Radiation Combined With BIspecific T-Cell Engager in DLL3 Expressing Tumors

1. Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures. 2. Subjects ≥ 18 years of age at the time of signing the informed consent. 3. Histologically or cytologically confirmed relapsed/refractory: 1. SCLC 2. Other tumors of small cell histology 3. High grade / poorly differentiated neuroendocrine histology tumor histologies with high prevalence of DLL3 (≥50% prevalence of ≥1% positivity), including but not limited to: melanoma, medullary thyroid cancer, esthesioneuroblastoma, bladder cancer, testicular cancer, glioblastoma multiforme, cervical cancer; large cell neuroendocrine tumor of lung, non-small cell lung cancers with mixed neuroendocrine features, and Merkel cell carcinoma OR 4. DLL3+ (≥1% by IHC) Note: If patients are DLL3 negative per IHC but have a DLL3 prevalant tumor type, they will be allowed to enroll on the study. 4. Subjects who progressed or recurred after at least one line of therapy and are considered treatment refractory per standard of care. 5. Subjects willing to provide archived tumor tissue samples (formalin fixed, paraffin embedded \[FFPE\] sample). If no archived tumor tissue is available, we request to undergo pretreatment tumor biopsy. Subjects who do not have archived tumor tissue available and are unable or unwilling to undergo a pretreatment tumor biopsy due to extenuating circumstances (i.e., cannot be performed safely or inaccessible, as determined by the investigator) may be allowed to enroll without a tumor biopsy upon agreement with sponsor. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 7. Minimum life expectancy of 12 weeks. 8. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen. 9. Measurable lesions as defined per RECIST 1.1 within 28 days prior to the first dose of tarlatamab. 10. Eligible for external beam radiation therapy to a previously unirradiated, measurable lesion as per standard of care. a. For the concurrent / sequential cohort of extracranial RT sites: i. A minimum of 10 subjects with thoracic lesions (lung, mediastinum, thoracic spine, rib, or other thoracic sites) will be treated ii. Subjects with treated brain metastases are eligible (untreated brain metastases are ineligible) provided they meet the following criteria: <!-- --> 1. Definitive therapy was completed at least 2 weeks prior to the first dose of tarlatamab. 2. There is no evidence of radiographic central nervous system (CNS) progression following therapy and by the time of study screening. 3. Patients manifesting progression in lesions previously treated with stereotactic radiosurgery may still be eligible if pseudoprogression can be demonstrated by appropriate means. 4. Any CNS disease is asymptomatic for at least 7 days (unless symptoms are deemed irreversible by the investigator), the patient is off steroids for at least 7 days (physiologic doses of steroids are permitted), and the subject is off or on stable doses of anti-epileptic drugs for malignant CNS disease for at least 7 days. b. For the concurrent/sequential cohort of cranial RT sites: i. Previously untreated brain lesions / metastases are eligible ii. Subjects with previously irradiated brain lesions are eligible provided they meet one of the following criteria: <!-- --> 1. Prior PCI or whole brain radiation therapy per standard of care with new and/or recurrent brain metastases to be treated with SRS or hfSRT 2. Prior course(s) of SRS or hfSRT or other localized therapy with new lesion(s) to be treated with whole brain radiation therapy iii. Whole brain re-irradiation will be ineligible iv. Re-irradiation with SRS or hfSRT of previously irradiated lesion with SRS or hfSRT will be ineligible v. Craniospinal irradiation will not be allowed c. For the tarlatamab monotherapy cohort: i. Patient must have at least one measurable lesion, however that lesion does not need to be amenable to RT 1\. Patients with previously irradiated lesions that have recurred or progressed are eligible 11. Adequate organ function, defined as follows: a. Hematological function: i. Absolute neutrophil count ≥ 1.5 x 109/L ii. Platelet count ≥ 100 x 109/L iii. Hemoglobin \> 9 g/dL (90 g/L) b. Coagulation function: i. Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) ≤ 1.5 x institutional upper limit of normal (ULN). Subjects on chronic anticoagulation therapy who do not meet the criteria above may be eligible to enroll after discussion with the medical monitor. c. Renal function: i. Estimated glomerular filtration rate (eGFR) based on Modification of Diet in Renal Disease (MDRD) calculation \> 30 mL/min/1.73 m2 d. hepatic function: i. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) \< 3 x ULN (or \< 5 x ULN for subjects with liver involvement) ii. Total bilirubin \< 1.5 x ULN (or \< 2 x ULN for subjects with liver metastases) e. Pulmonary function: i. No clinically significant pleural effusion ii. Baseline oxygen saturation \> 90% on room air f. cardiac function (if obtained as part of standard of care): i. Cardiac ejection fraction ≥ 50%, no clinically significant pericardial effusion as determined by an echocardiogram (ECHO) or multigated acquisition (MUGA) scan, and no clinically significant electrocardiogram (ECG) findings

Re-irradiation, unless it is SRS/hfSRT after whole-brain radiation therapy (WBRT) or PCI or WBRT after SRS/hfSRT; re-irradiation of same lesion, unless verified with the Principal Investigator; patients with lesions not amenable to RT (including previously irradiated) will be only allowable on the tarlatamab monotherapy cohort. Disease Related 1. Subjects are excluded from the study if any of the following criteria apply: a. No lesion(s)/site(s) amenable to radiation therapy (only eligible for tarlatamab monotherapy if open) b. Planned re-irradiation of a previously irradiated site c. Leptomeningeal disease requiring craniospinal irradiation 2. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 3. Subjects who experienced recurrent pneumonitis (grade 2 or higher) or severe, life-threatening immune-mediated adverse events or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents. 4. Unresolved toxicity from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, or to levels dictated in the eligibility criteria with the exception of alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for \> 21 days) which may be allowed if they are not otherwise described in the