This study is designed to assess the efficacy and safety of QLC5508 in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) who have experienced disease progression following treatment with a platinum-based systemic therapy and an immune checkpoint inhibitor (ICI) compared with investigator's choice of chemotherapy (ICC).

Inclusion Criteria:

• Voluntarily consent to participate in this study and sign the informed consent form.

• Males and females aged ≥18 years old;

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 within 7 days before the first dose;

• Estimated survival time of more than 3 months.

• A serum pregnancy test must be performed within 7 days prior to randomization for premenopausal women of childbearing potential, and the result must be negative and must not be lactating;

• All enrolled patients and the partners should take adequate barrier contraception during the entire treatment cycle and for 6 months after the end of treatment.

• Capable of understanding trial requirements, willing and able to comply with trial and follow-up procedures.

• Toxicity of previous antineoplastic therapy has returned to ≤ grade 1 defined by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 6.0 (v6.0);

• Has histologically or cytologically documented unresectable locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) according to American Joint Committee on Cancer 8th edition staging system on ESCC.

  • Has at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) as assessed by the investigator.

• Sufficient bone marrow and organ function.

Exclusion Criteria:

• Diagnosis of other primary malignancies within 5 years prior to signing the informed consent form.
• Having histologically or cytologically confirmed adenosquamous carcinoma subtype.
• Brain metastases (unless asymptomatic and no progression confirmed by imaging ≥4 weeks prior to randomization);
• Presence of leptomeningeal metastases or brainstem metastases;
• Spinal cord compression (identified via imaging, regardless of symptoms);
• Previous or ongoing treatment with topoisomerase I inhibitors
• Having previously received B7-H3-targeted therapy.
• Being ineligible to any chemotherapies in the control arm due to prior progression or intolerance.
• Insufficient washout of prior anticancer therapies prior to randomization.
• Having underwent major organ surgery (excluding biopsy) or significant trauma within 4 weeks prior to randomization;
• Requiring elective surgery during the study.
• Having received live vaccine or live attenuated vaccine within 4 weeks before study randomization.
• Having received treatment with systemic corticosteroids (prednisone at >10 mg/day, or similar drugs at equivalent dose) or other immunosuppressive agents within 14 days prior to randomization;
• Moderate to severe pulmonary disease significantly impairing lung function, including idiopathic pulmonary fibrosis, autoimmune/connective tissue disorders with lung involvement, or prior pneumonectomy.
• Having a history of interstitial lung disease (ILD)/ non-infectious pneumonitis that required corticosteroids, current ILD/ non-infectious pneumonitis, or suspected ILD/ non-infectious pneumonitis that cannot be ruled out by imaging at screening;
• Active tuberculosis;
• Autoimmune diseases not in clinical remission, other acquired or congenital immunodeficiency diseases,
• A history of allogeneic stem cell, bone marrow, or organ transplantation.
• Serious infections (e.g., bacteremia, or severe pneumonia) within 4 weeks prior to randomization;
• active infection requiring systemic antibiotic therapy within 1 weeks prior to randomization;
• Has positive results in virus serology tests (hepatitis B virus infection participants receiving antiviral treatment other than interferon are allowed to be enrolled);
• Uncontrolled or significant cardiovascular disease.
• Clinically uncontrolled third-space effusion.
• Known hypersensitivity to investigational product components, analogues, or control drugs (e.g., docetaxel, paclitaxel, irinotecan hydrochloride).
• Drug abuse;
• Any other medical conditions that may interfere with study participation or the results of the clinical study as per the discretion of investigator;
• Has alcohol or drug dependence.
• Poor compliance as per investigator discretion;
• Has a history of other serious systemic diseases.