Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) combined with Perjeta (pertuzumab) as first-line treatment improved progression-free survival (PFS) versus standard care for patients with HER2-positive advanced or metastatic breast cancer, according to findings from the phase 3 DESTINY-Breast09 trial presented in a press briefing at the 2025 ASCO Annual Meeting.
Data showed a median PFS of 40.7 months with Enhertu plus Perjeta versus 26.9 months with a taxane plus trastuzumab (Herceptin) and Perjeta. In the Enhertu and THP arms, respectively, the PFS rates were 93% versus 87.8% at 6 months, 85.9% versus 72.4% at 12 months and 70.1% versus 52.1% at 24 months.
As of the data cutoff of February 26, 2025, data were immature.
“The combination of [Enhertu and Perjeta] demonstrated a statistically significant and clinically meaningful improvement in PFS compared with THP,” lead study author Dr. Sara M. Tolaney, chief of the division of Breast Oncology at Dana-Farber Cancer Institute, in Boston, Massachusetts, stated during the press briefing. “These data suggest that the combination of [Enhertu and Perjeta] may represent a new first-line standard of care for patients with metastatic HER2-positive breast cancer.”
Glossary:
Progression-free survival (PFS): time during and after treatment that a patient lives without cancer growing or spreading.
Duration of response (DOR): length of time a treatment keeps cancer under control after it first responds.
Overall survival (OS): time from treatment start or diagnosis until death from any cause.
De novo disease: cancer that is already advanced or metastatic at the time of diagnosis, rather than recurring after earlier treatment.
PIK3CA mutation: a genetic alteration found in some cancers that may affect how the disease behaves or responds to treatment.
ECOG performance status: a scale used to assess how a patient’s disease affects their daily living abilities, ranging from fully active (0) to completely disabled (5).
According to Tolaney, the PFS benefit with the Enhertu regimen extended across all subgroups, which included patients regardless of de novo or recurrent disease, hormone receptor status, and PIK3CA mutation status. Additionally, the median duration of response (DOR) was 39 months with the Enhertu combination, with complete responses reported in 15.1% and 8.5% of the investigational and comparator arm, respectively. Tolaney also noted that early overall survival (OS) data highlighted a trend towards improved outcomes with Enhertu plus Perjeta.
The safety profile of Enhertu plus Perjeta in the DESTINY-Breast09 trial was comparable to prior reports of each individual agent. Any-grade treatment-emergent adverse effects (TEAEs) in the Enhertu and THP arms, respectively, included nausea (71.1% versus 28.8%), diarrhea (55.9% versus 54.2%), neutropenia (48.8% versus 44.5%) and fatigue (48.3% versus 34.6%). Additionally, the most common grade 3 (severe) or higher TEAEs in each arm included neutropenia (23.9% versus 33.2%), hypokalemia (10.2% versus 1.6%) and anemia (8.4% versus 3.7%).
In the multicenter, open-label DESTINY-Breast09 study, patients with HER2-positive metastatic or advanced breast cancer were randomly assigned 1:1:1 to receive Enhertu at 5.4 milligram per kilogram (mg/kg) every three weeks plus placebo (387 patients), Enhertu plus Perjeta (383 patients), or a taxane consisting of paclitaxel or docetaxel in combination with trastuzumab and Perjeta (387 patients). Tolaney noted that outcomes in the Enhertu plus placebo arm would remain blinded until the time of the final PFS analysis.
The trial’s primary end point was PFS per blinded independent central review. A key secondary end point was OS. Other secondary end points included PFS per investigator evaluation, objective response rate, DOR and safety and tolerability.
Patients 18 years and older with pathologically documented advanced or metastatic HER2-positive breast cancer, and no prior chemotherapy or HER2-targeted agents for advanced or metastatic disease, or only 1 prior line of endocrine therapy in the metastatic setting, were eligible for enrollment on the trial. Other requirements for study entry included having adequate organ and bone marrow function and an ECOG performance status of 0 or 1. Investigators stratified patients by whether they had de novo or recurrent disease, hormone receptor — positive or hormone receptor — negative disease and detected or non-detected PIK3CA mutations.
Reference:
“Trastuzumab deruxtecan plus Perjeta versus standard therapy for first-line HER2-positive advanced breast cancer” by Dr. Sara Tolaney, et al., Journal of Clinical Oncology.
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