The decision follows phase 3 trial results that demonstrated improved progression-free survival and confirmed the safety of Dato-DXd in patients with breast cancer.
The FDA has accepted a biologics license application (BLA) for datopotamab deruxtecan (Dato-DXd; AstraZeneca, Daiichi Sankyo) to treat adult patients with unresectable or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior systemic therapy for unresectable or metastatic disease. The BLA comes after positive results from the phase 3 TROPION-Breast01 clinical trial (NCT05104866) demonstrated statistically and clinically meaningful progression-free survival (PFS) in patients.1
Dato-DXd is an investigational TROP2-directed antibody drug conjugate (ADC) that is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody that attaches to topoisomerase 1 inhibitor payloads through tetrapeptide-based cleavable linkers. Its safety and efficacy are currently being evaluated in more than 20 clinical trials that include multiple types of cancer, such as triple-negative breast cancer; HR-positive, HER2-negative breast cancer; and non-small cell lung cancer (NSCLC).1
“Despite marked progress in the treatment of HR-positive, HER2-negative breast cancer, most patients with advanced disease develop endocrine resistance and face the prospect of one or several lines of chemotherapy,” said Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, in a press release. “If approved, Dato-DXd has the potential to provide these patients an efficacious and better tolerated alternative to conventional chemotherapy.”1
TROPION-Breast01 is a global, randomized, multicenter, open-label phase 3 clinical trial that evaluated the efficacy and safety of Dato-DXd and compared it with single-agent chemotherapy—eribulin, capecitabine, vinorelbine, or gemcitabine—in more than 700 patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who received at least 1 additional systemic therapy. These patients also had their disease progress and are no longer candidates for endocrine therapy. The dual primary end points for the trial are PFS and overall survival (OS), and key secondary end points include objective response rate (ORR), duration of response, investigator-assessed PFS, disease control rate, time to first therapy following treatment initiation, and safety.1,2
Trial Name: A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator's Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01)
ClinicalTrials.gov ID: NCT05104866
Sponsor: AstraZeneca
Completion Date (Estimated): August 15, 2025
According to the findings, compared with chemotherapy alone, Dato-DXd was shown to reduce the risk of disease progression or death by approximately 37% in patients with HR-positive, HER2-negative breast cancer (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.52-0.76; p < 0.001). In addition, the median PFS in patients treated with Dato-DXd was longer (6.9 months) than those treated with chemotherapy (4.9 months), with consistent PFS benefit across different subgroups.2
In addition, the findings also demonstrated a confirmed ORR of 36.4% in patients who were treated with Dato-DXd, and 22.9% with chemotherapy. The study authors note that although OS data appeared to favor Dato-DXd over chemotherapy (HR 0.84; 95% CI 0.62-1.14), the results were not considered statistically significant, requiring the trial to continue to assess OS.2
The findings demonstrated a favorable safety profile for Dato-DXd over chemotherapy, with no new safety concerns being identified. Treatment-related adverse events (TRAEs) occurred in 21% and 45% of patients in the Dato-DXd and chemotherapy cohorts, respectively, and were grade 3 or higher in severity. The most common grade 3 or higher TRAEs reported by patients across the 2 treatment groups were (1%; 3%), stomatitis (6%; 3%), fatigue (2%; 2%) and anemia (1%; 2%). Instances of all-grade interstitial lung disease (ILD) was low (3%) and the majority of events were low-grade; however, there was 1 occurrence of grade 5 ILD reported.2
Following endocrine therapy, the most common prior treatments for patients in the Dato-DXd and chemotherapy groups, respectively, included 1 (63%; 61%) to 2 (37%; 38%) lines of chemotherapy and CDK4/6 inhibitors (82%; 78%). By the July 17, 2023, data cut-off, 93 patients continued treatment with Dato-DXd, and 39 remained on chemotherapy.2
“The FDA’s acceptance of the BLA brings us closer to providing patients with previously treated HR-positive, HER2-negative breast cancer an alternative option to conventional chemotherapy earlier in the metastatic setting,” said Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, in the press release. “Following our recently accepted application for advanced nonsquamous NSCLC in the US, along with additional regulatory reviews underway in China, the EU, Japan, and other regions, we are working swiftly to bring Dato-DXd as a potential new treatment option to patients around the world.”1
