Enfortumab Vedotin

Enfortumab vedotin is an antibody-drug conjugate directed against Nectin-4, an adhesion protein on the surface of urothelial cancer cells. It joins a fully human IgG1 kappa antibody to the cytotoxic agent monomethyl auristatin E (MMAE) through a protease-cleavable maleimidocaproyl valine-citrulline linker, so that the toxin is delivered mainly to cells that carry the target.

Mechanism of Action

• Targeting: the antibody part binds Nectin-4, which is highly expressed in urothelial cancers.
• Internalisation and release: the conjugate–Nectin-4 complex is taken up into the cell, where proteases cut the linker and free MMAE.
• Cell kill: MMAE disrupts the microtubule network, which causes cell-cycle arrest, apoptosis and immunogenic cell death.
• Bystander effect: MMAE released from targeted cells can diffuse into neighbouring cells with low Nectin-4 expression and kill them as well.
• With PD-1 inhibitors: combination with a PD-1 inhibitor gives enhanced anti-tumour activity in laboratory models, consistent with the complementary effects of MMAE cytotoxicity, immunogenic cell death and the up-regulation of immune function by PD-1 blockade.
• Skin: Nectin-4 is also present in the skin, which is why skin reactions are linked to the medicine.
• Cardiac electrophysiology: at 1.25 mg/kg there was no clinically relevant prolongation of the mean QTc interval.

Pharmacokinetics

• Distribution: steady-state volume of distribution of the conjugate about 12.8 L at 1.25 mg/kg. Free MMAE is 68–82% bound to human plasma proteins in vitro; it is unlikely to displace or be displaced by highly protein-bound medicines and is a substrate of P-glycoprotein.
• Metabolism: the conjugate is expected to be broken down to small peptides, amino acids, free MMAE and MMAE metabolites. Only a small fraction of released MMAE is metabolised, in vitro mainly by oxidation through CYP3A4.
• Elimination: mean clearance about 0.11 L/h for the conjugate and 2.11 L/h for free MMAE; half-lives about 3.6 days and 2.6 days. Elimination of free MMAE appears limited by its rate of release from the conjugate.
• Excretion: for MMAE, mainly in faeces (about 72% of the recovered amount) and less in urine; data come from another MMAE-containing conjugate, and a similar pattern is expected.
• Special populations: age (24–90 years), race and sex had no clinically meaningful effect. Mild, moderate and severe renal impairment (creatinine clearance 15 to below 30 mL/min) did not change exposure significantly; end-stage renal disease has not been evaluated. In mild hepatic impairment conjugate exposure was unchanged and free MMAE concentrations were 16–37% higher; the effect of moderate or severe hepatic impairment and of liver transplantation is unknown (only 5 and 1 patients studied).

Enfortumab vedotin is indicated in adults for:

• Muscle invasive bladder cancer (MIBC): in combination with pembrolizumab, as neoadjuvant treatment and then, after radical cystectomy, as adjuvant treatment, in resectable MIBC.
• Unresectable or metastatic urothelial cancer: in combination with pembrolizumab, as first-line treatment in patients who are eligible for platinum-containing chemotherapy.
• Locally advanced or metastatic urothelial cancer: as monotherapy in patients who have previously received platinum-containing chemotherapy and a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

• Hypersensitivity to enfortumab vedotin or to any of the excipients.

With pembrolizumab (1,134 patients), the most common reactions were pruritus (44.2%), diarrhoea (37.1%), alopecia (35.4%), fatigue (35%), peripheral sensory neuropathy (34%), decreased appetite (31.5%), anaemia (29.1%), weight decreased (29.1%), nausea (28.5%), maculo-papular rash (27.7%) and dysgeusia (25.1%). As monotherapy (793 patients) they were alopecia (47.7%), decreased appetite (47.2%), fatigue (46.8%), diarrhoea (39.1%), peripheral sensory neuropathy (38.5%), nausea (37.8%), pruritus (33.4%), dysgeusia (30.4%) and anaemia (29.1%). The most common serious reactions with pembrolizumab were sepsis (3%), diarrhoea (2.6%), pneumonia (2.6%) and pneumonitis (2.2%); as monotherapy, diarrhoea and hyperglycaemia (2.1% each). Enfortumab vedotin was permanently stopped for adverse reactions in 38% of patients with pembrolizumab and 21% on monotherapy, most often because of peripheral sensory neuropathy. Doses were interrupted in 59% and 62%, and reduced in 31% and 38%, respectively.

Very common (≥1/10): urinary tract infection, anaemia, hyperglycaemia, decreased appetite, peripheral sensory neuropathy, dysgeusia, dry eye, diarrhoea, vomiting, nausea, alopecia, pruritus, rash, maculo-papular rash, dry skin, fatigue, increased alanine and aspartate aminotransferases, weight decreased; with pembrolizumab also hypothyroidism.

