Dr McCann on the Potential Use of T-DXd Followed by THP in HER2+ Breast Cancer

“A lot of our medications don’t cross the blood-brain barrier. THP doesn’t, neither [does] ddAC, so if I’m worried about a patient with very advanced disease and the prospect of brain metastases, and I’m not going to use neratinib later on, that is a consideration for using this neoadjuvant strategy.”

Kelly Elizabeth McCann, MD, PhD, an associate professor at the University of California San Diego, discussed the clinical implications of the FDA approval of neoadjuvant fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by a taxane plus trastuzumab (Herceptin) and pertuzumab (Perjeta; THP) for the treatment of patients with HER2-positive early breast cancer, which was supported by data from the phase 3 DESTINY-Breast11 trial (NCT05113251).

This trial explored several treatment arms, including T-DXd for 8 cycles—an arm that has since closed—and a sequence of 4 cycles of T-DXd followed by THP. These regimens were evaluated against dose-dense doxorubicin (Adriamycin) plus cyclophosphamide (ddAC) followed by THP (ddAC-THP), although McCann noted that contemporary practice has largely shifted away from this regimen and toward TCHP or various treatment de-escalation strategies.

DESTINY-Breast11 results were notably positive for the sequence of T-DXd followed by THP, which elicited an improvement in pathological complete response (pCR) rates. Beyond pCR rates, McCann emphasized a critical therapeutic advantage: T-DXd’s ability to cross the blood-brain barrier. This is a significant differentiator, as standard regimens like THP or ddAC do not possess this capability.

Consequently, McCann indicated that for high-risk patients, such as those with inflammatory breast cancer or more advanced disease, the neoadjuvant T-DXd–based strategy serves as an important clinical consideration. She explained that this approach is relevant when faced with concern about the prospect of brain metastases and do not intend to use neratinib (Nerlynx) as a subsequent therapy. McCann concluded that the ability to target potential central nervous system involvement early in the HER2-positive early breast cancer treatment course provides a strategic benefit for this vulnerable patient population.