How Enhertu Trials Are Transforming Treatment for HER2-Positive Breast Cancer

Dr. Sara Nunnery, a breast medical oncologist and the director of Breast Cancer Research at Tennessee Oncology in Nashville, is the host of Breast Cancer Briefing, a podcast series that breaks down the latest news in breast cancer research — one conversation at a time.

In the latest episode, filmed live onsite at the 43rd Annual Miami Breast Cancer Conference, Dr. Nunnery sat down with Dr. Kelly E. McCann, a breast medical oncologist in the University of California system.

Their conversation centered around the evolving HER2-positive breast cancer treatment paradigm. The experts highlighted that although this disease was once associated with a poor prognosis, targeted therapies like Herceptin (trastuzumab) have revolutionized management, making these cancers highly curable.

They noted the role of Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd), an antibody-drug conjugate (ADC) that delivers chemotherapy directly to cancer cells and uses a bystander effect to kill neighboring malignant cells. The phase 3 DESTINY-Breast11 trial evaluated Enhertu in the neoadjuvant setting for patients with high-risk, HER2-positive early breast cancer. Results showed significantly higher pathological complete response rates with T-DXd followed by docetaxel, Herceptin and Perjeta (pertuzumab) compared with standard chemotherapy. Responses were even more pronounced in patients with hormone receptor–negative disease.

Furthermore, they spotlighted the phase 3 DESTINY-Breast05 trial, which examined Enhertu as adjuvant therapy for high-risk patients with residual HER2-positive disease. In this study, Enhertu generated an improvement in invasive disease–free survival compared with standard Kadcyla (ado-trastuzumab emtansine). They noted that a significant benefit of Enhertu is its ability to cross the blood-brain barrier, offering the potential for preventing brain metastases. However, the experts expressed caution regarding interstitial lung disease, a potentially fatal adverse effect associated with Enhertu. Because of this risk, patients who receive Enhertu require frequent, expensive CT monitoring, which Nunnery and McCann explained can pose logistical and insurance challenges in standard practice.

Although adjuvant Enhertu has been added to the National Comprehensive Cancer Network Clinical Practice Guidelines for HER2-positive breast cancer, the neoadjuvant regimen has not yet been included, likely awaiting more mature survival data. Both oncologists conclude that although ADC-associated toxicities require vigilant management, these treatment advancements provide powerful new tools for potentially curing high-risk patients with HER2-positive breast cancer.