# Datopotamab deruxtecan

Datopotamab deruxtecan, sold under the brand name Datroway, is an anti-cancer medication used for the treatment of breast cancer. It is a Trop-2-directed antibody and topoisomerase inhibitor antibody-drug conjugate.
The most common adverse reactions, including laboratory abnormalities, include stomatitis, nausea, fatigue, decreased leukocytes, decreased calcium, alopecia, decreased lymphocytes, decreased hemoglobin, constipation, decreased neutrophils, dry eye, vomiting, increased ALT, keratitis, increased AST, and increased alkaline phosphatase.
Datopotamab deruxtecan was approved for medical use in the United States in January 2025.

## Medical uses

Datopotamab deruxtecan is indicated for the treatment of adults with unresectable or metastatic, hormone receptor positive, human epidermal growth factor receptor 2-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.

## Side effects

Datopotamab deruxtecan is associated with a range of adverse events.

## Pharmacology
### Mechanism of action

As a antibody-drug conjugate (ADC), datopatomab deruxtecan binds to Trop-2 and undergoes receptor internalization, allowing the payload (i.e., the active anti-cancer drug) to be transported into the cell. It is transported into lysosomes. Inside the cell, it is split by selective cleaving of the tetrapeptide linker (Gly-Gly-Phe-Gly) by enzymes specific to tumor cells, such as cathepsins. It results in the release of exatecan, which acts on topoisomerase, an enzyme essential to DNA replication that controls coiling of the DNA helix, leading to DNA damage, cell replication arrest and, consequently, apoptosis. Then, exatecan is able to penetrate into neighboring cells, thereby causing a cascade of cell death. The minimum ihibitory concentration (MIC) of exatecan in vitro was shown to be equal to 0.31 μM. Exatecan is a derivative of camptothecin, a substance found in Camptotheca acuminata.

### Pharmacodynamics

Datopatamab deruxtecan pharmacodynamic parameters after the first dose of 6 mg/kg :
| Parameter | Datopatamab deruxtecan | Deruxtecan |
| C$_{max}$ | 154 μg/mL | 2.8 ng/mL |
| AUC | 671 μg*day/mL | 18 ng*day/mL |
| mean steady state volume | 3.5 | n/d |
| plasma protein binding | n/a | 98% |
| blood-to-plasma concentration ratio | n/d | 0.6 (in vitro) |
| half life (t$_{1/2}$) | 4.8 days | 5.5 days |
| clearance | 0.6 L/day | n/d |

#### Metabolism and interactions

Deruxtecan is metabolised by CYP3A4, whitout notable glucuronidation. Moreover, it is a substrate of several transporter systems, i.e. OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1 and BCRP. Therefore, use with itraconazole (CYP3A inhibitor) and ritonavir (OATP1B/CYP3A inhibitor) is contraindicated.

## History

Efficacy was evaluated in TROPION-Breast01 (NCT05104866), a multicenter, open-label, randomized trial. Participants must have experienced disease progression, been deemed unsuitable for further endocrine therapy, and have received one or two lines of prior chemotherapy for unresectable or metastatic disease. Participants were excluded for a history of ILD/pneumonitis requiring steroids, ongoing ILD/pneumonitis, clinically active brain metastases, or clinically significant corneal disease. Participants also were excluded for ECOG performance status >1. Randomization was stratified by previous lines of chemotherapy, prior CDK4/6 inhibitor treatment, and geographical region. A total of 732 patients were randomized (1:1) to datopotamab deruxtecan-dlnk (n=365) or investigator's choice of chemotherapy (n=367); eribulin (60%), capecitabine (21%), vinorelbine (10%), or gemcitabine (9%).

## Society and culture
### Legal status

Datopotamab deruxtecan was approved for medical use in the United States in January 2025. In December 2024, the US Food and Drug Administration granted the application for datopotamab deruxtecan breakthrough therapy designation.
In January 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Datroway, intended for the treatment of breast cancer. The applicant for this medicinal product is Daiichi Sankyo Europe GmbH.

### Names

Datopotamab deruxtecan is the international nonproprietary name, and the United States Adopted Name.
Datopotamab deruxtecan is sold under the brand name Datroway.