CLINICAL TRIAL / NCT05280470

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 with at least two cycles of therapy (except in the case of early objective PD) and beginning with protocol version 3.0, a minimum of two previous lines of systemic therapy. - 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, including I-DXd. - Prior discontinuation of an antibody drug conjugate (ADC) that consists of an exatecan derivative (eg, trastuzumab deruxtecan) due to treatment-related toxicities. - 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 another 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 (dose of 10 mg daily or more prednisone equivalent), except for low-dose inhaled steroids (for asthma/COPD) or topical steroids (for mild skin conditions) or intra-articular steroid injections. - 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. - Has 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. - Known human immunodeficiency virus (HIV) infection that is not well controlled.