The Evolving Role of T-DXd in HER2+ Metastatic Breast Cancer

EP: 1.Current Treatment Approaches in HER2+ Metastatic Breast Cancer

EP: 2.Optimizing Maintenance Therapy After First-Line Treatment in HER2+ Metastatic Breast Cancer

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EP: 3.The Evolving Role of T-DXd in HER2+ Metastatic Breast Cancer

EP: 4.Strategies for Monitoring and Managing T-DXd-Related Adverse Effects

The panel shifted focus to the positioning of trastuzumab deruxtecan (T-DXd), with a clear consensus that the DESTINY-Breast03 trial firmly established T-DXd as the preferred second-line treatment for HER2-positive metastatic breast cancer. This was based on a striking improvement in progression-free survival (PFS)—from 7.2 months with T-DM1 to 29 months with T-DXd—along with a very favorable overall survival trend. The uptake in both academic and community settings has been rapid, reflecting the robustness of the data and the visual clarity of the survival curves.

However, the discussion acknowledged that ado-trastuzumab emtansine (T-DM1) remains a very effective drug, albeit now relegated to later lines of therapy. Panelists expressed some regret that such a strong agent could get lost in an increasingly crowded treatment landscape. The conversation also touched on historical shifts in standard care—such as the synergy between taxanes and trastuzumab—which laid the foundation for the current treatment paradigms and emphasized the flexibility built into older studies, such as permitting taxane switches mid-trial.

The conversation then moved to DESTINY-Breast09, a first-line trial comparing 3 arms: standard CLEOPATRA regimen (taxane, trastuzumab, and pertuzumab), T-DXd alone, and T-DXd plus pertuzumab. Interim data showed a significant PFS advantage for the T-DXd plus pertuzumab arm (approximately 40 months vs 26 months with CLEOPATRA), with early signals of improved overall survival. Yet concerns were raised about the generalizability of the trial population—about 50% had de novo metastatic disease, and very few had prior HER2-targeted therapy, which differs from typical US patient profiles. In addition, limited access to certain drugs in some countries impacted treatment patterns within the trial. These nuances highlight the need for cautious interpretation of global trial results when applying them to domestic practice.