Datopotamab Deruxtecan

Datopotamab deruxtecan is a TROP2-directed antibody-drug conjugate (ADC). A humanised anti-TROP2 IgG1 monoclonal antibody, produced in Chinese Hamster Ovary cells, is covalently linked by a tetrapeptide-based cleavable linker to deruxtecan, an exatecan derivative (DXd) that inhibits topoisomerase I. About four deruxtecan molecules are attached to each antibody. TROP2 is a transmembrane protein that is overexpressed in several tumour types and has low, restricted expression in healthy tissue, so the conjugate delivers its cytotoxic payload mainly to tumour cells.

Mechanism of Action

• Binding: the antibody part binds TROP2 on the surface of certain tumour cells. The conjugate is stable in plasma.
• Internalisation and release: after binding, the conjugate is taken up into the tumour cell, where lysosomal enzymes cleave the linker and release DXd.
• Payload action: DXd binds topoisomerase I and stabilises its cleavable complex with DNA. This causes DNA breaks, blocks DNA replication and leads to apoptotic cell death.
• Indirect effects: in vitro, the conjugate may also kill tumour cells through antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and a bystander effect of DXd on neighbouring tumour cells.
• Exposure and safety: higher exposure to the conjugate has been linked with more serious adverse reactions, more dose interruptions and reductions, and more stomatitis and eye reactions. A relationship between exposure and efficacy has not been characterised in breast cancer.
• Immunogenicity: across clinical studies at 6 mg/kg (median treatment period 5.8 months), anti-drug antibodies were found in 16% of 1,350 patients and neutralising antibodies in 2.7%. They had no apparent effect on pharmacokinetics or effectiveness and no clinically meaningful effect on safety.

Pharmacokinetics

• Exposure: after the first dose at the recommended dosage, the geometric mean peak concentration (Cmax) of the conjugate is 154 µg/mL and its AUC is 671 µg·day/mL. For released DXd the values are 2.82 ng/mL and 18.5 ng·day/mL.
• Distribution: the steady-state volume of distribution of the conjugate is 3.52 L. In vitro, 96.8–98.0% of DXd is bound to human plasma proteins, and its blood-to-plasma concentration ratio is 0.59–0.62.
• Metabolism: inside the cell, lysosomal enzymes cleave the linker and release DXd. The antibody is expected to be broken down into small peptides and amino acids by the same catabolic pathways as endogenous IgG. In human liver microsomes, DXd is metabolised mainly by CYP3A4 through oxidation, with no significant contribution from UGT or other CYP enzymes.
• Elimination: clearance of the conjugate is about 0.57 L/day. The median elimination half-life is 4.82 days for the conjugate and about 5.50 days (apparent) for released DXd. In vitro, DXd is a substrate of P-gp, OATP1B1, OATP1B3, MATE2-K, MRP1 and BCRP. Excretion of DXd has not been studied in humans.
• Effect on other medicines (in vitro): DXd does not inhibit or induce the main CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A) and does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP or BSEP.
• Special populations: at 6 mg/kg, serious adverse reactions were more frequent in patients with moderate renal impairment at baseline. Data in moderate and severe hepatic impairment are limited (see Administration and Dosage).

Datopotamab deruxtecan is used as monotherapy in adults with breast cancer:

• Triple-negative breast cancer (TNBC): first-line treatment of adults with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.
• Hormone receptor (HR)-positive, HER2-negative breast cancer: treatment of adults with unresectable or metastatic HR-positive, HER2-negative breast cancer who have received endocrine therapy and at least one line of chemotherapy in the advanced setting.

• Hypersensitivity to datopotamab deruxtecan or to any of the excipients (L-histidine, L-histidine hydrochloride monohydrate, sucrose, polysorbate 80).

The pooled safety profile comes from four clinical studies in 841 patients who received 6 mg/kg for breast cancer (median exposure 6.4 months, range 0.7 to 38 months). The most common reactions were stomatitis (64.3%), nausea (52.7%), fatigue (40.4%), alopecia (36.9%), constipation (34.7%), vomiting (25.0%), dry eye (23.9%), anaemia (19.3%), decreased appetite (17.6%), keratitis (16.6%), increased aspartate aminotransferase (15.7%), rash (15.2%), neutropenia (14.9%), COVID-19 (13.1%), leukopenia (12.5%), increased alanine aminotransferase (11.9%) and diarrhoea (10.2%). The frequencies below are all-cause adverse event frequencies, so some events may have other causes such as the disease or other medicines.

