A Study of I-DXd in Combination With Atezolizumab With or Without Carboplatin as First-Line Induction or Maintenance in Subjects With Extensive Stage-Small Cell Lung Cancer (IDeate-Lung03)

Open to people ages 18 years and up

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 therapy.
4. For Cohort 1 Part A, 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.
5. For Cohort 1 Part B and Cohort 2, participant has received no prior treatment for ES-SCLC.
6. For Cohort 1 Part B and 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.
7. For Cohort 1 Part B and 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.
8. Has ECOG PS of ≤1 (assessed within 7 days before enrollment/randomization). 8. Has adequate organ function within 7 days before the start of study treatment as specified in the study protocol.
9. If the participant is a female of childbearing potential, she must have a negative serum pregnancy test during Screening (within 28 days prior to randomization). Male and female participants of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for females and 4 months for males after the last dose of study drug.
10. Male participants must not freeze or donate sperm starting at enrollment/randomization, throughout the Treatment Period, and for at least 4 months following the last dose of the study drug. Preservation of sperm may be considered prior to enrollment/randomization.
11. Female participants must not donate, or retrieve for their own use, ova from the time of enrollment/randomization and throughout the Treatment Period and for at least 7 months following the last dose of the study drug.
12. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

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 (CTLA-4), anti-PD-1, and anti-PD-L1 therapeutic antibodies, except for atezolizumab for Cohort 1 Part A.
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 known human immunodeficiency virus (HIV) infection that is not well controlled.
18. Has active or uncontrolled hepatitis B or C 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