Participants must meet all of the following criteria to be eligible for randomization into the study: 1. Participants aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old). 2. Has histologically or cytologically documented unresectable locally advanced or metastatic ESCC according to American Joint Committee on Cancer 8th edition staging system on ESCC. 3. Has disease progression post a platinum-based chemotherapy and an ICI treatment per global or local guidelines, with a maximum of 1 prior line of systemic therapy for unresectable advanced or metastatic ESCC. 4. The participant must provide adequate baseline tumor samples with sufficient quantity and quality of tumor tissue content as defined in the Laboratory Manual. 5. Has at least 1 measurable lesion on computed tomography (CT)/magnetic resonance imaging (MRI) according to RECIST v1.1 as assessed by the investigator. Measurable lesions should not be from a previously irradiated site. If the lesion at a previously irradiated site is the only selectable target lesion, a radiological assessment showing significant progression of the irradiated lesion should be provided by the investigator. 6. Has an ECOG PS of 0 or 1 within 7 days prior to Cycle 1 Day 1.

Participants who meet any of the following criteria will be disqualified from entering the study: 1. Has received prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents, including I-DXd. 2. Has received any topoisomerase inhibitor. 3. Has histologically or cytologically confirmed adenosquamous carcinoma subtype. 4. Is ineligible to all the chemotherapies in the comparator arm due to prior progression or intolerance. 5. Has tumor invasion into organs located adjacent to the esophageal disease site (eg, aorta or respiratory tract) at an increased risk of bleeding or fistula as assessed by the investigator. 6. Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and not requiring treatment with corticosteroids or anticonvulsants) may be included in the study. Subjects must have a stable neurologic status and discontinue corticosteroid usage for at least 2 weeks prior to Screening. 7. Has any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, other arterial thromboembolic event, or pulmonary embolism. 8. Has a clinically significant corneal disease. 9. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at Screening. 10. Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of the study randomization, severe asthma, chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc), and potential pulmonary involvement caused by any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc), prior pneumonectomy, or requirement for supplemental oxygen. 11. Is on chronic steroid treatment (dose of 10 mg daily or more prednisone equivalent), except for low-dose inhaled steroids (for asthma/COPD), topical steroids (for mild skin conditions), or intra-articular steroid injections.