Enfortumab vedotin
Indications
Enfortumab vedotin is used for:
Urothelial Carcinoma
Adult Dose
Urothelial Carcinoma
Indicated for locally advanced or metastatic urothelial cancer in patients who have received a PD-1/L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting
1.25 mg/kg (up to 125 mg) IV on Days 1, 8 and 15 of a 28-day cycle
Weight >100kg: Not to exceed 125 mg/dose
Continue until disease progression or unacceptable toxicity
Hepatic impairment
Mild (Child-Pugh A): No dose adjustment required
Moderate or severe (Child-Pugh B or C): Avoid use; not studied
Child Dose
Renal Dose
Renal impairment
Mild, moderate, or severe (CrCl ?90 mL/min): No dose adjustment required
Administration
IV Preparation
Reconstitution
Reconstitute each vial with 2.3 mL (20-mg vial) or 3.3 mL (30-mg vial) of sterile water for injection (SWFI), resulting in 10 mg/mL
If possible, direct stream of SWFI along walls of vial and not directly onto lyophilized powder
Slowly swirl each vial until contents are completely dissolved
Allow reconstituted vial(s) to settle for at least 1 min until the bubbles are gone
Do not shake vial; do not expose to direct sunlight
Visually inspect for particulate matter and discoloration befire administration, whenever solution and container permit
Reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles
Add reconstituted solution to the infusion bag immediately
Discard unused vials with reconstituted solution beyond the recommended storage time
Dilution
Calculate dosage volume (mL) and withdraw dose from vial(s)
Patients weighing >100 kg: dose should be calculated for 100 kg
Dilute reconstituted solution to allow enough diluent to achieve a final concentration of 0.3-4 mg/mL
Gently invert bag to mix solution; do not shake
Do not expose to direct sunlight
Visually inspect the infusion bag for any particulate matter or discoloration before use; reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles
Do not use the infusion bag if particulate matter or discoloration is observed
Discard any unused portion left in the single-dose vial
IV Administration
Infuse over 30 min
Do not administer as an IV push or bolus
Contra Indications
Precautions
Peripheral neuropathy, predominantly sensory, occurred in nearly half of patients treated; consider dose interruption or reduction if symptom occur/worsen; permanently discontinue if severe
Ocular disorders in nearly half of patients treated; most events involved the cornea, including keratitis, blurred vision, limbal stem cell deficiency, and other conditions associated with drug eyes; monitor for symptoms; consider dose interruption or reduction if symptomatic
Hyperglycemia occurred in patients, including death; diabetic ketoacidosis reported in patients with and without preexisting diabetes mellitus; incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and with higher baseline A1C; closely monitor blood glucose, and if elevated (>250 mg/dL) withhold dosing
Skin reactions (eg, maculopapular rash, pruritus) occurred in over half of treated patients; severe skin reactions also reported (eg, symmetrical drug-related intertriginous and flexural exanthema [SDRIFE], bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia
Skin and soft tissue reactions secondary to extravasation reported; symptoms may be delayed until 4-7 days following extravasation
Pregnancy-Lactation
Pregnancy
Based on the mechanism of action and findings in animals, can cause fetal harm
There are no available human data regarding use in pregnancy
Advise patients of potential risk and verify pregnancy status in females of reproductive potential before initiating
Animal studies
In an animal reproduction study, administration to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations, and skeletal anomalies at maternal exposures approximately similar to the exposures at the recommended human dose of 1.25 mg/kg
Contraception
Females of reproductive potential: Use effective contraception during treatment and for 2 months after the last dose
Males with female partners of reproductive potential: Use effective contraception during treatment and for 4 months after the last dose
Infertility
Males: Based on findings from animal studies, may impair male fertility
Lactation
Data are not available regarding the presence of enfortumab vedotin in human milk, effects on the breastfed child, or effects on milk production
Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment and for at least 3 weeks after the last dose
Interactions
CYP3A4 inhibitors
Enfortumab vedotin is an antibody-drug conjugate that releases monomethylauristatin E (MMAE) via proteolytic cleavage
MMAE is primarily metabolized by CYP3A4 in vitro
Coadministration with strong CYP3A4 inhibitors may increase free MMAE exposure, which may increase the incidence or severity of toxicities; monitor
Side Effects
Side effects of Enfortumab vedotin :
>10%
All grades
Fatigue (56%)
Peripheral neuropathy (56%)
Decreased appetite (52%)
Rash (52%)
Alopecia (50%)
Nausea (45%)
Diarrhea (42%)
Dysgeusia (42%)
Dry eye (40%)
Dry skin (26%)
Pruritus (26%)
Vomiting (18%)
Grade 3 or more
Rash (13%)
1-10%
Grade 3 or more
Fatigue (6%)
Diarrhea (6%)
Peripheral neuropathy (4%)
Nausea (3%)
Decreased appetite (2%)
Pruritus (2%)
Vomiting (2%)
Mode of Action
Enfortumab vedotin is an antibody-drug conjugate (ADC) composed of an anti-nectin-4 monoclonal antibody attached to the cell-killing agent, monomethylauristatin E (MMAE)
Nectin-4 is a cell adhesion molecule that is expressed on many solid tumors; once the antibody attaches to nectin-4, the complex is internalized in the lysosome, which releases MMAE