A Front-Line Window-of-Opportunity Phase 2 Study of Tarlatamab (Bispecific T Cell Engager: DLL3-CD3) in Patients With Extensive-Stage Small-Cell Lung Cancer

Inclusion Criteria: * Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information * NOTE: HIPAA authorization may be included in the informed consent or obtained separately * Age ≥ 18 years at the time of consent * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2 * Have a histologically or cytologically documented new diagnosis of the extensive-stage (i.e., metastatic and/or recurrent) SCLC. Patients with multiple lung nodules and/or lymph node involvement that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan are allowed * Recurrent limited-stage SCLC disease after 6 months of completing standard-of-care systemic platinum-based chemotherapy and radiation can be considered after discussion with the sponsor * Measurable disease according to RECIST v 1.1 * All patients must have brain MRI. Subjects with brain metastases are eligible provided they meet the following criteria: * Patients with treated brain metastases are eligible if they completed definitive therapy at least 1 week prior to the first dose of tarlatamab, are asymptomatic (unless symptoms are deemed irreversible by the investigator), and on stable dose of steroids (=\< 10 mg prednisone equivalent) for at least 7 days prior to study treatment * Patients with asymptomatic untreated brain metastases with no radiological evidence of vasogenic edema may be considered for inclusion after discussion with the sponsor * Absolute neutrophil count (ANC) ≥ 1500 cells/uL * Platelets ≥ 100,000/uL * Hemoglobin ≥ 9.0 g/dL * Lymphocyte count ≥ 500/uL * Estimated glomerular filtration rate (eGFR) based on MDRD (Modification of Diet in Renal Disease) calculation ≥ 30 mL/min/1.73 m\^2 * Total bilirubin \< 1.5 x upper limit of normal (ULN) (or \< 2 x ULN for subjects with liver metastases, or \< 3 x ULN for subjects with known Gilbert disease) * Aspartate aminotransferase (AST) \< 3 x ULN (or \< 5 x ULN for subjects with liver involvement) * Alanine aminotransferase (ALT) \< 3 x ULN (or \< 5 x ULN for subjects with liver involvement) * Alkaline phosphatase (ALP) \< 3 x ULN (or \< 5 x ULN for subjects with liver involvement) * Albumin ≥ 2.5 g/dL * Patients with indwelling catheters (e.g., PleurX®) are allowed * Baseline oxygen saturation ≥ 90% on room air * Chronic obstructive pulmonary disease (COPD) patients on stable supplementary oxygen (O2) for at least 6 months may be considered for inclusion after discussion with the sponsor * Left ventricular ejection fraction (LVEF) ≥ 50%, no clinically significant pericardial effusion as determined by an ECHO or MUGA, and no clinically significant electrocardiogram (ECG) findings * As determined by the enrolling physician or protocol designee, the ability of the subject to understand and comply with study procedures for the entire length of the study * Availability of archival tissue, preferably a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (or ideally at least 15 newly cut unstained slides). For eligibility, only confirmation of archival tissue is needed. Verification of tumor burden in the biopsy is encouraged. For optimal biomarker results, tumor content should be \> 30% of total tissue area * Be willing to provide peripheral blood samples at specified time-points during the study Exclusion Criteria: * Patients currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy within 4 weeks of the first dose of treatment * Patients with a prior or concurrent malignancy whose natural history or treatment could potentially interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial * Symptomatic brain metastases and/or leptomeningeal disease * Clinically significant cardiovascular disease per the investigator. Examples include unstable arrhythmia, unstable angina, myocardial infarction, and/or symptomatic congestive heart failure (New York Heart Association class II) within 3 months of the first dose of tarlatamab * Current history of active and uncontrolled central nervous system (CNS) disease, such as stroke, transient ischemic attack, epilepsy, CNS vasculitis, or neurodegenerative disease * Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 6 months and have no residual neurologic deficits as judged by the investigator are permitted to enroll * Patients with a history of epilepsy who have had controlled symptoms and no seizures in the past 2 years are allowed * Subject with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of tarlatamab administration * Subject has known active infection requiring parenteral antibiotic treatment. Upon completion of parenteral antibiotics and resolution of symptoms, the subject may be considered eligible for the study from an infection standpoint * NOTE: Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with sponsor. Subjects requiring oral antibiotics who have been afebrile for \> 72 hours, have no leukocytosis, nor clinical signs of infection are eligible. Screening for chronic infectious conditions is not required unless otherwise noted as an exclusion criterion * Subjects with active hepatitis or HIV infection, testing is required * Patients with a past or resolved hepatitis B virus (HBV) infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of hepatitis B virus surface antigen \[HBsAg\]) are eligible * In patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA * Subjects with HIV/AIDS with adequate antiviral therapy to control viral load (i.e., undetectable) and lymphocyte count would be allowed if they are stable and have been on treatment for ≥ 4 weeks prior to the first dose of study drug(s) * Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy * Subject has known sensitivity and immediate hypersensitivity to any components of tarlatamab * Prior treatment for SCLC. Subjects with limited-stage SCLC (LS-SCLC) who progressed after 6 months from completing chemotherapy and radiation may be considered for inclusion after discussion with the sponsor * Palliative radiotherapy is allowed to non-target lesions, and must have been completed at least 7 days prior to the first dose of tarlatamab * Subjects with irreversible toxicity (defined as having been present and stable for \> 21 days) that, in the opinion of the treating physician, is not reasonably expected to be exacerbated by the investigational product may be included (e.g., neuropathy, alopecia, hearing loss, hormone deficiency requiring replacement therapy) * Subjects who received major surgery within 30 days. Subjects must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * Subjects with known active autoimmune disease or immune deficiency that has required systemic treatment or steroids (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study * Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment * Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. * Physiologic doses of steroids are permitted * Subjects with a known history of solid organ transplantation * Subjects with evidence of interstitial lung disease or active, non-infectious pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. Subjects with history of radiation pneumonitis in the radiation field (fibrosis) are permitted * Subjects with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial * Live and live attenuated vaccination are prohibited within 28 days prior to the first dose of tarlatamab treatment and for the duration of study. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination should be avoided during screening at least 14 days prior to the first day of tarlatamab treatment * Subjects of both genders of child-bearing potential who are not willing to practice an acceptable method(s) of effective birth control while on study, and through 60 days (for female subjects) or through 60 days (for male subjects) after receiving last dose of tarlatamab * Females who are pregnant or planning to become pregnant or breastfeeding or who plan to breastfeed while on study through 60 days after receiving the last dose of tarlatamab. Subjects who are willing to suspend breastfeeding prior to starting treatment with tarlatamab and do not intend to resume breastfeeding 60 days after receiving the last dose of tarlatamab can be enrolled. * Males who are unwilling to abstain from sperm donation while on study and through 60 days after receiving the last dose of tarlatamab * Symptomatic pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Patients with indwelling catheters (e.g., PleurX) are allowed * Subjects with uncontrolled respiratory symptoms or concern about impending respiratory failure due to tumor compression requiring urgent intervention * Subjects with a history or current evidence of clinically significant disease, condition, therapeutic intervention, or laboratory abnormality that would pose a risk to subject safety and might confound the study evaluation, procedures or completion or may interfere with the subject's participation for the full duration of the trial, in the opinion of the treating investigator