The purpose of this study is to evaluate the safety, tolerability and preliminary antitumor activity of SKB500 combinations in patients with Esophageal Squamous Cell Carcinoma. The study is divided into three parts: the safety run-in phase, randomized enrollment phase and cohort expansion phase.

This is a Phase II, multicenter, open-label study to evaluate the safety, tolerability and preliminary antitumor activity of SKB500 combinations in patients with Esophageal Squamous Cell Carcinoma. The study is divided into three parts: the safety run-in phase, randomized enrollment phase and cohort expansion phase.

Inclusion Criteria:

1. Age ≥18 years and ≤75 years

2. Histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC), who are ineligible for curative-intent therapies:

   • Safety run-in phase (Cohort 1, 2 and 3): received no more than 1 prior line of systemic therapy for locally advanced or metastatic ESCC.
   • Safety run-in phase (Cohort 4), randomized enrollment phase and cohort expansion phase: no prior systemic therapy for locally advanced or metastatic ESCC.

3. Participants are required to provide tumor tissue samples for biomarker analysis.

4. Has at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Life expectancy ≥ 12 weeks.

Exclusion Criteria:

1. Histology or cytology confirms the presence of concurrent adenocarcinoma components.
2. Leptomeningeal, brainstem, spinal, spinal cord compression, or active CNS metastases.
3. Risk of esophagotracheal/esophagopleural fistula, or symptomatic invasion/compression of vital organs/major blood vessels.
4. Active autoimmune disease requiring systemic therapy within past 2 years.
5. Weight loss ≥10% within 4 weeks prior to the first dose, or Nutritional Risk Index (NRI) < 83.5.
6. Severe infection within 4 weeks or active infection requiring systemic treatment within 2 weeks pre-dose.
7. Uncontrolled comorbidities (e.g., decompensated liver cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, Grade ≥2 peripheral neuropathy).
8. Cardiovascular/cerebrovascular events within 6 months pre-dose (e.g., Myocardial Infarction, unstable angina, acute/persistent ischemia, Grade 3/4 Heart Failure, symptomatic/uncontrolled arrhythmia, Cerebrovascular Accident, Transient Ischemic Attack).
9. Uncontrolled hypertension, diabetes, or recurrent pleural/pericardial/abdominal effusion requiring drainage.
10. History of interstitial lung disease (ILD) or noninfectious pneumonitis that require steroid treatment, or currently has ILD/noninfectious pneumonitis.
11. Unresolved to grade ≤ 1 of prior anti-cancer treatment toxicities criteria per CTCAE v6.0.
12. Previously received B7-H3-targeted agents, including antibody, antibodydrug conjugate (ADC), and other agents.
13. Previously received treatment with an ADC that consists of a topoisomerase l inhibitor.
14. Pregnant or lactating women.