Tisotumab Vedotin

Tisotumab vedotin is an antibody-drug conjugate directed against tissue factor (TF), a cell-surface protein that is present at higher levels on a variety of solid tumours than on normal tissue. The antibody carries the cytotoxic agent MMAE to TF-expressing cells, so that the toxin is released mainly inside the tumour cell.

Mechanism of Action

• Targeting: the antibody binds to TF on tumour cells, and the conjugate–TF complex is taken up into the cell.
• Payload release: inside the cell, the linker is cut by proteases and MMAE is released. MMAE disrupts the microtubule network of dividing cells, which causes cell cycle arrest and apoptotic cell death.
• Other effects shown in vitro: bystander cytotoxicity towards neighbouring cells, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and immunogenic cell death.
• Immunogenicity: anti-drug antibodies were detected in 5% of patients across clinical studies. No effect on pharmacokinetics, efficacy or safety was seen, but data are limited.
• Cardiac electrophysiology: at 2 mg/kg every 3 weeks (153 patients evaluated) there was no clinically meaningful effect on the QTc interval.

Pharmacokinetics

• Exposure: after an intravenous dose, the conjugate peaks near the end of the infusion and unconjugated MMAE peaks about two to three days later. Peak conjugate levels rise in proportion to the dose, there is no accumulation, and steady state is reached after one treatment cycle.
• Distribution: the central volume of distribution is about 3.10 L. MMAE binds to human plasma proteins by 68–82% in vitro.
• Metabolism: the conjugate is expected to be broken down to small peptides, amino acids, unconjugated MMAE and MMAE-related catabolites. Released MMAE is mainly metabolised by CYP3A4 in vitro, although only a small fraction of it appears to be metabolised in vivo.
• Elimination: the median terminal half-life is about 4.04 days for the conjugate and about 2.56 days for MMAE. Linear clearance of the conjugate is about 1.42 L/day, and about 60% of a 2 mg/kg dose is eliminated by linear clearance; MMAE clearance is about 42.8 L/day. MMAE elimination appears limited by its rate of release from the conjugate. Excretion has not been fully characterised; after a dose of another MMAE-containing conjugate, 17% of the MMAE was recovered in faeces and 6% in urine over a week, mostly unchanged.
• Special populations: age (21 to 81 years) and sex have no clinically meaningful effect. Mild or moderate renal impairment made no clinically meaningful difference to exposure; the effect of severe renal impairment or end-stage renal disease is unknown. Exposure is expected to rise in mild hepatic impairment, and the product has not been studied in moderate or severe hepatic impairment.

• Cervical cancer: as monotherapy for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy.

• Hypersensitivity to the active substance or to any of the excipients (L-histidine, L-histidine hydrochloride monohydrate, sucrose, D-mannitol).

The frequencies come from 425 patients who received at least one dose of 2 mg/kg for a median of 3.7 months. The most common reactions (25% or more) were peripheral neuropathy (39%), nausea (37%), epistaxis (33%), conjunctivitis (32%), alopecia (31%), anaemia (27%) and diarrhoea (25%). Severe (grade 3 or higher) reactions occurred in 56% of patients; the most common were anaemia (10%), peripheral neuropathy (6%), fatigue (5%), abdominal pain (3%) and neutropenia (3%). Serious reactions occurred in 37% and fatal reactions in 2%. Reactions led to permanent discontinuation in 15% of patients (mainly peripheral neuropathy 7%, conjunctivitis 2% and keratitis 2%), to dose interruption in 37% and to dose reduction in 25%.

Very common (≥1/10): anaemia, decreased appetite, peripheral neuropathy, conjunctivitis, dry eye, keratitis, epistaxis, nausea, diarrhoea, constipation, abdominal pain, vomiting, alopecia, rash, pruritus, fatigue, pyrexia, asthenia.

Common (≥1/100 to <1/10): neutropenia; eye irritation, blepharitis, punctate keratitis, ulcerative keratitis, eye pruritus, ocular hyperaemia, conjunctival ulcer, entropion, conjunctival hyperaemia, episcleritis, meibomianitis; erythema multiforme, bullous dermatitis, Stevens-Johnson syndrome.

Uncommon (≥1/1,000 to <1/100): febrile neutropenia; further ocular surface reactions, including corneal erosion, conjunctival scarring, symblepharon, corneal opacity, scarring or thinning, trichiasis, madarosis, eyelid oedema and non-infective conjunctivitis.

