AstraZeneca and Daiichi Sankyo's Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd) has been accepted by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior systemic therapy for unresectable or metastatic disease. The FDA action date is set for the first quarter of 2025.
The BLA is supported by results from the pivotal TROPION-Breast01 Phase III trial. The trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with datopotamab deruxtecan compared to investigator's choice of chemotherapy in patients previously treated with endocrine-based therapy and at least one systemic therapy. Interim overall survival (OS) results favored datopotamab deruxtecan, but data were not mature at the cutoff, with further assessment planned.
TROPION-Breast01 Trial Details
TROPION-Breast01 is a global, randomized, multicenter, open-label Phase III trial. It evaluated datopotamab deruxtecan versus single-agent chemotherapy (eribulin, capecitabine, vinorelbine, or gemcitabine) in patients with unresectable or metastatic HR-positive, HER2-negative breast cancer who had progressed on and were not suitable for endocrine therapy and had received at least one additional systemic therapy. The dual primary endpoints were PFS (assessed by blinded independent central review) and OS. Key secondary endpoints included objective response rate, duration of response, investigator-assessed PFS, disease control rate, and safety. The trial enrolled over 700 patients across multiple continents.
Datopotamab Deruxtecan: A Novel ADC
Datopotamab deruxtecan is an investigational TROP2-directed antibody-drug conjugate (ADC) utilizing Daiichi Sankyo’s DXd ADC Technology. It comprises a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload (DXd) via cleavable linkers. This ADC is one of several DXd ADCs in Daiichi Sankyo's oncology pipeline and a key program in AstraZeneca's ADC platform.
Clinical Context and Unmet Need
HR-positive, HER2-negative breast cancer is the most common subtype, accounting for over 65% of diagnosed cases. While endocrine therapy is the standard initial treatment, most patients with advanced disease develop resistance, highlighting the need for additional options. TROP2 is highly expressed in HR-positive, HER2-negative breast cancer and is associated with increased tumor progression and poor survival.
Expert Commentary
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, noted that most patients with advanced HR-positive, HER2-negative breast cancer develop endocrine resistance and face chemotherapy. She stated that datopotamab deruxtecan, if approved, could provide an efficacious and better-tolerated alternative to conventional chemotherapy.
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, added that the FDA's acceptance brings them closer to providing an alternative to chemotherapy earlier in the metastatic setting. He also mentioned ongoing regulatory reviews in other regions for both lung and breast cancer indications.
Ongoing Development
An additional BLA for datopotamab deruxtecan is under review in the US for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC), based on the TROPION-Lung01 Phase III trial. Further regulatory submissions are underway globally for lung and breast cancer indications.
