The Scottish Medicines Consortium (SMC) has accepted enfortumab vedotin (Padcev, Astellas Pharma and Pfizer) in combination with pembrolizumab for restricted use in NHS Scotland. The combination is indicated as a first-line treatment for adults with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy. Under the SMC restriction, pembrolizumab treatment is limited to 2 years.

SMC Chair Dr Robert Peel also highlighted the clinical significance of the decision, saying enfortumab vedotin used with pembrolizumab “brings the most significant improvement in extending life expectancy for bladder cancer patients in a long time.”

Disease Background and Drug Mechanism

Urothelial carcinoma includes cancers of the lower and upper urinary tracts, with bladder cancer accounting for approximately 90% of cases. About 12% of patients present with unresectable or metastatic disease. The condition predominantly affects men and individuals over 65 years of age, with smoking linked to around 50% of diagnoses. Unresectable or metastatic disease carries a poor prognosis, with 5-year survival rates below 10%.

Enfortumab vedotin is an antibody-drug conjugate that targets the Nectin-4 protein found on the surface of urothelial cancer cells. The drug forms a complex that enters cells and releases monomethyl auristatin E, a microtubule-disrupting agent that causes cell cycle arrest, apoptosis and immunogenic cell death. Monomethyl auristatin E can also move into nearby cells with low Nectin-4 expression, resulting in cytotoxic cell death.

Pembrolizumab is a humanised monoclonal antibody that binds to the PD-1 receptor on T-cells, blocking its interaction with the ligands PD-L1 and PD-L2. This blockade enhances T-cell responses, resulting in immune-mediated antitumour activity.

Clinical Evidence 

The acceptance was based on evidence from the phase 3 EV-302 study, which enrolled 886 patients with untreated locally advanced or metastatic urothelial carcinoma. Participants were randomly assigned to receive either enfortumab vedotin plus pembrolizumab or platinum-based chemotherapy.

At a data analysis point with a median follow-up of 29.1 months, the combination showed a median progression-free survival of 12.5 months compared with 6.3 months for chemotherapy, representing a 55% reduction in the risk of disease progression or death. Median overall survival reached 33.8 months versus 15.9 months for chemotherapy, corresponding to a 49% reduction in the risk of death. The objective response rate was 68% with the combination compared with 44% for chemotherapy.

Grade 3 or higher treatment-related adverse events occurred in 57% of patients receiving enfortumab vedotin plus pembrolizumab and 70% of those receiving chemotherapy. The most common treatment-related adverse events with the combination were peripheral sensory neuropathy, pruritus, and alopecia; with chemotherapy, they were anaemia, neutropenia, and nausea.

Dosing and Implementation

When administered in combination with pembrolizumab, the recommended dose of enfortumab vedotin is 1.25 mg/kg, up to a maximum 125 mg for patients weighing more than 100 kg, on days 1 and 8 of every 3-week cycle by intravenous infusion. Pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks by intravenous infusion, or 395 mg every 3 weeks or 790 mg every 6 weeks by subcutaneous injection. Treatment continues until disease progression or unacceptable toxicity.

The decision applies only under approved NHS Scotland Patient Access Scheme arrangements that deliver cost-effectiveness results upon which the decision was based. The advice considered views from a Patient and Clinician Engagement meeting, where participants emphasised this represents a “generational change” in frontline therapy for urothelial cancer.