Taking a Bite Out of Small Cell Lung Cancer By Leveraging Precision-Directed Delta-Like Ligand-3 Therapies

Abstract

The therapeutic landscape of small cell lung cancer (SCLC) is undergoing a paradigm shift with the emergence of delta-like ligand-3 (DLL3)-directed therapies, particularly tarlatamab, a first-in-class bispecific T-cell engager designed to bind to cluster of differentiation-3 on T cells and DLL3 on tumors cells, demonstrating promising efficacy, including potential intracranial activity, and a manageable safety profile. By leveraging biologic insights into SCLC subtypes and DLL3 expression, these therapies mark a step forward in precision immunotherapy for this recalcitrant disease. As new DLL3-targeting agents continue to evolve through bispecific, trispecific constructs, antibody-drug conjugates, and chimeric antigen receptor-based approaches, they bring hope for improved outcomes in SCLC and other high-grade neuroendocrine carcinomas. Importantly, the thoughtful incorporation of toxicity mitigation strategies, equitable access, and multidisciplinary care models will be critical to ensure that clinical advances translate into meaningful, real-world benefits. The challenge ahead lies in balancing efficacy with patient quality of life, financial burden, and time toxicity, an effort that requires continuous innovation, collaboration, and a patient-centered approach.