A full list of inclusion/exclusion criteria are available in the protocol.

Inclusion Criteria

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

1. Sign and date the informed consent form (ICF), prior to the start of any study-specific qualification procedures.
2. Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
3. Has histologically or cytologically confirmed diagnosis of ES-SCLC who will require first-line (IL) therapy.
4. For Cohort 1, participant has received 4 cycles of 1L induction therapy with carboplatin, etoposide, and atezolizumab for ES-SCLC with ongoing CR PR, CR, or SD per RECIST v1.1 assessed by the investigator.

   For Cohort 2, participant has received no prior treatment for ES-SCLC.

5. For Cohort 2, participant has at least one measurable lesion according to RECIST v1.1 on computed tomography (CT) or magnetic resonance imaging (MRI) as assessed by the investigator.
6. For Cohort 2, participant must have at least one lesion, amenable to core biopsy, and must consent to provide a pretreatment biopsy tissue sample and on-treatment biopsy.
7. Has ECOG PS of ≤1 (assessed within 7 days before enrollment/randomization).
8. Has adequate organ and bone marrow function within 7 days before the start of study treatment as specified in the study protocol.
9. A female subject of childbearing potential (POCBP) is eligible to participate if the following conditions are met:
   1. Subject is not pregnant as confirmed by highly sensitive pregnancy test during Screening (within 3 days prior to enrollment/randomization)
   2. Subject does not breastfeed during the treatment period and for at least 8/5/6 months after last dose of I-DXd/atezolizumab/carboplatin, respectively.
   3. Subject agrees to adhere to a contraceptive method that is highly effective and agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during the treatment period and for at least the time needed to eliminate each study drug after the last dose. The length of time required to continue contraception and avoid donating/freezing eggs after last dose for I-DXd/atezolizumab/carboplatin is 8/5/6 months, respectively. Preservation of eggs may be considered prior to first dose of study drug.
10. A male subject capable of producing sperm is eligible to participate if he agrees to

    the following during the intervention period and for at least the time needed to eliminate each study drug. The length of time required to continue contraception and avoid donating sperm after last dose for I-DXd/atezolizumab/carboplatin is 6/5/6 months, respectively.

    1. Avoid donating sperm.
    2. Adhere to either of the contraception methods: true abstinence from penile-vaginal intercourse or uses a penile/external condom when having penile-vaginal intercourse with a non-subject of childbearing potential plus partner use of an additional contraceptive method.
11. Is willing and able to comply with scheduled visits, drug administration plan,

    laboratory tests, other study procedures, and study restrictions.

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 targeted agents, including I-DXd.
2. Prior discontinuation of an ADC that consists of an exatecan derivative (eg, trastuzumab deruxtecan) due to treatment-related toxicities.
3. Has received prior treatment with CD137 agonists or ICIs, including anti-cytotoxic T-cell lymphocyte-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, except for atezolizumab for Cohort 1.
4. Has inadequate washout period before enrollment/randomization as specified in the study protocol.
5. Has any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, or another arterial thromboembolic event.
6. Has clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.
7. Has clinically significant corneal disease.
8. Has uncontrolled or significant cardiovascular disease,.
9. Has history of (non-infectious) 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
11. Is on chronic steroid treatment (dose of 10 mg daily or more prednisone equivalent), except for low-dose inhaled steroids (for asthma/chronic obstructive pulmonary disease, topical steroids (for mild skin conditions), or intra-articular steroid injections.
12. Has history of malignancy other than SCLC within the 5 years prior to randomization/enrollment, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial gastrointestinal tract tumors, and non-muscle invasive bladder cancer curatively resected by endoscopic surgery.
13. Has history of allogeneic bone marrow, stem cell, or solid organ transplant.
14. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE V5.0, Grade ≤1 or baseline.
15. Has history of hypersensitivity to the drug substances, inactive ingredients in the drug product or severe hypersensitivity reactions to other monoclonal antibodies.
16. Has evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.
17. Has active or uncontrolled human immunodeficiency virus (HIV) infection.
18. Has active or uncontrolled hepatitis B or C virus (HBV or HCV) infection.
19. Has history of autoimmune disease.
20. Has any evidence of severe or uncontrolled systemic diseases.
21. Has received a live vaccine within 30 days prior to the first dose of study drug.
22. Is a female who is pregnant or breastfeeding or planning to become pregnant.
23. Has 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; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results.
24. Has psychological, social, familial, or logistical factors that would prevent regular follow-up