Regulatory Decision Summary for Padcev (enfortumab vedotin)

This Supplemental New Drug Submission (SNDS) was submitted to seek authorisation for the use of Padcev in combination with pembrolizumab, for the treatment of patients, with locally advanced or metastatic urothelial cancer.

After evaluation of the submitted data package, Health Canada authorised Padcev for the following indication:

Padcev, in combination with pembrolizumab, is indicated for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer (mUC) with no prior systemic therapy for mUC.

See Padcev Product Monograph for other authorised indications for urothelial cancer.

The authorization of Padcev was based on the safety and efficacy results of a Phase 3 global, multi-centre, randomized, open-label, controlled clinical trial EV-302/KEYNOTE-A39. Patients (n = 886) with unresectable, locally advanced or metastatic disease received either Padcev (1.25 mg/kg on Days 1 and 8 of a 21-day) plus pembrolizumab (200 mg on Day 1 of a 21-day cycle) or gemcitabine (1,000 mg/m² on Days 1 and 8 of a 21-day cycle) and investigator’s choice of cisplatin (70 mg/m²) or carboplatin (AUC 4.5 or 5 mg/mL/min) on Day 1 of a 21-day cycle.

The dual primary efficacy endpoints were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR). Study EV-302/KEYNOTE-A39 met its primary endpoints, with statistically significant improvements in PFS by BICR at the final analysis and OS at the pre-specified interim analysis.

The most common (≥20% incidence) treatment-emergent adverse events (TEAEs) in patients treated with Padcev plus pembrolizumab in EV-302 were peripheral sensory neuropathy, pruritus, diarrhea, fatigue, alopecia, rash maculo-papular, decreased appetite, weight decreased, constipation, nausea, anemia, dysgeusia, and urinary tract infection. The most common Grade 3 (≥5% incidence) events were: rash, peripheral neuropathy, hyperglycemia, anemia, diarrhea, fatigue, urinary tract infection, acute kidney injury, hyponatremia, and neutropenia. These findings were consistent with previous observations and there were no new safety signals.

The risks associated with Padcev plus pembrolizumab treatment differ from those of fluoropyrimidine- and platinum-based systemic chemotherapy due to the different targets (i.e. Nectin-4 and the immune response, respectively). Acute kidney injury, urinary tract infection, diarrhea, pneumonia, pneumonitis and pyrexia were identified as serious TEAEs. Fatal events due to TEAE occurred in both arms of EV-302 at similar low incidences. Given the low overall occurrence of these events, the risk is manageable for the target population through close monitoring and the use of treatment modifications as described in the product monographs of both products. The overall risk/benefit is considered positive for this target population given the improvements noted in OS and PFS over the systemic chemotherapy regimen.

The recommended dose of Padcev in combination with pembrolizumab for this indication is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered intravenously over 30 minutes on days 1 and 8 of a 21-day cycle until unacceptable toxicity or disease progression.

Health Canada granted this application priority review and participated in Project Orbis.

For further details about Padcev, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.