Peripheral neuropathy in the SmPC covers sensory, motor and sensorimotor neuropathy, paraesthesia, muscle weakness, neuralgia and burning sensation. Important serious reactions are ocular surface damage, peripheral neuropathy (including grade 3 events) and severe skin reactions, including fatal or life-threatening Stevens-Johnson syndrome.

No formal drug interaction studies have been done with tisotumab vedotin; the points below come from studies with another MMAE-containing conjugate.

• Strong CYP3A4 inhibitors: ketoconazole raised MMAE exposure without changing the conjugate exposure, and a similar effect is likely with tisotumab vedotin. Use caution and monitor closely for adverse reactions with strong CYP3A4 inhibitors (for example boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole).
• Strong CYP3A4 inducers: rifampicin lowered MMAE exposure without changing the conjugate exposure, and a similar effect is likely with tisotumab vedotin.
• CYP3A4 substrates: a sensitive CYP3A4 substrate was not affected by another MMAE-containing conjugate, and tisotumab vedotin is not expected to alter the exposure of medicines metabolised by CYP3A4.
• Transporters: in vitro, MMAE is a substrate of P-glycoprotein but not an inhibitor of it.

Treatment must be started and supervised by a physician experienced in anti-cancer therapy. Before the first infusion, and as clinically indicated, an eye care professional should do an eye examination including visual acuity and slit lamp examination. The dose is given as an intravenous infusion over 30 minutes; it must not be given as an intravenous push or bolus. Reconstitution and dilution are described in section 6.6 of the SmPC.

Recommended Dose

2 mg/kg (up to a maximum of 200 mg for patients weighing 100 kg or more) every 3 weeks, until disease progression or unacceptable toxicity.

Dose Reductions

• Starting dose: 2 mg/kg (maximum 200 mg).
• First reduction: 1.3 mg/kg (maximum 130 mg).
• Second reduction: 0.9 mg/kg (maximum 90 mg).
• Treatment is stopped permanently in patients who cannot tolerate 0.9 mg/kg.

Dose Modifications for Adverse Reactions

Grades follow the NCI-CTCAE version 5.0. Patients with new or worsening eye symptoms should be sent to an eye care professional as soon as possible.

• Keratitis: grade 1, withhold until clinically stable and resume at the same dose. Grade 2, first or second occurrence, withhold until grade 1 or lower and resume at the next lower dose level; on the second occurrence, stop permanently if it does not improve to grade 1 or lower. Grade 2, third occurrence, stop permanently. Grade 3 or 4, stop permanently.
• Conjunctival ulceration: grade 1 or 2, withhold until clinically stable and resume at the next lower dose level (on a second or later occurrence, stop permanently if there is no stabilisation or improvement). Grade 3 or 4, stop permanently.
• Conjunctival or corneal scarring or symblepharon: any grade, stop permanently.
• Conjunctivitis and other ocular reactions: grade 1, withhold until clinically stable and resume at the same dose. Grade 2, first occurrence, withhold until grade 1 or lower and resume at the same dose; second occurrence, withhold until grade 1 or lower and resume at the next lower dose level, stopping permanently if it does not improve; third occurrence, stop permanently. Grade 3 or 4, stop permanently.
• Peripheral neuropathy: grade 2 or 3 (new, or worsening of an existing condition), withhold until grade 1 or lower and resume at the next lower dose level. Grade 4, stop permanently.
• Severe cutaneous adverse reactions, including Stevens-Johnson syndrome: if suspected at any grade, withhold at once and consult a specialist to confirm the diagnosis. If grade 3 or 4 is confirmed, stop permanently.

Eye Care

To reduce the risk of ocular reactions, patients should follow these measures:

• Examination at each infusion: before each infusion the treating healthcare provider inspects the eyes, including normal eye movement, and asks about any eye signs or symptoms; any such sign or symptom leads to referral to an eye care professional.
• Corticosteroid eye drops (preservative-free; for example dexamethasone 0.1% three times a day, or the equivalent as prescribed): one drop in each eye three times daily, starting 1 day before each infusion and continuing as prescribed for 3 days after each infusion.
• Ocular vasoconstrictor drops (preservative-free; for example brimonidine tartrate 0.2%, 3 drops per eye, or the equivalent as prescribed): given in each eye immediately before each infusion.
• Cold packs: after the eye drops, cooling eye pads are applied before the infusion starts and used during the infusion and for 30 minutes afterwards.
• Lubricating eye drops (preservative-free): used several times every day throughout treatment and for 30 days after the last dose.
• Contact lenses: avoid wearing them for the whole of treatment unless the eye care professional advises otherwise.

