A Phase II Study of Anlotinib + PD-1 Inhibitor vs. PD-1 Inhibitor Maintenance After First-Line Chemoimmunotherapy in Advanced ESCC (Esophageal Squamous Cell Carcinoma)

Prior treatment

• Patients who can be cured by surgery or radiotherapy;
• Presence of complete esophageal obstruction requiring interventional treatment; prior esophageal or tracheal stent placement before enrollment; or presence of factors that significantly affect the absorption of oral drugs (anlotinib), such as inability to swallow tablets, chronic diarrhea, or intestinal obstruction;
• Prior treatment with anlotinib; or treatment with other VEGF small-molecule tyrosine kinase inhibitors (TKIs) within 6 months before the first dose (Note: patients who received other VEGF TKIs during (neo)adjuvant/radical therapy and whose last dose was more than 6 months before this recurrence/progression may be enrolled);
• Patients who experienced grade ≥3 immune-related adverse events (irAEs) during PD-1 inhibitor combined with chemotherapy, or for whom the investigator considers continued PD-1 inhibitor treatment inappropriate due to toxicities;
• Presence of symptomatic brain metastases or meningeal metastases (Note: patients whose brain metastases have been locally treated and remained stable for at least 4 weeks before enrollment without the need for glucocorticoids to reduce intracranial pressure may be allowed to enroll);
• Bleeding tendency: clinically significant active bleeding within 2 months before screening (such as gastrointestinal bleeding, hematemesis, melena, etc., with a daily blood loss ≥2.5 mL); or patients with abnormal coagulation function, a bleeding tendency, or currently receiving thrombolytic or anticoagulant therapy (except prophylactic use of low-dose aspirin or low-molecular-weight heparin);
• History of thrombosis: arterial or venous thrombotic events within 6 months before enrollment, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism;
• Surgery and trauma: major surgery (such as thoracotomy or laparotomy) within 4 weeks before the first dose, or presence of long-term non-healing wounds or fractures, or expected need for major surgery during the study period;
• Investigator's judgment: presence of severe concomitant diseases (such as uncontrolled diabetes, severe liver or kidney disease, etc.), psychiatric disorders, or psychological, family, social, or other factors that the investigator considers may jeopardize patient safety and compliance.

Other illness

• Known or suspected allergy to the study drug or to any drug administered in connection with this trial;
• Endoscopic or imaging findings indicating obvious deep ulceration of the esophageal lesion; or obvious invasion of adjacent vital organs (such as the aorta or trachea) by the tumor with a very high risk of bleeding or perforation; or formation of an esophageal-tracheal fistula/esophageal-mediastinal fistula;
• Patients with a history of other malignancies besides esophageal cancer before enrollment, except for melanoma skin cancer, carcinoma in situ of the cervix, or cured early-stage prostate cancer;
• Poor blood pressure control despite antihypertensive medication (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg); or patients using two or more antihypertensive drugs to control blood pressure; patients with a history of hypertensive crisis or hypertensive encephalopathy;
• Active infection: presence of active infection requiring intravenous systemic anti-infective therapy, or known active tuberculosis;
• Immune-related deficiency: known history of immunodeficiency, including positive HIV test, or other acquired or congenital immunodeficiency diseases, or a history of solid organ transplantation;

Lab values

• Severe cardiovascular disease: myocardial infarction, severe/unstable angina, NYHA class III-IV heart failure, left ventricular ejection fraction (LVEF) \<50% on echocardiography, severe arrhythmia requiring pharmacological intervention, or prior coronary/peripheral artery bypass grafting within 6 months before enrollment;

Other

• High renal risk: patients with urine protein ≥++ on urinalysis and confirmed 24-hour urinary protein \>1.5 g;
• Female patients who are pregnant or breastfeeding;

• Pathologically confirmed esophageal squamous cell carcinoma;
• Unresectable locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma that has not received prior systemic therapy, or recurrence more than 6 months after completion of (neo)adjuvant/radical therapy;
• Patients who have completed 4-6 cycles of PD-1 inhibitor combined with platinum-based doublet chemotherapy, who may receive local therapy if the investigator determines a benefit from local treatment, and who have not progressed after the above treatment;
• Enrollment window: randomization must be performed within 42 days after completion of the last treatment (including local therapy);
• Expected survival greater than 3 months;
• Age 18-75 years;
• ECOG performance status score of 0-1;
• Laboratory tests within 7 days before the first dose must meet the following requirements: Hematology: neutrophils ≥1.5×10\^9/L, platelets ≥75.0×10\^9/L, hemoglobin ≥80 g/L; Liver function: total bilirubin ≤1.5 × ULN, ALT/AST ≤2.5 × ULN (≤5 × ULN if liver metastasis is present); Renal function: serum creatinine ≤1.5 × ULN or creatinine clearance \>60 mL/min; Coagulation function: international normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN; no concomitant severe organic disease;
• The patient understands the details of the trial and has signed the informed consent form.