The Current Paradigm for Selecting and Sequencing ADCs in Metastatic TNBC
Key Points
- Sacituzumab govitecan and datopotamab deruxtecan (Dato-DXd) are antibody-drug conjugates (ADCs) approved for PD-L1–negative triple-negative breast cancer (TNBC).
- Selecting a first-line ADC should take into account patients’ comorbidities and characteristics and the different administration and safety of each agent.
- The mechanisms behind reduced efficacy with sequential ADCs remain poorly understood, and standard chemotherapy remains a relevant option after first-line ADCs.
Coinciding with the 2026 American Society of Clinical Oncology Annual Meeting, breast medical oncologists Alexis LeVee, MD, of UCLA Health, and Hope Rugo, MD, FASCO, of City of Hope, discussed how to select a first-line ADC in metastatic TNBC and considered the ongoing questions related to treatment sequencing.
Sacitizumab govitecan and Dato-DXd are both TROP-2–directed ADCs approved for patients with PD-L1–negative metastatic TNBC. Picking between sacituzumab govitecan and Dato-DXd should be a shared decision made with patients based on the different administration schedules and toxicity profiles of each ADC and how they align with patients’ logistics and treatment goals, said Dr. Rugo.
With multiple ADCs approved for TNBC, treatment sequencing has emerged as a prominent challenge. Typically, patients treated with an ADC have worse efficacy when treated with a second ADC. This may be driven by resistance to topoisomerase–directed cytotoxic payloads, which all currently available ADCs utilize, but more data are needed. Until resistance is better understood, standard chemotherapy remains an important sequencing option in later lines of therapy.
Ultimately, in the current era, Dr. Rugo suggested sequencing decisions should be individualized based on patients’ toxicities with their first-line ADC, disease progression characteristics, prior chemotherapy exposure, or disease-free interval.