Very common (≥1/10): COVID-19, anaemia, neutropenia, leukopenia, decreased appetite, dry eye, keratitis, stomatitis, nausea, constipation, vomiting, diarrhoea, alopecia, rash, fatigue, increased aspartate aminotransferase, increased alanine aminotransferase.

Common (≥1/100 to <1/10): urinary tract infection, pneumonia, dysgeusia, conjunctivitis, increased lacrimation, keratopathy, blepharitis, meibomian gland dysfunction, blurred vision, photophobia, visual impairment, interstitial lung disease or pneumonitis, dyspnoea, rhinorrhoea, dry mouth, skin hyperpigmentation, dry skin, pruritus, madarosis (loss of eyebrows or eyelashes), increased amylase, infusion-related reaction.

Uncommon (≥1/1,000 to <1/100): sepsis, anaphylactic reaction.

The most common grade 3 or 4 reactions were stomatitis (8.1%), increased amylase (3.9%), fatigue (3.8%), anaemia (3.0%), increased aspartate aminotransferase (1.9%), pneumonia (1.9%), keratitis (1.8%), neutropenia (1.8%), vomiting (1.7%), increased alanine aminotransferase (1.3%), nausea (1.1%) and urinary tract infection (1.1%). Fatal (grade 5) reactions occurred in 0.5% of patients and were due to interstitial lung disease (ILD)/pneumonitis, dyspnoea and sepsis. The most common serious reactions were pneumonia (1.9%), COVID-19 (1.5%), ILD/pneumonitis (1.1%) and vomiting (1.1%).

Treatment was stopped because of adverse reactions in 3.6% of patients, most often for ILD/pneumonitis (1.7%). Doses were reduced in 22.1%, mainly for stomatitis (11.5%), fatigue (3.4%), keratitis (1.8%), nausea (1.4%) and increased amylase (1.3%), and interrupted in 22.7%, mainly for stomatitis (5.0%), COVID-19 (3.8%) and pneumonia (2.0%).

No clinical drug interaction studies have been done with datopotamab deruxtecan itself. The available information comes from studies with trastuzumab deruxtecan, which carries the same DXd payload.

• CYP3A4 and transporter inhibitors: ritonavir (an inhibitor of CYP3A4, OATP1B1 and OATP1B3) and itraconazole (a CYP3A4 inhibitor) did not change the peak level of DXd and raised its AUC only 1.2-fold, which was not clinically relevant. Inhibitors of CYP3A4, OATP1B1 and OATP1B3 will therefore most likely not have a clinically relevant effect on the pharmacokinetics of deruxtecan released from datopotamab deruxtecan.
• Effect on other medicines: in vitro, DXd does not inhibit or induce the main CYP450 enzymes and does not inhibit the main uptake and efflux transporters (listed under Pharmacokinetics).

Datroway should be prescribed by a physician and given under the supervision of a healthcare professional experienced in the use of anticancer medicinal products. It is for intravenous use only. A healthcare professional must reconstitute and dilute it and give it as an infusion; it must never be given as an intravenous push or bolus. The product contains a cytotoxic component covalently attached to the antibody, so the special handling and disposal procedures in the SmPC apply.

Patient Selection

For unresectable or metastatic HR-positive, HER2-negative breast cancer, patients should be selected on the basis of a documented HER2-negative result, assessed by a CE-marked in vitro diagnostic device if available or by an alternative validated test.

Recommended Dose

• 6 mg/kg of body weight (up to a maximum of 540 mg for patients weighing 90 kg or more) as an intravenous infusion once every 3 weeks (21-day cycle), until disease progression or unacceptable toxicity.
• First infusion: over 90 minutes. Patients are observed during the infusion and for at least 30 minutes after the first dose for signs or symptoms of infusion-related reactions.
• Later infusions: over 30 minutes if the earlier infusions were tolerated, with observation during the infusion and for at least 30 minutes afterwards.

