Background: SCLC remains an aggressive malignancy with limited therapeutic options after progression. Tarlatamab, a DLL3-directed bispecific T-cell engager, has a demonstrated survival benefit in clinical trials, but real-world data remain limited. We evaluated the safety, radiographic response, and treatment durability of Tarlatamab in a real-world cohort treated at a single academic center. Methods: We performed a retrospective review of patients with extensive-stage SCLC who received Tarlatamab at the University of Miami Sylvester Comprehensive Cancer Center between 2024 and 31 October 2025. Demographic, clinical, radiographic, and toxicity data were abstracted from electronic medical records. Radiographic response was defined as partial response or stable disease on follow-up imaging. PFS and overall survival OS were estimated using the Kaplan–Meier method. Results: Twenty-three patients were included (median age 72 years), of whom 61% were Hispanic and 61% had brain metastases prior to treatment. Forty-three percent had received two or more prior lines of therapy. CRS and ICANS occurred primarily during Cycle 1 and were limited to grade 1–2 events, with no grade ≥3 toxicities. Median time on treatment was 92 days with a median of four cycles. Among 18 evaluable patients, partial response was observed in 27.7% and stable disease in 16.7%, yielding a disease control rate of 44.4%. Median PFS was 139 days and median OS was 323 days (95% CI, 31–614). Conclusions: In a predominantly Hispanic, heavily pre-treated real-world population with high CNS disease burden, Tarlatamab demonstrated feasible administration, manageable immune-mediated toxicity, and clinically meaningful antitumor activity.