SUMMARY: The FDA on January 17, 2025, approved Datopotamab deruxtecan-dlnk (DATROWAY®, Dato-DXd)), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for adult patients with unresectable or metastatic, Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.
Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.
Datopotamab-deruxtecan (Dato-DXd) is an ADC composed of a TROP2-directed monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker. Trop-2 is a transmembrane calcium signal transducer that stimulates cancer cell growth. TROP-2 is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. It has been associated with poor Overall and Disease-Free Survival in several types of solid tumors. TROP-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to TROP-2, the anti-TROP-2 monoclonal antibody is internalized and delivers the payload directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables the payload to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Dato-DXd showed encouraging antitumor activity in the TROPION-PanTumor01 trial, an ongoing multicenter, open-label study, evaluating Dato-DXd in different dose levels in solid tumors.
The present FDA approval was based on TROPION-Breast01, which is an open-label, global, Phase III study in which 732 patients (N=732) with HR-positive, HER2-negative previously treated metastatic breast cancer were randomly assigned in a 1:1 ratio to receive either Dato-DXd (N=365) or investigators choice of chemotherapy (N=367). Dato-DXd was given at a dose of 6 mg/kg IV on day 1 every 3 weeks. Investigator choice of chemotherapy consisted of Eribulin mesylate, Vinorelbine, or Gemcitabine, all given IV on days 1 and 8 every 3 weeks, as well as Capecitabine given orally on days 1-14 every 3 weeks. Treatment continued until disease progression or unacceptable toxicities. The median age was 55 yrs, and enrolled patients had received 1 or 2 prior lines of chemotherapy in the inoperable or metastatic setting. Eligible patients had progressed on or were deemed unsuitable for endocrine therapy. Patients were stratified by the number of lines of chemotherapy received in the unresectable/metastatic setting, and treatment with a previous CDK4/6 inhibitor. The Co-Primary end points were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary end points included Overall Response Rate (ORR), Safety, Patient Reported Outcomes (PRO), and Time to First Subsequent Therapy (TFST).
The Median PFS by BICR in the Dato-DXd arm was 6.9 months versus 4.9 months in the chemotherapy arm (HR=0.63; P < 0.0001). The PFS benefit with Dato-DXd over chemotherapy was noted irrespective of brain metastases and prior duration of treatment with CDK4/6 inhibitors. Although OS data were immature, a trend favoring Dato-DXd was observed. The confirmed ORR was 36.4% and 22.9% and median Duration of Response was 6.7 months and 5.7 months in the Dato-DXd and chemotherapy groups, respectively. The median Time to First Subsequent Therapy was 8.2 months with Dato-DXd and 5.0 months with chemotherapy. Dato-DXd also demonstrated a delay in time to deterioration in global health status/quality of life, compared to chemotherapy. Grade 3 or more treatment-related adverse events with Dato-DXd was lower than with chemotherapy (20.8% versus 44.7%) and the most common toxicities were nausea and stomatitis with Dato-DXd and neutropenia in the chemotherapy arm.
In conclusion, patients receiving Dato-DXd showed statistically significant and clinically meaningful improvement in Progression Free Survival compared to chemotherapy, with a favorable and manageable safety profile. The improved outcomes were observed across subgroups, supporting the benefit of this novel treatment option, for previously treated patients with inoperable/metastatic HR-positive, HER2-negative breast cancer.
Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. Bardia A, Jhaveri K, Im S-A, et al. for the TROPION-Breast01 Investigators. J Clin Oncol. 2025;43:285-296.
