Following FDA approval, datopotamab deruxtecan (Dato-DXd; Datroway) is set to be integrated into the standard treatment paradigm for patients with unresectable or metastatic hormone receptor-positive (HR+), HER2-negative breast cancer who have previously undergone systemic therapy. However, uncertainties persist regarding the optimal sequencing of antibody-drug conjugates (ADCs) and the comparative real-world toxicities among available options.
ADC Sequencing and Toxicity Profiles
According to Virginia G. Kaklamani, MD, DSc, a professor of medicine at The University of Texas Health Science Center San Antonio, a key consideration is how to sequence ADCs with similar payloads, particularly topoisomerase inhibitors. While sacituzumab govitecan (Trodelvy) appears to be associated with more severe cytopenias and diarrhea, Dato-DXd and trastuzumab deruxtecan (T-DXd; Enhertu) may present a higher risk of interstitial lung disease (ILD).
"It seems that sacituzumab will have a lot more cytopenias, more diarrhea, [and] no stomatitis. Dato-DXd and T-DXd will have some incidence of ILD. Dato-DXd [has] very little [incidence of] cytopenias. I think, based on what we're seeing, it looks like Dato-DXd will be more favorable as far as AEs compared with the other 2 ADCs," Kaklamani noted.
TROPION-Breast01 Trial Outcomes
Questions remain regarding the overall survival (OS) outcomes observed in the phase 3 TROPION-Breast01 trial (NCT05104866). The absence of a significant OS difference between Dato-DXd and chemotherapy has prompted speculation about whether this is attributable to crossover between treatment arms or other underlying efficacy issues. This underscores the importance of carefully considering ADC sequencing and the selection of the initial treatment approach, especially given the availability of subsequent treatment options following disease progression.
Clinical Implications
With the approval of Dato-DXd, clinicians face the challenge of determining the most effective sequencing strategies for ADCs in HR+/HER2- metastatic breast cancer. Factors to consider include the potential for overlapping toxicities, the mechanisms of action of different payloads, and the impact of prior therapies on treatment response. Further research and real-world data are needed to refine treatment algorithms and optimize outcomes for patients with this challenging disease.
