Daiichi Sankyo and AstraZeneca have launched a pivotal head-to-head trial comparing their antibody-drug conjugate ENHERTU (fam-trastuzumab deruxtecan-nxki) against the current standard of care, ado-trastuzumab emtansine (T-DM1), in the adjuvant setting for high-risk HER2-positive early breast cancer.
The global phase 3 DESTINY-Breast05 trial will evaluate these treatments in patients who have residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy, a population at elevated risk for disease recurrence.
Trial Design and Patient Population
DESTINY-Breast05 is a multicenter, randomized, open-label, active-controlled study that will enroll up to 1,600 patients across approximately 400 sites in North America, Europe, and Asia. Patients will be randomized 1:1 to receive either trastuzumab deruxtecan or T-DM1.
The trial focuses on two key high-risk populations:
- Patients with inoperable cancer at presentation (clinical stages T4, N0-3, M0 or T1-3, N2-3, M0)
- Patients with operable disease at presentation (clinical stages T1-3, N0-1, M0) who have positive pathological node status (ypN1-3) after neoadjuvant therapy
"Despite recent improvements and approvals of new medicines, there remain significant clinical needs for patients with HER2-positive early breast cancer with residual invasive disease after completing neoadjuvant treatment," said Antoine Yver, MD, MSc, Executive Vice President and Global Head of Oncology Research and Development at Daiichi Sankyo.
Collaborative Research Effort
The trial is being conducted in collaboration with several prestigious research organizations, including the National Surgical Adjuvant Breast and Bowel Project Foundation (NSABP), German Breast Group (GBG), Arbeitsgemeinschaft Gynäkologische Onkologie (AGO-B), and the SOLTI Breast Cancer Research Group.
Charles E. Geyer, Jr, MD, chair of the NSABP Foundation Breast Cancer Committee and Deputy Director of the Houston Methodist Cancer Center, emphasized the importance of this research: "NSABP and our academic collaborators are committed to designing and conducting trials that have potential for further improving the way breast cancer is treated by evaluating promising new therapies that may provide patients and physicians with additional treatment options."
Clinical Significance and Endpoints
The primary endpoint of DESTINY-Breast05 is invasive disease-free survival (IDFS) as assessed by investigators. Secondary endpoints include overall survival and disease-free survival.
This trial represents a significant step in advancing treatment options for early-stage HER2-positive breast cancer patients. Patients with residual invasive disease following neoadjuvant therapy face a substantially higher risk of recurrence or death compared to those who achieve a pathological complete response.
"This research builds on the data from DESTINY-Breast01 which showed durability of response in previously treated HER2-positive metastatic breast cancer," noted Dr. Yver. "DESTINY-Breast05 marks the first time we will evaluate the clinical benefit of ENHERTU in early breast cancer, reflecting our commitment to transforming treatment for even more patients with HER2-targetable disease."
Building on Previous Success
ENHERTU received accelerated approval in the United States in 2019 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. This approval was based on the phase 2 DESTINY-Breast01 trial, which demonstrated an impressive confirmed objective response rate of 60.3% per independent central review.
The drug's mechanism of action involves a HER2-directed antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker, utilizing Daiichi Sankyo's proprietary DXd ADC technology.
Safety Considerations
ENHERTU carries Boxed Warnings for Interstitial Lung Disease (ILD) and Embryo-Fetal Toxicity. In clinical studies of patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients, with fatal outcomes in 2.6%.
Other common adverse reactions (≥20%) observed in previous trials include nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia.
Broader Development Program
DESTINY-Breast05 is part of a comprehensive global development program for ENHERTU, which includes eight registrational trials evaluating its efficacy and safety across multiple HER2-targetable cancers including breast, gastric, and lung cancers.
The trial's initiation underscores the ongoing efforts to optimize treatment strategies for patients with HER2-positive breast cancer and potentially establish new standards of care in the adjuvant setting for those at high risk of recurrence.
