An Umbrella-designed Prospective Multicenter Randomized Open-label Superiority Trial Evaluating Multi-biomarker-guided Precision Therapy for First-line Treatment of Advanced Esophageal Squamous Cell Carcinoma

This is a prospective, multicenter, randomized, open-label, umbrella superiority clinical trial for patients with advanced metastatic esophageal squamous cell carcinoma who have not received prior anti-tumor treatment. All eligible participants will be randomly assigned into two cohorts: Cohort A (standard treatment group) and Cohort B (biomarker-guided precision treatment group). Patients in Cohort A will receive first-line standard therapy consisting of TP chemotherapy plus PD-1 inhibitor. All patients in Cohort B will first complete three biomarker tests, then be divided into 4 sub-groups based on biomarker results to receive biomarker-directed additional treatment combined with the same standard backbone therapy. Participants with all negative biomarkers or failed biomarker testing will receive the identical standard treatment as Cohort A. The primary objective is to compare the survival benefit between biomarker-guided multi-strategy precision therapy and conventional standard first-line treatment.

Inclusion Criteria: 1. Aged between 18 and 75 years (calculated on the date of signing the informed consent form); 2. Patients with metastatic esophageal squamous cell carcinoma (ESCC) confirmed by histopathology or cytology; 3. Treatment-naïve patients with no prior anti-tumor therapy; 4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, with an expected survival of more than 3 months; 5. Judged by the investigator to be suitable for first-line chemotherapy; 6. Presence of at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1); 7. Women of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, condoms) throughout the study period and for 6 months after the end of study treatment; they must have a negative serum or urine pregnancy test within 7 days prior to enrollment and shall not be breastfeeding. Male patients must agree to use effective contraception throughout the study period and for 6 months after the end of study treatment. Version: 1.0, Version Date: March 18, 2026 8. Voluntarily participate in this study and provide written informed consent. Exclusion Criteria: 1. Brain metastases with symptoms or symptom control duration less than 2 months; 2. History of or concurrent other malignant tumors within the past 3 years (excluding cured basal cell carcinoma of the skin and carcinoma in situ of the cervix); 3. Insufficient bone marrow hematopoietic function (without blood transfusion within 14 days): 1. Absolute Neutrophil Count (ANC) \< 1.5 × 10⁹/L; 2. Platelet count \< 100 × 10⁹/L; 3. Hemoglobin \< 90 g/L. 4. Hepatic abnormalities: 1. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) or Alkaline Phosphatase (ALP) \> 2.5 × Upper Limit of Normal (ULN) in patients without liver metastases; ALT, AST or ALP \> 5 × ULN in patients with liver metastases; 2. Serum total bilirubin \> 1.5 × ULN (\> 3 × ULN for patients with Gilbert's syndrome); 3. Decompensated liver cirrhosis (Child-Pugh liver function grade B or C); 4. Positive Hepatitis B Surface Antigen (HBsAg) with Hepatitis B Virus (HBV) DNA load ≥ 2000 IU/mL. Patients with positive HBsAg and HBV DNA load \< 2000 IU/mL must receive anti-HBV therapy for at least 2 weeks prior to the first study drug administration; 5. Positive Hepatitis C Virus (HCV) antibody with detectable HCV RNA. 5. Renal abnormalities: 1. Serum creatinine \> 1.5 × ULN or estimated creatinine clearance \< 60 mL/min calculated by the Cockcroft-Gault formula; 2. Urinalysis showing urine protein ≥ ++, confirmed with 24-hour urinary protein quantification \> 1.0 g; 3. Renal failure requiring hemodialysis or peritoneal dialysis; 4. Medical history of nephrotic syndrome. 6. Bleeding risks: 1. Abnormal coagulation function: Activated Partial Thromboplastin Time (APTT) or Thrombin Time (TT) \> 1.5 × ULN, or International Normalized Ratio (INR) \> 1.5 (\> 2.5 for subjects receiving anticoagulant therapy); 2. History of hemorrhage (hemoptysis), coagulopathy, or ongoing use of warfarin, aspirin, low-molecular-weight heparin and other antiplatelet drugs (except prophylactic aspirin at a dose ≤ 100 mg/day); 3. Any signs or history of bleeding diathesis regardless of severity; 4. Active gastrointestinal bleeding defined as hematemesis, hematochezia or melena within the past 3 months without evidence of resolution confirmed by gastroscopy or colonoscopy; 5. Any Grade ≥ 3 bleeding event per CTCAE occurring within 4 weeks prior to the first study drug administration. Version: 1.0, Version Date: March 18, 2026 7. Cardiovascular and cerebrovascular abnormalities: 1. Subjects with any of the following conditions within 12 months before the first study drug administration: grade ≥ II myocardial ischemia or myocardial infarction, arrhythmia, grade ≥ III cardiac insufficiency, uncontrolled angina, coronary/peripheral artery bypass graft surgery, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, etc.; 2. Deep vein thrombosis or pulmonary embolism occurring within 6 months before the first study drug administration; 3. Left Ventricular Ejection Fraction (LVEF) \< 50% assessed by Doppler echocardiography; 4. Average Fridericia-corrected QT interval (QTcF) (from at least 3 consecutive electrocardiograms): ≥ 450 ms for male patients, ≥ 470 ms for female patients; 5. Uncontrolled hypertension refractory to medication (systolic blood pressure ≥ 150 mmHg and diastolic blood pressure ≥ 100 mmHg recorded in at least two measurements). 8. History of immunodeficiency: 1. Confirmed Human Immunodeficiency Virus (HIV) infection; 2. Other acquired or congenital immunodeficiency disorders; 3. Scheduled or prior solid organ transplantation, hematopoietic stem cell transplantation within 60 days before the first study drug administration, or significant graft-versus-host disease; 4. Patients requiring immunosuppressants, systemic or absorbable local hormonal therapy for immunosuppressive purposes that must be continued within 7 days before the first study drug administration (excluding daily glucocorticoid dose \< 10 mg prednisone or equivalent steroids). 9. Active or uncontrolled severe infection (Grade ≥ 2 per CTCAE); 10. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage (judged by the investigator); 11. Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA-4 antibody, or any other antibodies targeting T cell co-stimulatory or checkpoint pathways (e.g., OX40, CD137, etc.); 12. Complicated with severe or poorly controlled diseases judged by the investigator to carry substantial risks for study participation (e.g., poorly controlled diabetes with screening fasting plasma glucose (FPG) \> 10 mmol/L); 13. Participation in another clinical trial of anti-tumor agents within 28 days prior to screening.