Sequential Use of Trastuzumab Deruxtecan and Sacituzumab Govitecan in Patients with Breast Cancer: A Pharmacological Approach to Support the Clinical Rationale - PubMed
4 hours ago
- #Antibody-drug conjugates
- #Sequential treatment
- #Breast cancer therapy
- Trastuzumab deruxtecan is a HER2-targeted ADC with a high drug-to-antibody ratio, cleavable linker, and potent exatecan payload, enabling a bystander effect in HER2-low tumors.
- Sacituzumab govitecan targets TROP-2, uses a hydrolysable linker and SN-38 payload with lower potency, allowing extracellular/intracellular release and bystander killing in heterogeneous tumors.
- Resistance mechanisms differ: trastuzumab deruxtecan resistance involves TOPO I mutations and lysosomal dysfunction, while sacituzumab govitecan resistance is linked to multidrug efflux proteins like BCRP.
- Clinical efficacy: trastuzumab deruxtecan works in HER2-positive and HER2-low breast cancer; sacituzumab govitecan is effective in triple-negative and hormone receptor-positive/HER2-negative breast cancers.
- Sequential use of these ADCs raises cross-resistance concerns due to shared topoisomerase I inhibitor payloads, but distinct targets and resistance pathways support a pharmacological rationale for sequencing.