Dr Wander on the Evolving First-Line and Post–T-DXd Landscape in HER2+ Metastatic Breast Cancer

“We need to do a lot more work in the translational research realm, understanding resistance mechanisms to ADCs, because that will ultimately guide our therapeutic approach.”

Seth A. Wander, MD, PhD, an assistant professor of medicine at Harvard Medical School, a medical oncologist at Massachusetts General Hospital, and director of Translational Research in the Breast Oncology Program and director of Precision Medicine at the Termeer Center for Targeted Therapies at the Mass General Cancer Center, discussed 3 recent FDA approvals in HER2-positive metastatic breast cancer and the challenge of resistance to antibody-drug conjugates, as discussed at the 2026 Bridging the Gaps in Breast Cancer Meeting.

Until approximately 4 to 6 months ago, most patients with this disease received the same treatment algorithm, Wander said. However, recent FDA-approved regimens include fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) in the first-line setting, based on the phase 3 DESTINY-Breast09 trial (NCT04784715). The FDA also approved 2 maintenance regimens: palbociclib (Ibrance) added to standard HER2-directed and endocrine maintenance therapies based on data from the phase 3 PATINA trial (NCT02947685) for hormone receptor–positive disease, and tucatinib (Tukysa) plus trastuzumab (Herceptin) and pertuzumab maintenance therapy from the phase 3 HER2CLIMB-05 trial (NCT05132582) for both estrogen receptor–positive and –negative disease, he explained.

Both maintenance studies were built on the phase 3 CLEOPATRA trial (NCT00567190) backbone of a taxane plus trastuzumab and pertuzumab and prompted vigorous debate about a unified approach, Wander noted. Open questions include whether all patients should receive first-line T-DXd, whether to continue T-DXd indefinitely or switch to maintenance therapy, and which maintenance regimen to use, he said. Because the 3 independent studies ran in parallel without overlap, Wander added that more prospective, real-world, and academic data are needed to help with this decision-making.

Data regarding treatment after T-DXd are limited, Wander said. Resistance to antibody-drug conjugates (ADCs) is complex and heterogeneous, he explained, and can arise from changes in the antibody target (HER2 expression), the cytotoxic payload, efflux pumps, and other genomic or molecular changes. Treatment options include HER2 TKIs, chemotherapy plus trastuzumab, and ADCs in development, but there is no one-size-fits-all approach, Wander concluded.