Moving ADCs to the Frontline in Metastatic HER2-Positive Disease

This segment examines the evolving role of T-DXd in the first-line treatment of metastatic HER2-positive breast cancer, driven by results from the DESTINY-Breast09 trial. The study evaluated T-DXd in combination with pertuzumab compared with the long-standing standard regimen of docetaxel, trastuzumab, and pertuzumab (THP). Results demonstrated a substantial improvement in progression-free survival (PFS), with median PFS approximately doubling from 20 to 40 months. These findings have led to regulatory approval and early adoption of the regimen in clinical practice.

Despite the strong efficacy signal, clinicians are carefully considering patient selection. Many favor first-line T-DXd–based therapy for patients with high-risk, bulky, or symptomatic disease, including those with baseline central nervous system involvement. For patients with lower-volume or indolent disease, THP followed by maintenance therapy remains a reasonable approach to preserve future treatment options.

Treatment duration and long-term tolerability are also key considerations. Prolonged exposure to T-DXd may be associated with cumulative fatigue and ongoing risk of ILD. As a result, some clinicians favor an induction strategy (treating to maximal response for approximately 6 to 9 cycles, followed by transition to a maintenance regimen).

Emerging maintenance strategies are informed by trials such as PERTAIN (for hormone receptor–positive disease) and HER2CLIMB-05 (for hormone receptor–negative disease), with particular interest in reducing central nervous system progression risk. Overall, the discussion reflects a shift toward earlier use of highly active ADC therapy, balanced by individualized decisions regarding sequencing, duration, and maintenance based on disease biology and patient tolerance.