Inclusion Criteria: 

• Sign and date the informed consent form (ICF), prior to the start of any study-specific qualification procedures.
• Adults ≥ 18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
• Has histologically or cytologically documented ES-SCLC.
• For Cohort 1 Part A, subject has received 4 cycles of 1L induction therapy with carboplatin, etoposide, and atezolizumab for ES-SCLC with ongoing PR, CR, or SD per RECIST v1.1 assessed by the investigator. Subject must be enrolled ≤ 9 weeks (63 days) from the last dose of platinum-based first-line chemotherapy. Subjects receiving PCI or brain radiation therapy must be enrolled ≤ 11 weeks (77 days) from the last dose of platinum-based first-line chemotherapy.
• For Cohort 1 Part B and Cohort 2, subject has received no prior treatment for ES-SCLC. Subjects who have received prior chemoradiotherapy for limited-stage SCLC must have been treated with curative intent and experienced a treatment-free interval of at least 6 months since the last chemotherapy, radiotherapy, or chemoradiotherapy from diagnosis of ES-SCLC.
• For Cohort 1 Part B and Cohort 2, subject 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. Measurable lesions should not be from a previously irradiated site. If the lesion at a previously irradiated site is the only selectable target lesion, a radiological assessment showing significant progression of the irradiated lesion should be provided by the investigator.
• For Cohort 1 Part B and Cohort 2, subject must have at least one lesion, amenable to core biopsy, and must consent to provide a pretreatment biopsy tissue sample and on-treatment biopsy. Fresh pretreatment biopsy may be waive for subjects who consent to provide archival tumor tissue from a biopsy performed within 6 months of consent and performed after treatment with their most recent cancer therapy regimen. If, after all efforts have been made, a newly obtained pretreatment biopsy is not feasible or the procedure is unsuccessful and an appropriate archival sample is not available, the subject may be considered for study eligibility at the investigator’s discretion after discussion with the Sponsor’s medical monitor.
• Has ECOG PS of ≤ 1.
• Has adequate organ function within 7 days before the start of study treatment as follows (Note: Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor administration is not allowed within 2 weeks prior to screening laboratory assessments): 
  • Platelet count ≥ 100 × 10^9 /L;
  • Hemoglobin ≥ 9 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1.5 × 10^9 /L;
  • Creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault equation;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN in subjects with no liver metastases and ≤ 5.0 × ULN in subjects with liver metastasis;
  • Total bilirubin ≤ 1.25 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline;
  • International normalized ratio (INR)/prothrombin time and either partial thromboplastin time (PTT) or activated PTT ≤ 1.5 × ULN, except for subjects receiving anti-vitamin K derivative anticoagulant therapy who must have PT-INR within therapeutic range as deemed appropriate by the investigator;
• If the subject 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 subjects 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. Methods considered as highly effective methods of contraception include the following:
  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
    •  Oral;
    • Intravaginal;
    • Transdermal.
  • Progestogen-only hormonal contraception associated with inhibition of ovulation:
    • Oral;
    • Injectable;
    • Implantable.
  • Intrauterine device;
  • Intrauterine hormone-releasing system;
  • Bilateral tubal occlusion;
  • Vasectomized partner;
  • Complete sexual abstinence defined as refraining from heterosexual 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. Periodic abstinence (calendar, symptothermal, or post-ovulation methods) is not an acceptable method of contraception;
  • Non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy or postmenopausal females defined as 12 months of spontaneous amenorrhea (Note: In questionable cases, a blood sample with simultaneous follicle-stimulating hormone > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory.);
  • Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to randomization/enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of postmenopausal status, HRT during the study can be resumed without the use of a contraceptive method.
• Male subjects 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 in this study.
• Female subjects 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. Preservation of ova may be considered prior to enrollment/randomization in this study.
• Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

Exclusion Criteria: 

