Bispecific T-Cell Engager Tarlatamab and TROP2 Targeted Antibody Drug Conjugate Sacituzumab Govitecan in Previously Treated Extensive-Stage Small Cell Lung Cancer and Extrapulmonary Neuroendocrine Cancer

Background: Small-cell lung cancer (SCLC) is the most deadly form of lung cancer. It kills at least 250,000 worldwide each year. Extra-pulmonary neuroendocrine cancer (EP-NEC) is a similar type of cancer that develops anywhere other than the lungs. EP-NEC is also very aggressive. Better treatments are needed for these cancers. Objective: To test 2 drugs (tarlatamab combined with sacituzumab govitecan \[SG\]) in people with SCLC or EP-NEC. Eligibility: People aged 18 years and older with SCLC or EP-NEC that either did not respond to or returned after treatment. Design: Participants will be screened with a physical exam, blood tests, heart function testing, and imaging scans. Both study drugs are given intravenously (through a needle in the arm). Participants will receive a small starter dose of tarlatamab (1 mg) 2 weeks before beginning regular treatment, followed by the full dose (10 mg) one week later. Treatment then follows a repeating 4-week cycle: tarlatamab (10 mg) on days 1 and 15, and sacituzumab govitecan (7.5 or 10 mg/kg) on days 1 and 8. Treatment continues for up to 2 years, unless the cancer worsens, the participant passes away, or side effects become too severe. Participants will have regular check-ups including physical exams, blood tests, and imaging scans to monitor safety and treatment response. Blood and tumor samples will be collected for research purposes. After stopping treatment, participants will return for a safety check at 30 days, then be contacted every 3 months to check on their health and survival. Those who stop treatment for reasons other than cancer progression will continue CT scans every 8 weeks until their disease progresses.

Background: * Small-cell lung cancer (SCLC) is the most fatal and metastatic form of lung cancer which kills at least 250,000 people globally each year including more than 30,000 in the United States. SCLC constitutes approximately 14% of all lung cancers. * SCLC consists of tumor cells with neuroendocrine (NE) and non-neuroendocrine (non-NE) features. SCLC subtypes exhibit distinct therapeutic vulnerabilities. Immunogenic plasticity and Notch signaling of non-NE SCLC underlie their responses to immune checkpoint blockade. NE SCLC is characterized by replication stress, rendering them susceptible to deoxyribonucleic acid (DNA) repair-targeted agents. * The inhibitory Notch delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of up to 85% of SCLC, mostly NE cells and minimally expressed in normal tissues, making it a compelling therapeutic target for NE SCLC. Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein aberrantly expressed in SCLC during its progression from NE to the non-NE cell state, making it a compelling therapeutic target of non-NE SCLC. * Tarlatamab is a bispecific T cell engager (BiTE) molecule which binds DLL3 on cancer cells and cluster of differentiation 3 (CD3) on T cells leading to T cell-mediated tumor lysis. Sacituzumab govitecan (SG) is an antibody drug conjugate (ADC) carrying a topoisomerase 1 (TOP1) inhibitor SN-38 payload to cancer cells expressing TROP2. * Extrapulmonary neuroendocrine cancers (EP-NEC) are rare and aggressive orphan cancers that share morphological and transcriptomic similarities and potentially therapeutic vulnerabilities with SCLC, with no standard treatments at relapse. * In the current study, combination therapies targeting DLL3 and TROP2, using a combination of tarlatamab and sacituzumab govitecan will be evaluated as potential drivers of durable response in SCLC and EP-NEC. Objectives: Phase I: -To determine the maximum tolerated dose (MTD) of bispecific T-cell engager tarlatamab and TROP2 targeted antibody drug conjugate sacituzumab govitecan in participants with previously treated relapsed SCLC or EP-NEC. Phase II: -To determine the clinical benefit in terms of objective response rates (ORR) in participants with previously treated relapsed SCLC or EP-NEC. Eligibility: -\>=18 years. * Histologically or cytologically confirmed SCLC or EP-NEC that has progressed or recurred after at least one previous platinum-based regimen and immunotherapy. * Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Design: * This is a Phase I/II, open label clinical trial aimed at identifying the MTD of Sacituzumab govitecan in combination with tarlatamab and assessing the efficacy with respect to objective response rate in recurrent SCLC and EP-NEC. * Participants will receive a step dose of 1mg tarlatamab 14 days prior to the first cycle followed by a full dose (10mg) starting a week later. Thereafter, tarlatamab will be administered on days 1 and 15 and sacituzumab govitecan (7.5 or 10 mg/Kg) will be administered on days 1 and 8 of every 4-week cycle. Treatment will be administered for up to 2 years or until disease progression/death or development of intolerable side effects (whichever occurs first). * During treatment, participants will have clinical assessments, laboratory evaluations, and imaging studies for safety and response assessment. Blood and tumor samples will be collected for correlative studies at various timepoints. * Participants will be followed for survival every 3 months following objective disease progression.