Premedication and Prophylaxis

• Before each infusion, a regimen to prevent infusion-related reactions should be considered: an antihistamine and paracetamol, with or without a glucocorticoid.
• Prophylactic antiemetics are recommended before the infusion and on later days as needed: dexamethasone with a 5-HT3 antagonist, and other medicines such as NK1 receptor antagonists.
• Eye drops against keratitis and a steroid-containing mouthwash against stomatitis are advised (see Special Instructions).

Dose Modifications for Adverse Reactions

• Management of adverse reactions may require a dose delay, a dose reduction or discontinuation. The dose is not raised again after a reduction.
• Dose levels: starting dose 6 mg/kg (maximum 540 mg for patients weighing 90 kg or more); first reduction 4 mg/kg (maximum 360 mg); second reduction 3 mg/kg (maximum 270 mg); a third reduction means permanent discontinuation.
• Infusion-related reactions: slow or interrupt the infusion; stop permanently for life-threatening reactions.
• Interstitial lung disease/pneumonitis: for asymptomatic (grade 1) disease, delay the dose until it has resolved to grade 0, then keep the dose if it resolved within 28 days of onset, or reduce by one level if it took longer than 28 days; consider corticosteroid treatment as soon as ILD/pneumonitis is suspected. For symptomatic (grade 2 or higher) disease, stop permanently and start corticosteroid treatment promptly. Grade 0 means full resolution, including the disappearance of radiological findings of active disease; residual scarring or fibrosis is not counted as active disease.
• Keratitis: grade 2, delay until it has resolved to grade 1 or less, then keep the dose; grade 3, delay until grade 1 or less, then reduce by one level; grade 4, stop permanently.
• Stomatitis: grade 2, delay until grade 1 or less and restart at the same dose for a first occurrence (consider a reduced dose if it recurs); grade 3, delay until grade 1 or less and restart at a reduced dose level; grade 4, stop permanently.
• Grades follow the NCI Common Terminology Criteria for Adverse Events, version 5.0.

Special Populations

• Elderly: no dose adjustment in patients aged 65 years or older; data in patients aged 85 years or older are limited.
• Renal impairment: no adjustment in mild to moderate impairment (creatinine clearance 30 to below 90 mL/min). The recommended dose has not been established in severe impairment, and these patients should be monitored carefully. In patients with moderate renal impairment at baseline given 6 mg/kg, serious adverse reactions were more frequent than in patients with normal kidney function.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin up to the upper limit of normal with any AST, or total bilirubin above 1 and up to 1.5 times the upper limit with any AST). Data are limited in moderate impairment (bilirubin above 1.5 to 3 times the upper limit) and insufficient in severe impairment (above 3 times the upper limit), so these patients are monitored carefully and Datroway is given with caution.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Delayed or Missed Dose

If a planned dose is delayed or missed, it should be given as soon as possible, without waiting for the next planned cycle. The schedule is then adjusted to keep a 3-week interval between doses.

Traceability

Datroway is a biological medicinal product, so the name and batch number of the product given must be clearly recorded.

Interstitial Lung Disease and Pneumonitis

Cases of interstitial lung disease (ILD), including pneumonitis, have been reported with Datroway, and some were fatal.

• Patients should be told to report cough, shortness of breath, fever or any new or worsening respiratory symptom immediately, and should be monitored for signs and symptoms of ILD/pneumonitis.
• Suspected cases must be investigated promptly and assessed by radiographic imaging; consultation with a pulmonologist should be considered.
• Asymptomatic (grade 1): consider corticosteroid treatment (for example prednisolone 0.5 mg/kg/day or more, or an equivalent). Datroway is delayed until recovery to grade 0 and may then be resumed as set out in the SmPC dose modification table.
• Symptomatic (grade 2 or higher): start systemic corticosteroid treatment promptly (for example prednisolone 1 mg/kg/day or more, or an equivalent), continue it for at least 14 days and taper gradually over at least 4 weeks. Datroway is permanently discontinued.
• Patients with a history of ILD/pneumonitis may be at higher risk and should be monitored carefully.

