Enfortumab – Uses, Dosage, Side Effects, Interaction

The clinical? development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics ^[rx] and it was first approved for use in the United States in December 2019 under the brand name Padcev^TM.^[rx] Enfortumab vedotin was later approved by the European Commission on April 13, 2022.^[rx]

Mechanism of action

Enfortumab vedotin is an antibody-drug conjugate comprised of multiple components.^[rx] It contains a fully human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein that is highly expressed in urothelial cancers,¹ attached to a chemotherapeutic microtubule-disrupting agent, monomethyl auristatin E (MMAE). These two components are joined via a protease-cleavable linker. Enfortumab vedotin binds to cells expressing Nectin-4 and the resulting enfortumab-Nectin-4 complex is internalized into the cell. Once inside the cell, MMAE is released from enfortumab vedotin via proteolytic cleavage and goes on to disrupt the microtubule network within the cell, arresting the cell cycle and ultimately inducing apoptosis.^[rx]

Enfortumab vedotin is an anti-cancer agent that destroys tumor? cells by inhibiting their ability to replicate.^[rx] Patients with moderate? to severe? hepatic impairment should not use enfortumab vedotin – although it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment.^[rx] Enfortumab vedotin may also cause significant hyperglycemia? leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl.^[rx]

Indications

• Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and platinum-containing chemotherapy? in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.^[rx,rx]
• Enfortumab vedotin is an antibody-drug conjugate comprised of a fully human monoclonal antibody and microtubule-disrupting chemotherapeutic agent used in the treatment of advanced or metastatic urothelial cancer.
• For locally advanced or metastatic urothelial cancer (mUC) who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting
• Locally Advanced Urothelial Cancer
• Metastatic Urothelial Cancer

Use in Cancer

Enfortumab vedotin-ejfv is approved to treat adults with:

• Urothelial cancer (a type of cancer in the bladder? or urinary tract) that has spread or cannot be removed by surgery. It is used in:
  • Patients who have received platinum chemotherapy and immunotherapy?.
  • Patients who have received at least one other type of treatment and cannot receive cisplatin.

Enfortumab vedotin-ejfv is also being studied in the treatment of other types of cancer.

Contraindications

• diabetes?
• a painful condition that affects the nerves in the legs and arms called peripheral neuropathy?
• high blood sugar?
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage?

Strengths: ejfv 20 mg; ejfv 30 mg

Urothelial Carcinoma?

• 1.25 mg/kg (up to a maximum of 125 mg for patients 100 kg or greater) IV over 30 minutes on Days 1, 8. and 15 of a 28-day cycle until disease progression? or unacceptable toxicity

Dose Adjustments

RECOMMENDED DOSE REDUCTION SCHEDULE:

• Starting dose: 1.25 mg/kg up to 125 mg
• First dose reduction: 1 mg/kg up to 100 mg
• Second dose reduction: 0.75 mg/kg up to 75 mg
• Third dose reduction: 0.5 mg/kg up to 50 mg

DOSE MODIFICATIONS:
HYPERGLYCEMIA:

• Blood glucose greater than 250 mg/dL: Withhold this drug until elevated blood glucose has improved to 250 mg/dL or less then resume therapy at the same dose level.

PERIPHERAL NEUROPATHY?:

• Grade 2: Withhold until Grade 1 or less, then resume therapy at the same dose level (if first occurrence); for a recurrence?, withhold until Grade 1 or less then, resume therapy reduced by one dose level.
• Grade 3 or greater: Permanently discontinue this drug.

SKIN REACTIONS:

• Grade 3 (severe): Withhold this drug until Grade 1 or less, then resume therapy at the same dose level or consider dose reduction by one dose level.
• Grade 4 or recurrent? Grade 3: Permanently discontinue this drug.

OTHER NONHEMATOLOGIC TOXICITY:

• Grade 3: Withhold this drug until Grade 1 or less, then resume therapy at the same dose level or consider dose reduction by one dose level.
• Grade 4: Permanently discontinue this drug.

HEMATOLOGIC TOXICITY:

• Grade 3 or 3 thrombocytopenia?: Withhold this drug until Grade 1 or less, then resume therapy at the same dose level or consider dose reduction by one dose level.
• Grade 4 thrombocytopenia: Withhold until Grade 1 or less, then reduce dose by one dose level or discontinue therapy.

Administration advice:

• After reconstitution, immediately administer the infusion IV over 30 minutes.
• If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than 8 hours at 2C to 8C (36 F to 46 F). NOTE: Do not freeze.
• Do not administer this drug as an IV push or bolus.
• Do not mix this drug with, or administer it as an infusion with, other medicinal products.

Side Effects

The Most Common

• diarrhea?
• vomiting?
• nausea?
• loss of appetite?
• weight loss?
• taste changes
• hair loss
• dry skin
• shortness of breath?
• trouble breathing
• cough?
• pale skin
• skin redness, swelling?, fever?, or pain at the injection site
• blurred vision, loss of vision, eye pain or redness, or other visual changes
• numbness, burning or tingling in hands or feet
• muscle weakness
• extreme tiredness or lack of energy

More common

• Blurred vision
• burning, dry, or itching eyes
• burning, numbness, tingling, or painful sensations
• discharge, excessive tearing
• dry eyes
• dry mouth
• eye redness, irritation, or pain
• flushed, dry skin
• fruit-like breath odor
• increased hunger
• increased thirst
• increased urination
• lack or loss of strength
• nausea
• rash with flat lesions or small raised lesions on the skin
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• stomach pain
• sweating
• trouble breathing
• unexplained weight loss
• unsteadiness or awkwardness
• unusual tiredness or weakness
• vomiting
• weakness in the arms, hands, legs, or feet

Rare

• Chest pain
• chills
• cough
• fever
• a general feeling of discomfort or illness
• thickening of bronchial secretions
• Blistering, peeling, or loosening of the skin
• diarrhea
• itching
• joint or muscle pain
• red irritated eyes
• red skin lesions, often with a purple center
• redness, tenderness, itching, burning, or peeling of the skin
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• Change in taste
• cracks in the skin
• decreased appetite
• dry skin
• hair loss or thinning of the hair
• loss of heat from the body
• loss of taste
• nausea
• painful blisters on the trunk of the body
• red, swollen skin redness, swelling, or pain of the skin
• scaling of the skin on the hands and feet
• skin blisters
• tingling of the hands and feet
• ulceration of the skin
• vomiting
• Pain, redness, or swelling at the injection site

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

This drug can harm a developing fetus. Adequate methods of contraception should be encouraged. Verify negative pregnancy status in females of reproductive potential prior to initiating therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Advise females of reproductive potential to use effective contraception during therapy and for 2 months after. Advise male patients with female partners of reproductive potential to use effective contraception during therapy and for 4 months after. This drug may impair male fertility.

Lactation

Use should be avoided. Excreted into human milk: Unknown Excreted into animal milk. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during therapy and for at least 3 weeks after.

References