Results from the phase III DESTINY-Breast09 clinical trial found that the combination of fam-trastuzumab deruxtecan-nxki (T-DXd) with pertuzumab may delay cancer growth for longer than the current standard of care in people with HER2-positive locally advanced or metastatic breast cancer. The research was presented at the 2025 ASCO Annual Meeting (Abstract LBA1008).
About the Study
“The DESTINY-Breast09 trial has the potential to establish a new first-line standard of care for metastatic HER2-positive breast cancer, a setting which hasn’t seen significant innovation in more than a decade. Trastuzumab deruxtecan represents a highly effective targeted therapy and has demonstrated promising outcomes in both the front-line and late-line HER2-positive metastatic breast cancer settings,” said lead study author Sara Tolaney, MD, MPH, FASCO, Chief of the Division of Breast Oncology, Dana-Farber Cancer Institute, Boston.
The current first-line treatment for people with locally advanced or metastatic HER2-positive breast cancer is a taxane given in combination with the HER2-targeted therapy drugs trastuzumab and pertuzumab (THP); this combination has been the standard of care for more than 20 years. However, most patients who receive THP experience cancer growth within 2 years of treatment.
T-DXd is an antibody-drug conjugate that is made up of trastuzumab attached to deruxtecan. It has shown promise as a treatment of metastatic breast cancer that has progressed after earlier treatments no longer work. In the DESTINY-Breast09 clinical trial, researchers wanted to learn whether T-DXd could also improve outcomes for patients in the first-line setting.
The study included 1,157 patients with HER2-positive locally advanced or metastatic breast cancer who had not received treatment with chemotherapy or HER2-targeted therapy. The patients were randomly assigned to receive either T-DXd with a placebo (n = 387), T-DXd with pertuzumab (n = 383), or THP (n = 387). However, at the time of this initial analysis, the researchers presented data only from the T-DXd with pertuzumab group and the THP group. Among the patients in these two groups, 52% had de novo disease where the cancer had metastasized at the time of diagnosis, 54% had hormone receptor (HR)-positive cancer, and 48% had disease that recurred after treatment in the early-stage setting. About half the patients in both groups were from Asia, and most patients were younger than age 65.
Key Findings
At a median follow-up of nearly 2.5 years (29 months), the study found that T-DXd with pertuzumab reduced the risk of disease progression or death by 44% for patients. The median progression-free survival was more than 3 years with T-DXd and pertuzumab (40.7 months). In the THP group, the median progression-free survival was slightly more than 2 years (26.9 months). This benefit was seen across all subgroups.
At 2 years, about 70% of patients in the T-DXd with pertuzumab group had not seen their cancer grow or spread, compared with about 52% in the THP group. For the patients who received T-DXd and pertuzumab, about 85% had their cancer shrink or disappear vs 78.6% of those in the THP group. About 15% of patients who responded to treatment with T-DXd and pertuzumab had no signs of cancer in response to the treatment vs 8.5% in the THP group.
The analysis of overall survival is immature, but researchers observed a trend in improvement in overall survival for those given T-DXd with pertuzumab. The researchers will continue to follow patients to better assess longer-term overall survival data.
Both groups experienced similar rates of serious adverse effects. However, the length of treatment was longer in the T-DXd group, and certain adverse effects—including nausea, vomiting, and constipation—were more common in this group. Interstitial lung disease, a known adverse effect of T-DXd, was reported in about 12% of patients in this group. However, most of these cases were not severe, according to the investigators.
The study will continue until a final progression-free survival analysis is done and until final overall survival is reported.
“The findings from Destiny-Breast09 represent a new first-line standard treatment option for HER2-positive metastatic breast cancer. The duration of therapy can now be measured in years and gives us the opportunity to look at appropriate sequencing of this new standard to optimize quality of life and toxicities,” said Rebecca Dent, MD, MSc, Deputy Chief Executive Officer (Clinical) at the National Cancer Center Singapore and an ASCO expert in breast cancer.
