As reported in The New England Journal of Medicine by Tolaney et al, interim analysis of the phase III DESTINY-Breast09 trial has shown significantly improved progression-free survival with fam-trastuzumab deruxtecan-nxki (T-DXd) plus pertuzumab vs a taxane (paclitaxel or docetaxel), trastuzumab, and pertuzumab (THP) in previously untreated patients with advanced or metastatic HER2-positive breast cancer.
Study Details
In the international open-label trial, 1,157 patients were randomly assigned 1:1:1 between April 2021 and October 2023 to receive T-DXd plus pertuzumab, trastuzumab deruxtecan plus placebo, or THP. The current interim analysis included a comparison between the T-DXd plus pertuzumab group (n = 383) and the THP group (n = 387); data from the T-DXd plus placebo group will remain blinded until final analysis of progression-free survival. In total, 49% of patients in both groups were from Asia. The primary endpoint was progression-free survival on blinded independent central review.
Key Findings
At the data cutoff (end of February 2025), median progression-free survival was 40.7 months (95% confidence interval [CI] = 36.5 months to not calculable) in the T-DXd plus pertuzumab group vs 26.9 months (95% CI = 21.8 months to not calculable) in the THP group (hazard ratio [HR] = 0.56, 95% CI = 0.44–0.71, P < .00001, exceeding the P value boundary for superiority of .00043). Rates at 24 months were 70.1% vs 52.1%.
Confirmed objective response was observed in 85.1% of the T-DXd plus pertuzumab group, with complete response in 15.1%, and in 78.6% of the THP group, with complete response in 8.5%. Median durations of response were 39.2 vs 26.4 months.
Grade 3 or higher adverse events occurred in 63.5% of the T-DXd plus pertuzumab group and 62.3% of the THP group; the most common were neutropenia (23.9%), hypokalemia (10.2%), and anemia (8.4%) in the T-DXd plus pertuzumab group, and neutropenia (33.2%), leukopenia (17.5%), and diarrhea (5.2%) in the THP group. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving T-DXd plus pertuzumab (grade 1 or 2 in 44 patients and grade 5 in 2 patients) and in 1.0% of those receiving THP (all grade 1 or 2).
The investigators concluded: “[T-DXd] plus pertuzumab led to a significantly lower risk of progression or death than THP when used as first-line treatment for HER2-positive advanced or metastatic breast cancer, with no new safety signals.”
Sara M. Tolaney, MD, of the Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by AstraZeneca and Daiichi Sankyo. For full disclosures of all study authors, visit nejm.org.
