Immunotherapy combined with chemotherapy has become the first-line standard of care for advanced esophageal squamous cell carcinoma (ESCC), significantly improving patient survival. However, with the widespread adoption of first-line immunotherapy, most patients eventually develop immune resistance. After first-line treatment failure, there is currently no established standard effective therapy for second-line ESCC. Therefore, more effective and safer treatment options are urgently needed for second-line advanced ESCC.

This is a prospective, single-arm, single-center, open-label, Phase II clinical study aiming to evaluate the efficacy and safety of Becotatug Vedotin combined with Tislelizumab and low-dose Lenvatinib in patients with advanced ESCC who have failed first-line therapy. Eligible patients will receive Becotatug Vedotin combined with Tislelizumab and low-dose Lenvatinib. The primary endpoint is objective response rate (ORR) assessed per RECIST v1.1. Secondary endpoints include progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety.

The study consists of two phases: a dose-run-in phase and a dose-expansion phase.

Phase 1 (Dose-Run-In Phase): After signing informed consent, 6 eligible patients will receive Becotatug Vedotin combined with Tislelizumab and low-dose Lenvatinib during the safety run-in period to evaluate the safety and tolerability of the regimen: Becotatug Vedotin (2.0mg/kg, iv, d1, q3w, for 4-6 cycles) combined with Tislelizumab (200mg, iv, d1, q3w) and low-dose Lenvatinib (4 mg, po，once daily at a fixed time). If no more than 1 patient among the 6 treated patients experiences a dose-limiting toxicity (DLT) and no unexpected unacceptable serious adverse events occur, the study will proceed to Phase 2.

Phase 2 (Dose-Expansion Phase): Eligible patients will receive the same combination regimen of Becotatug Vedotin, Tislelizumab, and low-dose Lenvatinib as in Phase 1. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of informed consent, death, pregnancy, investigator's decision to discontinue treatment, or study termination, whichever occurs first.

Inclusion Criteria:

1.Age ≥ 18 years, male or female. 2.Histopathologically or cytologically confirmed recurrent or metastatic esophageal squamous cell carcinoma.

3.Failed first-line or above standard systemic therapy for advanced disease. 4.Patients must be able to provide tumor specimens (paraffin blocks, paraffin-embedded sections, or fresh tissue sections) from primary or metastatic lesions for pathological testing. The most recent archived tumor tissue specimen may be used. If archived tissue is unavailable, a new biopsy is required.

5.ECOG PS 0-2. 6.Expected survival ≥ 3 months. 7.At least one measurable target lesion assessable by CT or MRI according to RECIST version 1.1 criteria.

8.Adequate organ and bone marrow function, as demonstrated by the following laboratory values:

1. Bone marrow: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L；Platelet count (PLT) ≥ 100×10⁹/L；Hemoglobin (HGB)≥90 g/L.
2. Liver: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×ULN; for patients with liver metastases, ALT and AST≤5×ULN.
3. Kidney: Creatinine clearance (Ccr) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula).
4. Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (except for patients receiving therapeutic anticoagulation).
5. Cardiac function: No severe cardiac dysfunction, with left ventricular ejection fraction (LVEF) ≥ 50%.

9.Female patients of childbearing potential must agree to use contraception during the study and for 6 months after the end of study participation, have a negative serum or urine pregnancy test within 7 days prior to study enrollment, and must not be breastfeeding. Male patients must agree to use contraception during the study and for 6 months after the end of study participation.

10.Patients must be able and willing to comply with the scheduled visits, treatment plans, laboratory tests, and other study-related procedures as outlined in the protocol.

11.Patients must be able to understand the study and voluntarily sign the informed consent form.

Exclusion Criteria:

1. Prior malignancy within 5 years, except for carcinoma in situ, basal cell carcinoma, or other malignancies considered cured with negligible risk of recurrence.
2. Known hypersensitivity to any component of the study regimen.
3. High risk of gastrointestinal bleeding, esophageal fistula, or esophageal perforation.
4. Untreated or unstable parenchymal brain metastases, spinal cord metastasis or compression, leptomeningeal disease, or meningeal metastases.
5. Evidence of active infection, including:1）Hepatitis B (HBsAg positive with HBV DNA ≥ 2000 IU/mL, excluding drug-induced or other causes of hepatitis);2）Hepatitis C (anti-HCV antibody positive with HCV RNA above the lower limit of detection);3）Human immunodeficiency virus (HIV) infection;4）Uncontrolled active bacterial, viral, fungal, rickettsial, or parasitic infections that have not resolved prior to study drug administration.
6. Third-space fluid that cannot be controlled by drainage (e.g., massive ascites, pleural effusion, pericardial effusion), or subjects requiring drainage to control third-space fluid within 14 days prior to first dose.
7. Any severe or uncontrolled systemic disease in the investigator's judgment.
8. Poorly controlled cardiac disease, including:

1）Heart failure > New York Heart Association (NYHA) class II; 2）Unstable angina pectoris; 3）Myocardial infarction within 1 year; 4）Clinically significant supraventricular or ventricular arrhythmias requiring treatment; 5）Long QT syndrome, with QTcF > 450 ms (male) or QTcF > 470 ms (female). 9.History of primary immunodeficiency or active autoimmune disease, or current use of immunosuppressants or systemic corticosteroids (≥ 10 mg/day prednisone or equivalent) continuing within 2 weeks prior to enrollment.

10.History of or concomitant interstitial lung disease (ILD), radiation pneumonitis, severe chronic obstructive pulmonary disease (COPD), severe pulmonary insufficiency, or symptomatic bronchospasm.

11.Positive serum pregnancy test or breastfeeding females who do not agree to use adequate contraception during the study and for 6 months after the last dose of study drug.

12.History of organ transplantation, including allogeneic peripheral stem cell or bone marrow transplantation.

13.Peripheral neuropathy ≥ Grade 2 (per CTCAE version 5.0). 14.Prior receipt of any of the following treatments:

1. Intravenous antibiotic therapy within 7 days prior to first dose.

2. Investigational drug from another clinical trial within 4 weeks prior to first dose.

3. Live attenuated vaccine within 4 weeks prior to first dose. Inactivated seasonal influenza vaccines or approved non-replicating COVID-19 vaccines are permitted.

4. Systemic immunostimulatory agents (including but not limited to interferon, interleukin-2, etc.) within 4 weeks prior to first dose.

5. Major surgical procedure (e.g., abdominal or thoracic surgery, excluding diagnostic puncture, infusion device placement, or gastrointestinal stent placement) within 4 weeks prior to first dose, or anticipation of major surgery not directed at the tumor during the study treatment period.

   15.History of substance abuse (psychoactive drugs) that cannot be abstained from, or psychiatric disorders.

   16.Concurrent participation in another interventional clinical study. 17.Any other condition that, in the investigator's judgment, makes the subject unsuitable for participation in this clinical trial.