Dr Tolaney on the PFS Benefit With First-Line T-DXd Plus Pertuzumab in HER2+ Breast Cancer

"In essence, T-DXd and pertuzumab almost doubled the duration of progression-free survival when compared with THP, and these benefits were seen across all the subgroups that were looked at."

Sara M. Tolaney, MD, MPH, chief of the Division of Breast Oncology at Susan F. Smith Center for Women's Cancers, associate director, Susan F. Smith Center for Women's Cancers; a senior physician at Dana-Farber Cancer Institute; and associate professor of medicine at Harvard Medical School, discusses the progression-free survival benefit seen with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) compared with standard-of-care trastuzumab (Herceptin) plus pertuzumab and a taxane (THP) for the first-line treatment of patients with HER2-positive advanced/metastatic breast cancer.

Notably, at the time of the interim analysis, the stringent criteria for superiority—a P value less than .00043—was met for the comparison of T-DXd plus pertuzumab vs THP but was not met for the comparison of T-DXd plus placebo vs THP, Tolaney noted. Therefore, the T-DXd plus placebo arm remains blinded until the final PFS analysis, Tolaney stated. Overall survival data were immature at this time point, Tolaney noted.

At the 2025 ASCO Annual Meeting, efficacy data comparing T-DXd plus pertuzumab with THP were presented, Tolaney stated. The combination demonstrated a statistically significant and clinically meaningful improvement in PFS, with a 44% reduction in the risk of disease progression or death compared with THP for first-line treatment of patients with metastatic HER2-positive breast cancer, she said. The median PFS with T-DXd plus pertuzumab was 40.7 months (95% CI, 36.5-not calculable [NC]) compared with 26.9 months (95% CI, 21.8-NC) for THP (HR, 0.56; 95% CI, 0.44-0.71; P < .00001), Tolaney stated.

These results were consistent across all subgroups, including prior treatment status, hormone receptor status, and PIK3CA mutation status, Tolaney stated. Objective response rates were also numerically higher with T-DXd plus pertuzumab (85.1%; 95% CI, 81.2%-88.5%) compared with THP (78.6%; 95% CI, 74.1%-82.5%), Tolaney noted. No new safety signals were identified, Tolaney stated. These data suggest that T-DXd plus pertuzumab may represent a new first-line standard of care for patients with metastatic HER2-positive breast cancer, Tolaney concluded.