Enfortumab

Introduction to Enfortumab

Enfortumab vedotin (trade name: Padcev) is an antibody-drug conjugate (ADC) developed by Astellas Pharma and Seattle Genetics. It received accelerated approval from the FDA in 2019 for the treatment of advanced urothelial cancer. Enfortumab vedotin consists of three key components:

  1. A fully human monoclonal antibody targeting Nectin-4, a cell adhesion molecule highly expressed in several types of solid tumors, including urothelial carcinoma
  2. A protease-cleavable linker
  3. Monomethyl auristatin E (MMAE), a potent microtubule-disrupting agent

This novel therapy represents a significant advancement in the treatment of advanced urothelial cancer, particularly for patients who have progressed on platinum-based chemotherapy and PD-1/PD-L1 inhibitors.

Mechanism of Action

Enfortumab vedotin works through a targeted mechanism:

  1. Binding: The antibody portion of enfortumab vedotin selectively binds to Nectin-4, which is highly expressed on the surface of urothelial cancer cells.
  2. Internalization: Upon binding, the ADC-Nectin-4 complex is internalized into the cancer cell.
  3. Release of cytotoxic agent: Inside the cell, lysosomal enzymes cleave the linker, releasing the cytotoxic agent MMAE.
  4. Cell death: MMAE disrupts the microtubule network within the cell, leading to cell cycle arrest and apoptosis.

This targeted approach allows for the delivery of a potent cytotoxic agent specifically to cancer cells expressing Nectin-4, potentially minimizing damage to healthy tissues and reducing systemic toxicity compared to traditional chemotherapy.

Indications

Enfortumab vedotin is primarily indicated for:

  • 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
  • Adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy

While initially approved for adult patients, research is ongoing to explore its potential use in pediatric populations with Nectin-4-expressing solid tumors.

Administration

Enfortumab vedotin is administered as an intravenous infusion. The typical dosing regimen is:

  • 1.25 mg/kg (up to a maximum of 125 mg) administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of a 28-day cycle
  • Treatment is continued until disease progression or unacceptable toxicity
  • Dose modifications may be necessary based on adverse reactions

It's important to note that enfortumab vedotin should be administered by healthcare professionals experienced in the use of antineoplastic therapies. Patients should be monitored during and after infusion for infusion-related reactions.

Adverse Effects

Common adverse effects of enfortumab vedotin include:

  • Fatigue
  • Peripheral neuropathy
  • Rash
  • Alopecia
  • Decreased appetite
  • Diarrhea
  • Nausea
  • Pruritus
  • Dry eye
  • Dysgeusia

Serious adverse reactions reported in ≥5% of patients included urinary tract infection, cellulitis, febrile neutropenia, diarrhea, sepsis, acute kidney injury, dyspnea, and rash. Peripheral neuropathy is a significant concern and may require dose modification or discontinuation.

Enfortumab vedotin carries a boxed warning for serious skin reactions, including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which can be fatal.

Monitoring

Patients receiving enfortumab vedotin should be closely monitored for:

  • Skin reactions: Monitor for severe skin reactions. Withhold or permanently discontinue treatment based on severity
  • Peripheral neuropathy: Assess for symptoms before each dose and consider dose modification if neuropathy worsens
  • Ocular disorders: Monitor for ocular disorders. Consider ophthalmologic evaluation if symptoms occur
  • Hyperglycemia: Monitor blood glucose levels in patients with and without preexisting diabetes mellitus
  • Infusion-related reactions: Monitor during infusion and for at least 60 minutes following completion of infusion
  • Complete blood counts: Monitor for neutropenia
  • Renal function: Monitor for changes in renal function

Regular assessment of these parameters is crucial for early detection and management of adverse effects, ensuring optimal patient outcomes.



Further Reading
Tags:

Powered by Blogger.