TROP2-Targeted Therapy Integration and Sequencing Strategies

Dr. Kruse discusses Dato-DXd placement in hormone receptor-positive, HER2-negative metastatic disease following TROPION-Breast01 results. The challenge involves managing overlapping targets or payloads when patients have received prior T-DXd (deruxtecan payload) or SG (TROP2 target). Dato-DXd requires significant patient engagement with preventive strategies including dexamethasone mouth rinses and ocular lubrication, creating substantial daily management burdens.

Primary indications for Dato-DXd include patients who cannot receive T-DXd due to existing pneumonitis, prior drug-related pneumonitis, or cardiomyopathy concerns. For true HER2 immunohistochemistry 0 patients requiring deruxtecan payload access, Dato-DXd represents an option, though SG would be prioritized based on OS benefits. Scheduling advantages include every-3-week dosing versus day 1 and day 8 administration, with shorter infusion times, but ocular toxicity and stomatitis create noticeable daily quality-of-life impacts.

Dr. Kang implements a "sandwich" approach using intervening therapies between ADCs with shared mechanisms to potentially re-sensitize patients to subsequent TROP2-directed therapy. Although Dato-DXd did not meet its secondary OS endpoint, this should not eliminate consideration given subsequent therapy access including T-DXd or SG that provide survival benefits. The speakers acknowledge limited understanding of resistance mechanisms, making sequencing decisions partially speculative while emphasizing the importance of ongoing translational research and real-world sequencing studies.