Dr Geyer on the FDA Approval of T-DXd Followed by THP for HER2+ Breast Cancer

“It is an important approval that is going to change the way we [manage] HER2-positive breast cancer here in the US.”

Charles E. Geyer, MD, a professor of medicine and chief of Malignant Hematology and Medical Oncology in the Department of Medicine at the University of Pittsburgh and the University of Pittsburgh Medical Center Hillman Cancer Center, discussed the significance of the FDA approval of neoadjuvant fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by a taxane, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) for patients with early-stage HER2-positive breast cancer.

On May 15, 2026, the FDA approved neoadjuvant T-DXd followed by THP for the treatment of adult patients with HER2-positive stage II or III breast cancer, based on data from the phase 3 DESTINY-Breast11 trial (NCT05113251).

The regimen adds value for high-risk populations, Geyer began, citing high pathologic complete response (pCR) rates in patients with estrogen receptor (ER)–negative, HER2-positive disease. He characterized the approval as essentially permitting the exercising of clinical judgment in selecting treatment in the neoadjuvant setting.

However, Geyer emphasized that delivering T-DXd before surgery introduces a central conundrum: How to proceed when a patient does not achieve a pCR. Historically, antibody-drug conjugates (ADCs) were reserved for the post-neoadjuvant setting after standard neoadjuvant therapy failed to eradicate the cancer, he explained. Moving these agents up front raises the unresolved question of what to offer patients with residual disease afterward, he said.

For patients who have received T-DXd in the neoadjuvant setting, sequencing to the less active ado-trastuzumab emtansine (T-DM1; Kadcyla) as adjuvant therapy is uncertain, as limited data exist on T-DM1 activity following T-DXd, Geyer noted. He stated that patients with hormone receptor–positive disease could receive endocrine therapy or neratinib (Nerlynx), whereas treatment selection for ER-negative disease poses a greater management challenge.

Geyer also framed the broader treatment decision: Pursuing a de-escalated approach and reserving ADCs as back-end rescue, vs intensifying up front to maximize pCR potential, acknowledging that many patients could achieve pCR with THP alone. He concluded that this practice-changing approval will reshape HER2-positive breast cancer management in the US, with global adoption worth watching.