.g., liver, bone, lung, brain, adrenal gland, peritoneum, etc.) at initial diagnosis;
3. Known or suspected allergy to the investigational drug(s) or any agent related to the trial regimen;
4. Presence of esophageal fistula and/or esophageal hemorrhage prior to enrollment;
5. Disease progression after chemoradiotherapy;
6. ≥Grade 2 radiation pneumonitis prior to enrollment;
7. History of ≥ Grade 3 immune-related adverse events prior to enrollment;
8. Prior treatment with targeted drugs;
9. History of other malignant tumors besides esophageal cancer, except for non-melanoma skin cancer, carcinoma in situ of the cervix, papillary thyroid carcinoma, or cured early-stage prostate cancer;
10. Patients with severe cardiac, pulmonary, hepatic, or renal dysfunction, hematopoietic system diseases, cachexia, or other conditions that make them unfit for chemotherapy;
11. Female patients who are pregnant or breastfeeding;
12. Inability to provide informed consent due to psychological, familial, social, or other factors;
13. Presence of CTC grade ≥2 peripheral neuropathy;
14. Patients with a history of diabetes for more than 10 years and poorly controlled blood glucose levels;
15. History of autoimmune disease or autoimmune disorders (e.g., colitis, systemic lupus erythematosus, rheumatoid arthritis, uveitis, hypophysitis, hyperthyroidism; not limited to these diseases or syndromes), immunodeficiency history, including HIV positivity, or other acquired/congenital immunodeficiency disorders, or history of organ transplantation or allogeneic bone marrow transplantation;
16. History of interstitial lung disease or non-infectious pneumonia;
17. Active hepatitis B (HBV DNA ≥2000 IU/mL or 10⁴ copies/mL) or hepatitis C (HCV antibody positive with HCV-RNA above the lower limit of detection);
18. Any unstable condition that may jeopardize patient safety or compliance.