Common (≥1/100 to <1/10): sepsis, pneumonia, thrombocytopenia, leukopenia, peripheral neuropathy (including motor and sensorimotor forms), paraesthesia, hypoaesthesia, gait disturbance, muscular weakness, pneumonitis or interstitial lung disease, skin exfoliation, conjunctivitis, bullous dermatitis, blisters, stomatitis, palmar-plantar erythrodysaesthesia syndrome, eczema, erythema, erythematous, macular, papular, pruritic and vesicular rashes, infusion site extravasation, infusion-related reaction; with pembrolizumab also neurotoxicity, generalised exfoliative dermatitis, dermatitis and increased lipase; on monotherapy also drug eruption.

Uncommon (≥1/1,000 to <1/100): polyneuropathy, dysaesthesia, neuralgia, peroneal nerve palsy, skin burning sensation, erythema multiforme, exfoliative rash, pemphigoid, allergic and contact dermatitis, intertrigo, skin irritation, stasis dermatitis; with pembrolizumab also myasthenia gravis, myositis and drug eruption; on monotherapy also demyelinating polyneuropathy, motor dysfunction, muscle atrophy, sensory loss and generalised exfoliative dermatitis.

Not known (post-marketing experience): neutropenia, febrile neutropenia and decreased neutrophil count, diabetic ketoacidosis, fungal infection, Stevens-Johnson syndrome, toxic epidermal necrolysis, epidermal necrosis, skin hyperpigmentation and discolouration, and symmetrical drug-related intertriginous and flexural exanthema.

Serious reactions to watch for:

• Skin reactions: occurred in 67% of patients given the combination (severe in 15%; one fatal case of toxic epidermal necrolysis) and in 57% on monotherapy (severe in 14%). Severe cases began at a median of 1.1 and 0.7 months.
• Pneumonitis or interstitial lung disease: 8.8% with pembrolizumab (severe in about 2.6%; three fatal cases) and 3.3% on monotherapy (no deaths).
• Hyperglycaemia: blood glucose above 13.9 mmol/L in 17% on monotherapy; severe in 7%, and fatal in 0.3% (one case each of hyperglycaemia and diabetic ketoacidosis). Higher body mass index and higher baseline HbA1c raised the risk.
• Peripheral neuropathy: 53% on monotherapy, severe in 5%; many patients had not fully recovered at last assessment.
• Dry eye: 30% on monotherapy; severe in 0.4%.
• Older patients: with pembrolizumab, serious reactions (61.3% against 47.9%) and grade 3 or higher reactions (79.2% against 68.2%) were more frequent in patients aged 65 or over.

No formal interaction studies have been done. The conjugate is not expected to cause clinically relevant interactions through CYP3A4.

• Strong CYP3A4 inhibitors (boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole): modelling with ketoconazole predicts a minor rise in free MMAE exposure and no change in conjugate exposure. Use with caution and monitor more closely for signs of toxicity.
• Strong CYP3A4 inducers (rifampicin, carbamazepine, phenobarbital, phenytoin, St John’s wort): may lower free MMAE exposure with a moderate effect.
• CYP3A4 substrates: free MMAE is not predicted to change the exposure of CYP3A4 substrates such as midazolam.
• Pembrolizumab: when both are given on the same day, pembrolizumab is given after enfortumab vedotin.

Treatment should be started and supervised by a physician experienced in anti-cancer therapies, and good venous access should be ensured before starting. The medicine is given as an intravenous infusion over 30 minutes and must never be given as a push or bolus injection. The powder is reconstituted and diluted before use (see the SmPC for the method).

Recommended Dose

• With pembrolizumab: 1.25 mg/kg (up to a maximum of 125 mg for patients weighing 100 kg or more) on days 1 and 8 of a 21-day cycle.
  • Neoadjuvant and adjuvant treatment of MIBC, cisplatin-eligible patients: 4 neoadjuvant cycles and 5 adjuvant cycles.
  • Neoadjuvant and adjuvant treatment of MIBC, cisplatin-ineligible patients: 3 neoadjuvant cycles and 6 adjuvant cycles. In both groups treatment stops earlier for disease progression that precludes curative-intent cystectomy (neoadjuvant) or for recurrence (adjuvant), or for unacceptable toxicity.
  • Unresectable or metastatic urothelial cancer: until disease progression or unacceptable toxicity.
  • Pembrolizumab is given after enfortumab vedotin when both are given on the same day; see the pembrolizumab SmPC for its dosing.
• As monotherapy: 1.25 mg/kg (up to 125 mg for patients weighing 100 kg or more) on days 1, 8 and 15 of a 28-day cycle, until disease progression or unacceptable toxicity.

Dose Reduction Levels

• Starting dose: 1.25 mg/kg up to 125 mg.
• First reduction: 1.0 mg/kg up to 100 mg.
• Second reduction: 0.75 mg/kg up to 75 mg.
• Third reduction: 0.5 mg/kg up to 50 mg.

