A Study of Ifinatamab Deruxtecan in Subjects With Pretreated Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) (IDeate-Esophageal01)

Inclusion Criteria:

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 ageof consent for study participation is >18 years old).

2. Has histologically or cytologically documented unresectable locally advanced ormetastatic ESCC according to American Joint Committee on Cancer 8th edition stagingsystem on ESCC.

3. Has disease progression post a platinum-based chemotherapy and an ICI treatment perglobal or local guidelines, with a maximum of 1 prior line of systemic therapy forunresectable advanced or metastatic ESCC.

4. The participant must provide adequate baseline tumor samples with sufficientquantity and quality of tumor tissue content as defined in the Laboratory Manual.

5. Has at least 1 measurable lesion on computed tomography (CT)/magnetic resonanceimaging (MRI) according to RECIST v1.1 as assessed by the investigator. Measurablelesions should not be from a previously irradiated site. If the lesion at apreviously irradiated site is the only selectable target lesion, a radiologicalassessment showing significant progression of the irradiated lesion should beprovided by the investigator.

6. Has an ECOG PS of 0 or 1 within 7 days prior to Cycle 1 Day 1.

Exclusion Criteria:

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 targetedagents, 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 priorprogression 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 assessedby the investigator.

6. Clinically active brain metastases, spinal cord compression, or leptomeningealcarcinomatosis, defined as untreated or symptomatic, or requiring therapy withsteroids or anticonvulsants to control associated symptoms. Subjects with clinicallyinactive or treated brain metastases who are asymptomatic (ie, without neurologicsigns or symptoms and not requiring treatment with corticosteroids oranticonvulsants) may be included in the study. Subjects must have a stableneurologic status and discontinue corticosteroid usage for at least 2 weeks prior toScreening.

7. Has any of the following within the past 6 months: cerebrovascular accident,transient ischemic attack, other arterial thromboembolic event, or pulmonaryembolism.

8. Has a clinically significant corneal disease.

9. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis thatrequired corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis thatcannot be ruled out by imaging at Screening.

10. Has clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses, including, but not limited to, any underlying pulmonary disorder (ie,pulmonary emboli within 3 months of the study randomization, severe asthma, chronicobstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion,etc), and potential pulmonary involvement caused by any autoimmune, connectivetissue, 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 mildskin conditions), or intra-articular steroid injections.