FDA Approves Datopotamab Deruxtecan for Advanced HR-Positive, HER2-Negative Breast Cancer

On 17 January 2025, the US Food and Drug Administration (FDA) approved a Trop-2-directed antibody and topoisomerase inhibitor conjugate for adults with metastatic or unresectable hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who had previously received endocrine-based therapy and chemotherapy for metastatic disease: datopotamab deruxtecan-dlnk (Datroway, Daiichi Sankyo, Inc.).

Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate (ADC), has received its first FDA approval.

What Is Trop-2? Which Cancer Drugs Target Trop-2?

Trop-2 (trophoblast cell surface antigen-2) is a transmembrane glycoprotein overexpressed in many epithelial cancers and involved in tumor cell growth, proliferation and metastasis. Treatments targeting Trop-2 have therefore become an important area of cancer research. 

Sacituzumab govitecan (Trodelvy) is an antibody-drug conjugate targeting Trop-2 and carrying the topoisomerase I inhibitor SN-38. After binding to Trop-2, the drug is taken into the cell and releases SN-38, inhibiting DNA replication and causing cancer cells to die. It is approved for breast and urothelial cancer (see details of the approvals).

Datopotamab deruxtecan is the second Trop-2-targeted anticancer drug to receive FDA approval.

FDA Approval Based on the TROPION-Breast01 Trial

This approval is based on findings from the randomized, multicenter, open-label TROPION-Breast01 trial involving 732 patients. The trial included patients who were not suitable for further endocrine therapy and had previously received chemotherapy twice.

Comparing 365 patients who received datopotamab deruxtecan (Dato-DXd) with 367 who received a choice of eribulin, capecitabine, vinorelbine or gemcitabine chemotherapy, the results demonstrated improvements in response rates and progression-free survival (PFS) with Dato-DXd.

Results

• Median PFS was significantly longer in the Dato-DXd arm than in the chemotherapy arm, at 6.9 and 4.9 months, respectively (hazard ratio [HR], 0.63).

• Median overall survival was 18.6 and 18.3 months, respectively, with no significant difference between the arms (HR, 1.01).
• Confirmed overall response rates were 36% and 23%, and median response durations were 6.7 and 5.7 months in the Dato-DXd and chemotherapy arms, respectively.

Adverse Events

Adverse reactions, including laboratory abnormalities, occurring in at least 20% of patients included stomatitis, nausea, fatigue, decreased leukocytes, decreased calcium, alopecia, decreased lymphocytes, decreased hemoglobin, constipation, decreased neutrophils, dry eye, vomiting, increased alanine aminotransferase, keratitis, increased aspartate aminotransferase and increased alkaline phosphatase.

The trial findings showed that patients receiving Dato-DXd experienced fewer grade 3 or higher toxicities and fewer dose reductions or interruptions than those receiving chemotherapy.

Dosage

The recommended Dato-DXd dose is 6 mg/kg by intravenous infusion once every three weeks, with a maximum of 540 mg for patients weighing 90 kg or more, until disease progression or unacceptable toxicity.

This US approval follows approval in Japan in December 2024. The FDA has also granted priority review to a Biologics License Application for Dato-DXd in certain non-small cell lung cancers. According to Daiichi Sankyo: "A comprehensive global clinical development program is ongoing, with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including non-small cell lung cancer, triple-negative breast cancer, and HR-positive breast cancer with HER2-low or negative expression."