• Has received prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents, including I-DXd.
• Has received prior treatment with an ADC that consists of an exatecan derivative (eg, trastuzumab deruxtecan).
• 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.
• Has inadequate washout period before enrollment/randomization, defined as follows:
  • Major surgery (placement of vascular access will not be regarded as a major surgery) < 4 weeks; surgery for low-invasive cases (eg, colostomy) < 2 weeks;
  • Radiation therapy < 4 weeks; palliative stereotactic radiation therapy without abdominal radiation ≤ 2 weeks; radiation therapy to the lung > 30 Gy < 6 months; palliative radiotherapy affecting lung areas at lower dose < 3 weeks
  • Any systemic anticancer therapy (including immunotherapy [other than antibodies] and investigational drugs) < 3 weeks or 5 half-lives, whichever is longer; hormonal therapy (except for luteinizing hormone-releasing hormone agonists/antagonists) < 2 weeks
  • Nitrosoureas or mitomycin C < 6 weeks
  • Antibody-based anticancer therapy < 3 weeks
  • Chloroquine or hydroxychloroquine ≤ 14 days
• Has any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, or another arterial thromboembolic event.
• 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. Subjects with untreated and asymptomatic brain metastases or subjects with treated brain metastases who are no longer symptomatic and who require no treatment with steroids may be included in the study If they have recovered from the acute toxic effect of radiotherapy. Note: A baseline MRI scan or CT of the brain is required for all subjects at baseline.
• Has clinically significant corneal disease. 8. Has uncontrolled or significant cardiovascular disease, including the following:
  • Has a corrected QT interval (QTcF) prolongation to  > 470 ms (females) or > 450 ms (males) based on average of the Screening triplicate12-lead electrocardiogram (ECG) determinations;
  • Diagnosed or suspected long QT syndrome or known family history of long QT syndrome;
  • History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes;
  • Bradycardia of less than 50 bpm unless the subject has a pacemaker;
  • History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers;.
  • Acute myocardial infarction within 6 months prior to Screening;
  • Uncontrolled angina pectoris within 6 months prior to Screening;
  • Symptomatic congestive heart failure (CHF) defined as New York Heart Association Class II to IV;
  • Coronary/peripheral artery bypass graft or any coronary/peripheral angioplasty within 6 months prior to Screening;
  • Grade ≥ 3 hypertension graded according to the NCI-CTCAE V5.0;
  • Complete left or right bundle branch block;
  • Left ventricular ejection fraction (LVEF) < 50% by either an echocardiogram (ECHO) or a multigated acquisition (MUGA) scan.
• 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.
• Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the study enrollment/randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural/pericardial effusion, idiopathic pulmonary fibrosis , active tuberculosis, etc) and potential pulmonary involvement caused by any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc), or prior complete pneumonectomy. History of radiation pneumonitis (Grade 1) in the radiation field (fibrosis) is permitted. Subjects with indwelling catheters (eg, PleurX) are allowed.
• 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.
• 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.
• Has history of allogeneic bone marrow, stem cell, or solid organ transplant.
• 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.
  • Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade > 2 for at least 3 months prior to enrollment/randomization and managed with SoC treatment) that the investigator deems related to previous anticancer therapy, following discussion with the Sponsor’s medical monitor, such as the following:
    • Chemotherapy-induced neuropathy;
    • Fatigue;
    • Endocrinopathies, which may include hypothyroidism, hyperthyroidism, Type 1 diabetes, hyperglycemia, adrenal insufficiency, and adrenalitis;
    • Skin hypopigmentation (vitiligo).
• Has history of hypersensitivity to the drug substances, inactive ingredients in the drug product or severe hypersensitivity reactions to other monoclonal antibodies.
• Has evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection. Note: Subjects with localized fungal infections of skin or nails are eligible. Subjects may be tested for human immunodeficiency virus (HIV) prior to enrollment/randomization if required by local regulations or institutional review board (IRB)/independent ethics committee (IEC).
• Has known HIV infection that is not well controlled. Subjects should be tested for HIV prior to randomization if required by local regulations or IRB/ethics committee (EC). All of the following criteria are required to define an HIV infection (positive HIV1/2 antibodies test) that is well controlled: viral ribonucleic acid (RNA) load 350 cells/µL, no history of acquired immunodeficiency syndrome-defining opportunistic infection within the past 12 months, and stable viral load for at least 4 weeks on the same anti-HIV retroviral medications.
• Has active or uncontrolled hepatitis B or C infection; subject is positive for hepatitis B or C virus (HBV and HCV, respectively) based on the evaluation of results of tests for hepatitis B (hepatitis B virus surface antigen [HBsAg], antibody to the hepatitis B surface antigen, antibody to the hepatitis B core antigen, and HBV deoxyribonucleic acid [DNA]) or hepatitis C (HCV antibody and HCV ribonucleic acid [RNA]) infection, as per local regulations. Subjects who are HBsAg+, with HBV infection for more than 6 months, have an HBV DNA viral load < 2000 IU/mL, have normal transaminase values prior to enrollment/randomization (or, if liver metastases are present, abnormal transaminases with a result of AST/ALT < 3 × ULN that are not attributable to HBV infection), and are willing to start and maintain antiviral treatment for the duration of the study, are allowed. Subjects who have received hepatitis B vaccination with only anti-HBs positivity and have no clinical signs of hepatitis and subjects who have been curatively treated for hepatitis C infection as demonstrated clinically and by viral serologies will be eligible.
• Has history of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Section 10.11.2 for a more comprehensive list of autoimmune diseases). Subjects with controlled Type 1 diabetes mellitus on an insulin regimen are eligible. Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (eg, subjects with psoriatic arthritis would be excluded) are eligible for the study provided that they meet the following conditions:
  • Rash must cover less than 10% of body surface area;
  • Disease is well controlled at baseline and only requires low-potency topical steroids;
  • No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, and high-potency or oral steroids).
• Has any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, psychiatric illness/social situations, substance abuse) or other factors that, in the investigator’s opinion, makes it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
• Is a female who is pregnant or breastfeeding or planning to become pregnant.
• 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 subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results.
• Has psychological, social, familial, or logistical factors that would prevent regular follow-up.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 12/1/23. Questions regarding updates should be directed to the study team contact.