Trastuzumab deruxtecan (T-DXd; Enhertu) significantly outperforms chemotherapy in patients with hormone receptor–positive, HER2-low or HER2-ultralow metastatic breast cancer (mBC) who experience rapid disease progression after prior endocrine-based therapy.
These findings were presented at the 2024 San Antonio Breast Cancer Symposium (SABCS) (Abstract LBA-4) and are based on a new analysis of the phase 3 DESTINY-Breast06 clinical trial. The results highlight the potential role of T-DXd as an early-line treatment after one or more lines of endocrine-based therapy for patients with hormone receptor–positive, HER2-low/-ultralow mBC.
“T-DXd demonstrated a clinically meaningful benefit versus standard chemotherapy, regardless of time to progression on first-line endocrine-based treatment,” said lead study author Aditya Bardia, MD, MPH, of the University of California Los Angeles, at SABCS. “This included patients with rapid disease progression on first-line endocrine-based treatment in this setting.”
The analysis examined the effect of prior response to endocrine-based therapy on treatment outcomes. Patients were classified into subgroups based on the time to progression (TTP) after first-line endocrine therapy (ET) plus a CDK4/6 inhibitor. The study included patients who had disease progression after one line of endocrine-based therapy, but who had not yet received chemotherapy in the metastatic setting. The subgroups included patients with progression within six months, from between 6 to 12 months, and after 12 months.
Across all subgroups, T-DXd demonstrated improved progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) compared with the physician’s choice of chemotherapy. For patients with the most rapid progression (<6 months TTP), the median PFS was 14.0 months with T-DXd versus 6.5 months with chemotherapy (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.25–0.59). The PFS benefit was also seen in the 6–12-month subgroup (13.2 vs 6.9 months; HR, 0.69; 95% CI, 0.43–1.12) and in the beyond-12-month subgroup (12.9 vs 8.2 months; HR, 0.67; 95% CI, 0.51–0.88).
ORRs were also higher for T-DXd in each subgroup. Among patients with less than 6 months TTP, the ORR was 67.7% for T-DXd compared with 25.4% for the chemotherapy group. For patients who received 6–12 months of chemotherapy, the ORR was 60.0% for T-DXd and 28.8% for chemotherapy. In the beyond-12-month subgroup, the ORR was 59.5% for T-DXd and 33.1% for chemotherapy. DOR similarly favored T-DXd, with a median of 11.1 months for patients with less than 6 months TTP compared with 7.3 months with chemotherapy.
A total of 89.3% of participants had received at least one prior line of ET plus a CDK4/6 inhibitor for mBC. Grade 3 treatment-emergent adverse events or higher were more frequent in patients treated with T-DXd compared with chemotherapy, with rates of 55.4% vs 42.4% in the less-than-6-month TTP subgroup, 59.3% vs 40.8% in the 6–12-month subgroup, and 45.8% vs 42.9% in the beyond-12-month subgroup. The safety profile was consistent with previous reports for T-DXd.
The results of the analysis are “reassuring” because T-DXd remained effective, even for patients who progressed quickly on prior CDK4/6 inhibitors, said Azka Ali, MD, medical oncologist at the Cleveland Clinic Taussig Cancer Institute in Ohio. Previously, the time spent on CDK4/6 inhibitors was seen as a marker of endocrine sensitivity, with data from the EMERALD trial suggesting that patients receiving these inhibitors for at least 12–18 months had the greatest benefit from elacestrant, she said.
Looking ahead, Dr. Ali, who was not a part of the study, said that the challenge is optimizing treatment sequencing in hormone receptor–positive, HER2-negative metastatic breast cancer. “A lot of these studies are coming out simultaneously, and the sequencing of this is what we are trying to figure out in real time,” she told Oncology News Central.
Additional analyses are ongoing to assess biomarker-driven responses. “We [will] be conducting biomarker analysis looking at PIK3CA, looking at other mutations, and also looking at HER2 by different analytical methods, and we will be presenting that in the future,” Dr. Bardia said.
Dr. Bardia reported various industry relationships.
Dr. Ali reported no relevant disclosures.