Navigating tarlatamab and bispecific T-cell engager therapy in small cell lung cancer: A narrative review

Small cell lung cancer (SCLC) remains one of the most aggressive solid malignancies, characterized by early metastasis and a historically dismal prognosis once resistance to platinum-based chemotherapy develops. For decades, therapeutic progress has been stagnant, with outcomes in the relapsed setting showing limited improvement. The recent FDA approval of tarlatamab, a first-in-class Delta-like ligand 3 (DLL3)-targeting bispecific T-cell engager (BiTE), marks a pivotal evolution in thoracic oncology. Unlike traditional immune checkpoint inhibitors that rely on pre-existing immune recognition, tarlatamab actively redirects cytotoxic T-cells to lyse tumor cells, validating DLL3 as a therapeutic target following the failures of earlier antibody-drug conjugates. However, the integration of BiTE therapy into solid tumor practice introduces unique clinical challenges previously confined to hematologic malignancies. This review provides a comprehensive, practical roadmap for the solid tumor oncologist navigating this new therapeutic landscape. We offer a detailed examination of the safety profile, specifically focusing on the recognition, grading, and management of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Furthermore, we address the critical operational hurdles, including step-up dosing schedules and the logistical considerations for transitioning from inpatient monitoring to outpatient administration. Finally, the review analyzes emerging data on resistance mechanisms such as antigen downregulation and T-cell exhaustion to provide evidence-based guidance on patient selection and future treatment sequencing strategies.