Introduction :
Datroway (datopotamab deruxtecan) infusion is used to treat a type of metastatic breast cancer to help slow cancer progression. It is used in adults whose cancer is: • hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer • unable to be removed by surgery (unresectable) or has spread to other parts of the body (metastatic) and • The patient has already received endocrine-based therapy (hormone therapy) and chemotherapy treatment for unresectable or metastatic cancer. Datroway was granted FDA approval on January 17, 2025, based on favorable outcomes from the TROPION-Breast01 clinical trial (NCT05104866).
About the breast cancer:
HER2-negative breast cancer is when cancer cells do not contain high levels of human epidermal growth factor receptor 2 (HER2). HER2 is a protein that controls cell growth. This means the cancer may grow more slowly and is less likely to spread or come back when compared to HER2-positive cancer.
Hormone receptor-positive (HR-positive) breast cancer: Estrogen receptors (ER receptors) and progesterone receptors (ER receptors) help control growth. However, in HR-positive cancer, there are more receptors to which estrogen and/or progesterone can bind which increases cancer growth. This can be treated with hormone therapy drugs that either lower estrogen levels or block estrogen receptors.
Advanced or metastatic breast cancer. Breast cancer is termed as advanced when it has spread locally to tissue near the breast, and as metastatic when breast cancer has spread to other parts of the body.
Mechanism of action:
Datroway is an antibody-drug conjugate (ADC) which is a medicine that has 3 sections,
• recombinant human anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody (MAAP-9001a)
• the anticancer molecule- topoisomerase I inhibitor
• a linker that joins the MAB and anticancer molecule.
Datroway is a Trop-2-directed antibody-drug conjugate (ADC) and works by the mAb section binding to TROP2 proteins on cancer cells. Its mechanism of action involves a combination of targeted delivery and cytotoxicity:
1. Trop-2 Targeting: Trop-2 (trophoblast cell-surface antigen 2) is a protein highly expressed on many cancer cells, including HR-positive, and HER2-negative breast cancer cells. Datroway binds specifically to Trop-2, ensuring targeted delivery of the cytotoxic drug to cancer cells.
2. Internalization and Release of the Cytotoxic Agent: Once bound to Trop-2 on the cancer cell surface, the Datroway-Trop-2 complex is internalized into the cancer cell. Inside the cell, the linker in the ADC is broken down, releasing the payload: DXd (a topoisomerase I inhibitor).
3. Cytotoxic Action of DXd: DXd, being a potent topoisomerase I inhibitor, interferes with the DNA replication process in rapidly dividing cells. It inhibits topoisomerase I, an enzyme essential for relieving torsional stress during DNA replication. This leads to DNA damage, disruption of the cell cycle, and ultimately, cancer cell death.
4. Bystander Effect: DXd has a membrane-permeable property, meaning, it can diffuse into nearby cancer cells. This results in a bystander effect, enhancing the drug's ability to kill neighboring cancer cells, even if they have lower Trop-2 expression.
Adverse effects:
The most common side effects of Datroway include: mouth ulcers and sores 59% (stomatitis), nausea 56%, tiredness 44% (fatigue), hair loss 38% (alopecia), constipation 34%, dry eye 27%, keratitis 25%, vomiting 24%, rash 19%, low appetite 16%, COVID 16%, cough 15%, diarrhea 11%, abdominal pain 11%, lung problems 15%, laboratory abnormality. These occurred in 10% or more of patients in the TROPION-Breast01 clinical trial.
Datroway does come with many serious ill-effects, like any other anti-cancer drug:
Interstitial Lung Disease/Pneumonitis: Datroway can cause severe, life-threatening lung diseases like ILD and pneumonitis. In clinical trials, 4.2% of patients experienced ILD/pneumonitis, with 0.5% being severe. It requires close monitoring for respiratory symptoms and a prompt corticosteroid treatment if detected.
Ocular Adverse Reactions: Datroway may cause ocular issues such as dry eyes and blurred vision, which occur in 51% of patients. Management includes using lubricating eye drops, regular eye exams, and discontinuing treatment if necessary.
Stomatitis: Stomatitis, including mouth ulcers, is common (59%) with Datroway. Prophylactic mouthwash with corticosteroids is recommended, and treatment interruption or dose adjustments may be required for severe cases.
Embryo-Fetal Toxicity: Datroway can harm a developing fetus due to its genotoxicity. Effective contraception is advised during and after treatment for both male and female patients of reproductive potential.
Adverse Reactions: Common adverse reactions include stomatitis, nausea, and fatigue. Serious reactions, including ILD and infections, were observed in 15% of patients, leading to dose adjustments or discontinuation in some cases.
Use in Specific Populations: Datroway should be avoided during pregnancy due to its potential harm to a fetus. It’s also not recommended during breastfeeding. Patients with renal or hepatic impairments need close monitoring for increased adverse effects. There’s limited data on its use in pediatric patients.
Clinical trials: TROPION-Breast01 Trial-
• The TROPION-Breast01 trial (NCT05104866) was a multicenter, open-label, randomized phase 3 study designed to evaluate the efficacy and safety of Dato-DXd in adult patients with HR-positive, HER2-negative breast cancer.
• The trial showed that treatment with Dato-DXd resulted in a statistically significant increase in progression-free survival (PFS), meaning that patients lived longer without their cancer worsening.
• Results were compelling, indicating Dato-DXd's potential to delay cancer progression and offer a new treatment option for patients whose cancer has become unresectable or metastatic.
Conclusion:
Datroway (Datopotamab Deruxtecan) offers a promising treatment option for patients with HR positive, and HER2-negative metastatic breast cancer. Its targeted mechanism, leveraging Trop-2 and topoisomerase inhibition, enhances cancer cell killing while minimizing systemic effects. Incorporating Datroway into treatment regimens offers hope for patients with difficult to-treat breast cancer, but it’s vital to balance its benefits with close monitoring to mitigate risks. Continued research and clinical observation will help refine its use in oncology practice.
References:
-By Kavya Laud
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