Drug Class:
Components:
- Monoclonal Antibody: Targets Nectin-4, a cell adhesion molecule highly expressed in urothelial carcinoma and other epithelial cancers.
- Cytotoxic Payload: Monomethyl auristatin E (MMAE) – a potent microtubule inhibitor.
- Linker: Protease-cleavable linker that allows intracellular release of MMAE after internalization.
FDA-Approved Indications (as of 2024):
- Locally advanced or metastatic urothelial carcinoma:
- After prior platinum-containing chemotherapy and a PD-1/PD-L1 checkpoint inhibitor.
- In combination with pembrolizumab for first-line treatment (recent approval in cisplatin-ineligible patients).
Mechanism of Action:
- The anti–nectin-4 antibody binds to the target on tumor cells.
- The ADC is internalized; MMAE is released intracellularly.
- MMAE disrupts microtubules, causing cell cycle arrest and apoptosis.
Dosing and Administration:
- Dose: 1.25 mg/kg (up to max 125 mg/dose)
- Schedule: IV on days 1, 8, and 15 of a 28-day cycle
- Route: IV infusion over 30 minutes
- Premedication: May be needed to reduce risk of infusion-related reactions
Key Toxicities:
1. Dermatologic:
- Rash (up to 55%): Can be severe (SJS/TEN reported)
- Onset typically in the first cycle
- Treat with topical/systemic steroids; may require dose hold or discontinuation
2. Peripheral Neuropathy:
- Common due to MMAE (similar to other auristatins)
- Cumulative and dose-dependent
- May require dose reduction or discontinuation
3. Ocular Toxicity:
- Dry eyes, blurred vision, keratitis
- Lubricating eye drops often recommended prophylactically
4. Hyperglycemia:
- Especially in patients with pre-existing risk factors (e.g. diabetes, obesity)
- Can be severe or life-threatening
5. Infusion-related Reactions:
- Most occur during early cycles
- Premedication with antihistamines and antipyretics may be used
Monitoring Parameters:
- Skin assessments: Especially in early cycles
- Neurologic exam: Baseline and periodically during treatment
- Blood glucose: Monitor closely in patients at risk
- Ophthalmologic evaluation: If vision changes occur
- CBC and renal/liver function: Routine monitoring