459 Translational science in antibody–drug conjugates (ADCs): Bridging genetic biomarkers and therapeutic moieties in HER2-low and triple-negative breast cancer (TNBC) within the US FDA Regulatory Landscape

Objectives/Goals: To develop a comparative framework evaluating FDA regulatory pathways for ADCs in HER2-low and TNBC, mapping biomarker translation, approval timelines, and labeling language, and conducting qualitative and quantitative analyses to identify determinants of global therapeutic access. Methods/Study Population: This study conducted a targeted review of scientific, regulatory, and epidemiological databases to examine the US FDA’s regulatory pathways for ADCs in HER2-low and TNBC populations. Literature from PubMed and Scopus was analyzed to trace the translation of biomarkers from gene targets to therapeutic moieties. FDA databases were reviewed to map approval timelines, labeling language, and evidentiary standards shaping ADC authorization. ClinicalTrials.gov, SEER, and GLOBOCAN data were integrated to contextualize trial geography, disease burden, and access disparities. Comparative synthesis connected molecular biomarker validation to regulatory decision-making, enabling the identification of translational and policy determinants influencing time to patient access within the FDA landscape. Results/Anticipated Results: Preliminary findings indicate that advances in biomarker characterization have accelerated the development and regulatory progression of ADCs in breast cancer. HER2-low and Trop-2 expression have enabled the evolution of Enhertu and Trodelvy from histopathological to molecularly guided indications. FDA approvals demonstrated reduced timelines and more detailed biomarker-specific labeling, supported by surrogate endpoints such as progression-free survival and overall response rate. Analysis of approval data and clinical trial mapping highlights a temporal correlation between biomarker discovery, therapeutic innovation, and expedited regulatory authorization for targeted ADC therapies, serving as a pathway toward improved global access. Discussion/Significance of Impact: This study provides a structured analysis of FDA regulation of ADCs in breast cancer, linking biomarker translation to therapeutic approval. Findings underscore the need for evidence-based and equity-driven frameworks to accelerate global access and support ADC transition to first-line therapy.