A Phase III Study of First-line Anlotinib Combined With Benmelstobart in Patients With Advanced Esophageal Squamous Cell Carcinoma

Inclusion Criteria

• •(1) Histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (excluding adenosquamous carcinoma); (2) No prior systemic therapy, or recurrence more than 6 months after completion of (neo)adjuvant therapy or definitive chemoradiotherapy; (3) Age: ≥18 years (calculated from the date of informed consent signature); ECOG PS score: 0-1; estimated life expectancy \>3 months; (4) Presence of TP53 mutation or FAT1 mutation, and absence of NOTCH3 mutation; (5) At least one measurable lesion as confirmed by RECIST 1.1 criteria; measurable lesions should not have received prior local treatment such as radiotherapy (lesions within prior radiation fields may be selected as target lesions if progression is confirmed); (6) Adequate major organ function meeting the following criteria:
• •Hemoglobin ≥90 g/L;
• •Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L;
• •Platelets ≥75 × 10\^9/L;
• •Total bilirubin ≤1.5 × upper limit of normal (ULN);
• •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if liver metastases present);
• •Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min;
• •Prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤1.5 × ULN (for patients not receiving anticoagulation);
• •Thyroid-stimulating hormone (TSH) ≤ULN (if TSH abnormal, normal free T3 and free T4 are acceptable); (7) Women of childbearing potential must agree to use effective contraception during the study and for 6 months after study completion, with negative serum or urine pregnancy test within 7 days prior to enrollment; men must agree to use effective contraception during the study and for 6 months after study completion, see Section 5.4 for details; (8) Voluntary participation in this study with signed informed consent and good compliance.
• •1. New York Heart Association (NYHA) Class II or greater heart failure or left ventricular ejection fraction (LVEF) \<50% by echocardiography;
• •2. History of clinically significant ventricular arrhythmia (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) or arrhythmia requiring continuous antiarrhythmic medication;
• •3. Unstable angina pectoris;
• •4. Myocardial infarction within 12 months;
• •5. Fridericia-corrected QT interval (QTcF) \>450 msec for males or \>470 msec for females (if abnormal, three consecutive measurements ≥2 minutes apart, use average);
• •6. Congenital long QT syndrome or family history;
• •7. History of deep vein thrombosis, pulmonary embolism, or other serious thromboembolism within 3 months prior to randomization (implanted port or catheter-related thrombosis, or superficial venous thrombosis not considered "serious");
• •8. Current use or recent use (within 7 days prior to study treatment) of aspirin (\>325 mg/day), dipyridamole, ticlopidine, clopidogrel, or cilostazol; (14) Active or uncontrolled severe infection (≥CTCAE Grade 2); (15) Renal failure requiring hemodialysis or peritoneal dialysis; (16) History of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency disorders; (17) Use of immunosuppressants or systemic or absorbable topical corticosteroids for immunosuppressive purposes within 7 days prior to first dose (except prednisone ≤10 mg daily or equivalent); (18) Epilepsy requiring treatment; (19) Tumor-related symptoms and treatment:
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• •1. Cytotoxic chemotherapy, immunotherapy within 3 weeks, or radiotherapy or small molecule targeted therapy within 2 weeks prior to first dose, or within 5 half-lives of drug (whichever is shorter) from last treatment; (prior radiotherapy: target lesions should not be within radiation field, or if within field, progression must be confirmed);
• •2. Traditional Chinese medicines with anti-tumor indications approved by NMPA within 2 weeks prior to first dose (including Compound Cantharis Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Brucea Javanica Oil Injection/Capsules, Xiaoaiping Tablets/Injection, Huachansu Capsules, etc.);
• •3. Imaging evidence of significant tumor invasion into adjacent organs (aorta or trachea) with increased risk of bleeding or fistula; ulcerative ESCC with increased bleeding risk due to proximity to vessels;
• •4. Known complete esophageal obstruction requiring interventional relief;
• •5. Post-esophageal or tracheal stent placement;
• •6. Uncontrolled pleural effusion, pericardial effusion, or moderate to severe ascites requiring repeated drainage (investigator judgment);
• •7. Known spinal cord compression, carcinomatous meningitis, or brain metastasis with symptoms or symptom control \<4 weeks; (20) Known hypersensitivity to study drug excipients; (21) Prior treatment with anlotinib hydrochloride or other anti-angiogenic agents, or any anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody; (22) Participation in other interventional clinical trials with investigational drug use within 4 weeks prior to first dose; (23) Pregnancy, lactation, or planned pregnancy during study period; (24) Any condition that, in the opinion of the investigator, would pose significant safety risk to the subject or interfere with completion of the study.