Deruxtecan: topoisomerase 1 inhibitor as ADC payload
Deruxtecan (DXd) is the cytotoxic payload of several modern antibody drug conjugates (ADCs), including trastuzumab deruxtecan (Enhertu, T-DXd) and datopotamab deruxtecan (Datroway, Dato-DXd). It is an exatecan derivative, i.e. a topoisomerase 1 inhibitor with particular stability in circulation and a cleavable tetrapeptide linker architecture that allows controlled release in the tumour cell.
The ADC strategy combines targeted recognition of a tumour antigen (HER2, TROP2 and others) by a monoclonal antibody with the action of a highly potent cytostatic. Deruxtecan has two special properties: a high drug antibody ratio (DAR around 8) and a bystander effect, in which the released payload also reaches neighbouring tumour cells that express the target antigen weakly or not at all.
Mechanism of action
Deruxtecan is a synthetic camptothecin derivative that inhibits topoisomerase 1. Topoisomerase 1 is an enzyme that introduces transient single-strand breaks in DNA to relieve tension during transcription. If topoisomerase 1 cannot religate after this step because deruxtecan stabilises the complex, DNA double-strand breaks and apoptosis result.
In the ADC architecture, deruxtecan is linked to the antibody via a GGFG tetrapeptide linker. After ADC binding to the tumour antigen, internalisation into the endosome and transfer to the lysosome takes place. There cathepsin cleaves the linker, free deruxtecan diffuses into the cytoplasm and nucleus and exerts its cytotoxic effect.
Because of its membrane permeability, released deruxtecan can also diffuse into neighbouring tumour cells, which explains the clinically valuable bystander effect. Deruxtecan ADCs are therefore active even with heterogeneous antigen expression.
Indications
- Trastuzumab deruxtecan (Enhertu): HER2 positive breast cancer (pretreated), HER2 low breast cancer, HER2 positive gastric cancer, HER2 mutated non-small cell lung cancer
- Datopotamab deruxtecan (Datroway): TROP2 positive metastatic breast cancer, NSCLC under trial conditions
- Patritumab deruxtecan: HER3 expressing tumours in clinical development
- Ifinatamab deruxtecan: B7-H3 expressing tumours in trials
Deruxtecan itself is not approved as monotherapy; only the antibody-drug conjugates are used clinically.
Dosing and administration
Trastuzumab deruxtecan: 5.4 mg per kg body weight intravenously every 3 weeks for breast cancer; 6.4 mg per kg for gastric cancer.
Datopotamab deruxtecan: 6 mg per kg intravenously every 3 weeks.
The first infusion is given over 90 minutes; further infusions can be shortened to 30 minutes if well tolerated. Antiemetic premedication is given before each dose, since marked nausea and vomiting are common.
Treatment duration depends on response and tolerability. Therapy is interrupted or stopped on disease progression, severe toxicity or pneumonitis.
Side effects
Very common: nausea, vomiting, fatigue, alopecia, anaemia, neutropenia, thrombocytopenia, diarrhoea, loss of appetite, stomatitis, raised liver transaminases.
Common: pneumonitis (interstitial lung disease), constipation, peripheral neuropathy, headache, cough, fever, infusion reactions.
Uncommon: left heart failure with decreased LVEF (especially with trastuzumab deruxtecan), tumour lysis syndrome, severe pneumonitis up to lung failure.
Pneumonitis as boxed warning:
- Most common serious side effect of deruxtecan ADCs
- Incidence around 10 to 15 % of all patients, severe in 1 to 3 %
- Symptoms: new cough, dyspnoea, fever
- Diagnosis: high-resolution CT, differential diagnosis infection
- Management: therapy interruption, steroids, in severe cases permanent discontinuation
- Patients and relatives must be informed about early signs
Interactions
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir): raised levels of free payload, caution or avoid combination
- Strong OATP1B inhibitors: theoretical level increase
- Other topoisomerase inhibitors (irinotecan, topotecan): additive toxicity, avoid combination outside trials
- Live vaccines: contraindicated
- Other immunosuppressive or myelotoxic therapies: additive toxicity, careful indication
Special considerations
Pregnancy: contraindicated, teratogenic potential based on animal data and mechanism of action. Reliable contraception during and several months after therapy for both sexes.
Breastfeeding: contraindicated.
Before starting therapy:
- Determination of target antigen (HER2 IHC and ISH, TROP2 expression depending on ADC)
- Echocardiography to determine LVEF, especially for T-DXd
- Lung function and CT in at-risk patients
- Blood count, liver values, electrolytes, pregnancy test
During treatment: echocardiography every 3 months (T-DXd), regular imaging for response assessment, clinical observation for pneumonitis.
Patient communication: diagnosis of pneumonitis is time-critical. Patients should report new or worsening respiratory symptoms immediately, even outside scheduled appointments.
Treatment success and quality of life: deruxtecan ADCs have shown remarkable efficacy in several trials (DESTINY Breast 03, DESTINY Lung, DESTINY Gastric), often with response rates above 60 % in pretreated patients. Quality of life is usually well preserved by outpatient administration and the side-effect profile.
Related substances
- Regorafenib, oral multikinase inhibitor
- Sotorasib, KRAS G12C inhibitor
- Fruquintinib, VEGFR TKI
- Sunitinib, multikinase inhibitor
Frequently asked questions
What is an antibody drug conjugate?
An ADC connects an antibody that binds a tumour antigen with a highly potent cytostatic via a linker. The cytostatic is delivered specifically into tumour cells while healthy cells are less stressed than with classic chemotherapy. Deruxtecan is the payload of several modern ADCs.
What is the bystander effect?
After uptake into the tumour cell, deruxtecan is released. Because of its membrane permeability it can diffuse into neighbouring cells and trigger apoptosis there too. This catches cells that express the target antigen weakly or not at all, which is a clinical advantage in heterogeneous tumours.
How dangerous is the pneumonitis?
Pneumonitis is the most important serious side effect. About 10 to 15 % of patients develop pneumonitis, severe in 1 to 3 %, fatal in rare cases. Early diagnosis and consistent steroid therapy are decisive. Patients should always take new respiratory symptoms seriously.
Which tumours benefit most?
Trastuzumab deruxtecan shows very good efficacy in HER2 positive and HER2 low breast cancer, HER2 positive gastric cancer and HER2 mutated NSCLC. Datopotamab deruxtecan shows promising results in TROP2 positive breast cancer and lung cancer. The exact therapy decision is molecularly guided.
Sources
- EMA Enhertu (trastuzumab deruxtecan) EPAR
- BfArM Federal Institute for Drugs and Medical Devices
- AWMF oncology guidelines
- Gelbe Liste ADC and oncology drugs
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