Special Populations

• Elderly: no dose adjustment at 65 years or older.
• Renal impairment: no adjustment in mild (creatinine clearance above 60 to 90 mL/min) or moderate (30–60 mL/min) impairment. It has not been studied in severe impairment (15 to below 30 mL/min) or end-stage renal disease (below 15 mL/min).
• Hepatic impairment: no adjustment in mild impairment (total bilirubin above 1 to 1.5 times the upper limit of normal with any AST, or bilirubin up to the upper limit with AST above it, by NCI criteria), but exposure is expected to rise, so caution is advised. It has not been studied in moderate or severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed Dose

If a planned dose is missed, give it as soon as possible and adjust the schedule to keep the proper interval between doses.

Ocular Adverse Reactions

The most common are conjunctivitis, dry eye, keratitis and blepharitis. A full eye examination (visual acuity and slit lamp) is needed before the first infusion and as clinically indicated, and the eyes are inspected before every infusion. Patients should report new or worsening eye signs or symptoms promptly. Tivdak is withheld, reduced or stopped according to severity, and the eye care measures above should be followed.

Peripheral Neuropathy

Peripheral neuropathy occurs, including grade 3 events. Monitor for paraesthesia, tingling or burning sensation, neuropathic pain, muscle weakness and dysaesthesia. New or worsening neuropathy may need dose interruption, reduction or permanent discontinuation.

Severe Cutaneous Reactions

Severe skin reactions, including fatal or life-threatening Stevens-Johnson syndrome, can occur. Watch for target lesions, worsening skin reactions, blistering or peeling of the skin, painful sores in the mouth, nose, throat or genital area, fever or flu-like symptoms and swollen lymph nodes. If they occur, withhold Tivdak at once until the cause is known, seek early specialist advice, and stop permanently for confirmed grade 3 or 4 reactions.

Embryo-foetal Toxicity

Tisotumab vedotin can cause foetal harm, including embryo-foetal toxicity and structural malformations. The pregnancy status of women of childbearing potential should be verified before starting.

Patients Excluded from Clinical Studies

Studies excluded patients with clinically significant active ocular surface disease, any earlier cicatricial conjunctivitis or ocular Stevens-Johnson syndrome, grade 2 or higher peripheral neuropathy, clinically significant bleeding problems or risks, or cardiovascular risks. In these patients, use it with caution after weighing benefit and risk individually.

Traceability

As a biological medicinal product, the name and batch number of each administered dose should be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 2 months after stopping. Men with female partners of reproductive 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. It should not be used during pregnancy unless the woman’s clinical condition requires treatment.
• Breastfeeding: it is not known whether tisotumab vedotin passes into human milk, and a risk to the breastfed child cannot be excluded. Breastfeeding should be stopped during treatment and for at least 3 weeks after the last dose.
• Fertility: animal studies suggest it may impair fertility in males and females.

Effect on Driving

Tisotumab vedotin has a moderate influence on the ability to drive and use machines. Because of possible ocular reactions and peripheral neuropathy, patients should take care when driving or using machines until they are sure that Tivdak does not affect them adversely.

Store the vials in a refrigerator at 2–8 °C, and do not freeze. Because Tivdak is a refrigerated product, it should travel and be kept in a cold chain until it is prepared. The vial is a 10 mL type I glass vial, one vial per carton. Storage after reconstitution and dilution is described under Shelf Life.

• Unopened vial: 5 years.
• Reconstituted solution in the vial: chemical and physical in-use stability has been shown for up to 24 hours at 2–8 °C or up to 8 hours at 9–25 °C.
• Diluted solution in the infusion bag, including infusion time, at 2–8 °C: up to 18 hours in sodium chloride 9 mg/mL (0.9%) injection, up to 24 hours in dextrose 50 mg/mL (5%) injection, and up to 12 hours in Ringer’s lactate injection.
• From a microbiological point of view, unless the method of reconstitution or dilution rules out the risk of contamination, the solutions should be used immediately; otherwise in-use times and conditions are the responsibility of the user.

Prescription only (Rx), subject to restricted medical prescription (Annex II B). Treatment is started and supervised by a physician experienced in anti-cancer therapy, and the infusion is given in hospital together with the eye care programme described above. Tivdak is therefore supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.