Hypersensitivity and Infusion-Related Reactions

Serious, anaphylactic reactions have been seen with datopotamab deruxtecan. They can look like an infusion-related reaction, so patients should be observed closely during and after the infusion. Medicines to treat these reactions and emergency equipment must be available for immediate use. After a serious hypersensitivity reaction, treatment must be stopped immediately and permanently.

Keratitis and Other Eye Effects

Datroway can cause effects on the surface of the eye, including keratitis. Signs and symptoms may include dry eye, increased tear production, sensitivity to light and changes in vision.

• Patients are advised to use preservative-free lubricant eye drops several times a day as prophylaxis and to avoid contact lenses unless an eye-care professional directs otherwise.
• Any new or worsening eye sign or symptom that could suggest keratitis calls for prompt referral for an ophthalmological assessment.
• If keratitis is confirmed, the dose is delayed, reduced or permanently stopped according to the grade (see Administration and Dosage).
• Patients with clinically significant corneal disease were excluded from the study. Patients with pre-existing keratitis should be monitored carefully.

Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, has been reported with Datroway.

• Good oral hygiene is advised when starting and throughout treatment, together with a daily steroid-containing mouthwash for prevention and treatment (for example dexamethasone oral solution 0.1 mg/mL four times a day, or a similar regimen).
• Where clinically indicated, antifungal agents may be considered in line with local guidelines.
• Without a steroid mouthwash, bland mouth rinses (for example non-alcoholic or bicarbonate-containing) are recommended per local guidelines. Ice chips or ice water held in the mouth during the infusion may also be considered.
• If stomatitis occurs, mouthwashes may be used more often and other topical treatments added. Depending on severity, the dose is delayed, reduced or permanently stopped.

Hepatic Impairment

Data in moderate and severe hepatic impairment are limited. Because metabolism and biliary excretion are the main routes of elimination of DXd, Datroway should be given with caution in these patients.

Pregnancy, Breastfeeding and Fertility

• Pregnancy status: it should be verified in women of childbearing potential before treatment starts.
• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 7 months after the last dose. Men with female partners of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: there are no data in pregnant women. Based on animal findings and the mechanism of action, the topoisomerase I inhibitor component (DXd) can be expected to cause embryo-foetal harm. Datroway is not recommended during pregnancy or in women of childbearing potential who are not using contraception. Patients should be told of the possible risk to the foetus and should contact their doctor at once if they become pregnant.
• Breastfeeding: it is not known whether datopotamab deruxtecan passes into human milk, but human IgG does. Because of the potential for serious adverse reactions in breast-fed children, women should stop breastfeeding before treatment starts and may begin again 1 month after treatment ends.
• Fertility: there are no human data. Animal toxicity studies suggest that Datroway may impair male and female reproductive function and fertility. Men and women should seek advice on fertility preservation before treatment.

Excipient with Known Effect

Each vial contains 1.5 mg of polysorbate 80 (E 433). Polysorbates may cause allergic reactions.

Effect on Driving

Datroway may influence the ability to drive and use machines. Patients who feel fatigue or notice changes in vision during treatment should take care when driving or operating machines.

Store the vials in a refrigerator at 2–8 °C and do not freeze. Keep the cold chain unbroken from dispatch until the vial is reconstituted. Reconstituted and diluted solutions have their own limits (see Shelf Life). Datroway is supplied as one 10 mL amber glass vial per carton. Keep out of the sight and reach of children.

• Unopened vial: 4 years.
• Reconstituted solution: chemical and physical in-use stability has been shown for up to 48 hours at 2–8 °C. From a microbiological point of view the product should be used immediately. If it is not, in-use times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C, unless reconstitution took place under controlled and validated aseptic conditions.
• Diluted solution: use immediately if possible. If not, the diluted solution can be kept at room temperature (up to 25 °C) for up to 4 hours or in a refrigerator at 2–8 °C for up to 24 hours, including preparation and infusion, protected from light.

Prescription only (Rx), on restricted medical prescription (Annex II B of the EU marketing authorisation). Datroway is prescribed by a physician and given under the supervision of a healthcare professional experienced in anticancer medicines. It is reconstituted, diluted and infused by healthcare professionals, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.