Inclusion Criteria:

Participants must meet all the following criteria to be eligible for enrollment into the study:

• Sign and date the informed consent form (ICF) prior to the start of any study-specific qualification procedures.
• Participant must have at least one lesion, not previously irradiated, amenable to core biopsy.
• Male or female subjects aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old).
• Histologically or cytologically documented ES-SCLC.
• At least one measurable lesion according to RECIST v1.1 as assessed by the investigator.
• Prior therapy with at least one platinum-based line as systemic therapy for extensive-stage disease.
• Documentation of radiological disease progression on or after most recent systemic therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

Exclusion Criteria:

Participants who meet any of the following criteria will be disqualified from entering the study:

• Prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents.
• Prior treatment with an ADC that consists of an exatecan derivative (eg, trastuzumab deruxtecan).
• 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.
• Any of the following conditions within the past 6 months: cerebrovascular accident, transient ischemic attack, or arterial thromboembolic event.
• Clinically significant corneal disease.
• Uncontrolled or significant cardiovascular disease.
• 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.
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses,
• Chronic steroid treatment (maximum dose of 10 mg daily prednisone equivalent), except for low-dose inhaled steroids (for asthma/COPD) or topical steroids (for mild skin conditions).
• History of malignancy other than SCLC within the 3 years prior to enrollment, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial gastrointestinal (GI) tract tumors and non-muscle invasive bladder cancer curatively resected by endoscopic surgery.
• History of allogeneic bone marrow, stem cell, or solid organ transplant.
• Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE V5.0), Grade ≤1 or baseline.
• History of hypersensitivity to the drug substances, inactive ingredients in the drug product or severe hypersensitivity reactions to other monoclonal antibodies.
• Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection (including HIV infection).
• Active or uncontrolled hepatitis B or C infection.
• Active, known, or suspected autoimmune disease.
• Any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, psychiatric illness/social situations, substance abuse).
• Has received a live vaccine within 30 days prior to the first dose of study drug.
• Female who is pregnant or breast-feeding or intends to become pregnant during the study.
• Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the participant.