Dose Modifications for Side Effects

• Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or bullous lesions: withhold immediately and refer to specialised care.
• Skin reactions: permanently discontinue for confirmed SJS or TEN, grade 4 or recurrent grade 3. For worsening grade 2, grade 2 with fever, or grade 3, withhold until grade 1 or less, consider referral to specialised care, then resume at the same dose level or consider reducing by one level.
• Hyperglycaemia: if blood glucose is above 13.9 mmol/L (250 mg/dL), withhold until it is 13.9 mmol/L (250 mg/dL) or lower, then resume at the same dose level.
• Pneumonitis or interstitial lung disease: grade 2, withhold until grade 1 or less, then resume at the same dose or consider reducing by one level. Grade 3 or higher, discontinue permanently.
• Peripheral neuropathy: grade 2, withhold until grade 1 or less; resume at the same dose level at first occurrence, and one level lower if it recurs. Grade 3 or higher, discontinue permanently.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no adjustment in mild, moderate or severe impairment (creatinine clearance 15 mL/min or more). Not evaluated in end-stage renal disease (below 15 mL/min).
• Hepatic impairment: no adjustment in mild impairment (total bilirubin 1–1.5 times the upper limit of normal with any AST, or bilirubin within normal limits with AST above normal). Only a few patients with moderate or severe impairment have been treated; exposure to MMAE is expected to rise, so monitor closely for adverse events. No specific dose recommendation can be given.
• Children and adolescents: there is no relevant use in the paediatric population for these indications.

Skin Reactions

Skin reactions result from binding to Nectin-4 in the skin. They are mostly mild to moderate maculo-papular rash and are more frequent with pembrolizumab than alone. Severe cutaneous reactions, including SJS and TEN with fatal outcome, have occurred, mostly in the first cycle. Fever or flu-like symptoms may be the first sign. Patients should be monitored from the first cycle; topical corticosteroids and antihistamines can be considered for mild to moderate reactions. For suspected SJS or TEN or bullous lesions, treatment is withheld at once and the patient referred to specialised care.

Pneumonitis and Interstitial Lung Disease

Severe, life-threatening and fatal pneumonitis has occurred, more often with pembrolizumab. Patients should be monitored for hypoxia, cough, dyspnoea or interstitial infiltrates on imaging. Corticosteroids are given for grade 2 or higher events (for example prednisone 1–2 mg/kg/day or equivalent, then tapered).

Hyperglycaemia and Diabetic Ketoacidosis

Hyperglycaemia and diabetic ketoacidosis, including fatal events, occurred in patients with and without diabetes, more often with pre-existing hyperglycaemia or a body mass index of 30 kg/m² or more. Patients with baseline HbA1c of 8% or more were excluded from the studies. Blood glucose should be checked before each dose and periodically in patients with or at risk of diabetes or hyperglycaemia.

Serious and Opportunistic Infections

Serious infections such as sepsis and pneumonia (including fatal ones) and opportunistic infections such as fungal infections have been reported. Patients should be monitored carefully.

Peripheral Neuropathy

Peripheral neuropathy, mainly sensory, has occurred, including grade 3 or higher. Patients with existing grade 2 or higher neuropathy were excluded from the studies. Monitor for new or worsening symptoms, which may require a delay, dose reduction or discontinuation.

Ocular Disorders

Dry eye is the main eye disorder. Patients should be monitored; artificial tears can be considered to prevent dry eye, and an ophthalmology review if symptoms do not resolve or worsen.

Infusion Site Extravasation

Skin and soft tissue injury has occurred after extravasation. Ensure good venous access, watch the infusion site during administration, and if extravasation occurs, stop the infusion and monitor for adverse reactions.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of reproductive potential should have a pregnancy test within 7 days before starting, and use effective contraception during treatment and for at least 6 months after stopping. Men are advised not to father a child during treatment and for at least 4 months after the last dose.
• Pregnancy: enfortumab vedotin can cause foetal harm (reduced numbers of viable foetuses, smaller litters and more early resorptions in rats). It is not recommended in pregnancy or in women of childbearing potential not using effective contraception.
• Breastfeeding: not known whether it passes into human milk; a risk to the breast-fed child cannot be excluded. Breastfeeding should stop during treatment and for at least 6 months after the last dose.
• Fertility: testicular toxicity in rats suggests male fertility may be affected, and MMAE has aneugenic properties. Men are advised to have sperm samples frozen and stored before treatment. There are no human fertility data.

Polysorbate 20

The medicine contains 0.40 mg (20 mg dose) or 0.60 mg (30 mg dose) of polysorbate 20, which may cause allergic reactions.

Patient Information and Traceability

The prescriber must discuss the risks of treatment, including combination with pembrolizumab, with the patient and provide the patient information leaflet and patient card with each prescription. The product name and batch number of each administration should be clearly recorded.

Effect on Driving

Enfortumab vedotin has no or negligible influence on the ability to drive and use machines.

Store unopened vials in a refrigerator at 2–8 °C. Do not freeze. Keep the cold chain unbroken during transport and handling. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vial: 4 years.
• Reconstituted solution in the vial: add to the infusion bag immediately. If not used immediately, the user is responsible for storage; normally no longer than 24 hours at 2–8 °C. Do not freeze.
• Diluted solution in the infusion bag: administer immediately. If not used immediately, the user is responsible for storage; normally no longer than 16 hours at 2–8 °C, including infusion time. Do not freeze.

Prescription only (Rx); treatment is started and supervised by a physician experienced in anti-cancer therapies. Enfortumab vedotin is given as an intravenous infusion in hospital or clinic, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions at 2–8 °C.