Trastuzumab Deruxtecan in the Curative Setting: Neoadjuvant and Adjuvant Advances

Segment 4 discusses the curative-intent setting, highlighting groundbreaking data supporting T-DXd in high-risk early-stage HER2-positive breast cancer. The DESTINY-Breast11 trial is reviewed, which evaluated neoadjuvant T-DXd followed by THP versus standard anthracycline-based regimens. The trial demonstrated markedly higher pathologic complete response rates, reaching approximately 67% overall and approaching 80% in HR-negative patients. Importantly, these results were observed in a high-risk population with bulky, node-positive, or inflammatory disease.

The discussion then turns to DESTINY-Breast05, which evaluated T-DXd versus T-DM1 in patients with residual disease after neoadjuvant therapy. In this very high-risk group, T-DXd significantly improved invasive disease-free survival, with early analyses showing three-year disease-free survival rates exceeding 90%. The panel notes that using T-DXd earlier may allow a broader group of patients to benefit from this highly effective therapy.

Key clinical questions are raised regarding optimal sequencing, particularly how to manage patients who do not achieve pathologic complete response after neoadjuvant T-DXd. Although T-DM1 remains a strong option, ongoing trials evaluating varying durations of neoadjuvant T-DXd may further refine its role. This segment reflects a paradigm shift toward more potent, non–cross-resistant regimens in early disease.