Balancing Efficacy and Safety of ADCs in HER2– Metastatic Breast Cancer

Datopotamab Deruxtecan Integration and ADC Sequencing Challenges

The TROPHY-01 trial established datopotamab deruxtecan as an effective option for hormone receptor–positive, HER2-negative metastatic breast cancer after 1 to 2 prior chemotherapy regimens, positioning it earlier in the treatment sequence than sacituzumab govitecan. Median progression-free survival showed a 2- to 4-month advantage over physician’s choice chemotherapy, depending on assessment methodology. This approval creates a landscape of 3 antibody-drug conjugates (ADCs) in hormone receptor–positive disease, all sharing topoisomerase I inhibitor payloads but differing in linker technology and toxicity profiles.

Key differences between ADCs include linker mechanisms and toxicity patterns that influence clinical selection. Sacituzumab govitecan features a hydrolyzable linker that can cleave in peripheral circulation, whereas datopotamab deruxtecan requires enzymatic cleavage within target cells. Toxicity profiles vary significantly: Sacituzumab govitecan causes universal alopecia, depression, and high febrile neutropenia risk requiring growth factor support, whereas datopotamab deruxtecan presents primarily with stomatitis and ocular toxicity requiring prophylactic management.

The challenge of sequencing 3 topoisomerase I inhibitor–containing ADCs remains unresolved, with limited retrospective data suggesting decreased efficacy with sequential ADC use. Clinical trials including the SERIES and TraDeD studies are investigating optimal sequencing through prospective biomarker analysis. Current practice often employs a “sandwich approach,” separating ADCs with alternative mechanisms such as capecitabine to potentially restore sensitivity to subsequent topoisomerase I inhibitor exposure.