Regulatory Decision Summary for Padcev

The authorization of Padcev was based on the safety and efficacy results of a Phase 3 multi-centre, randomized, open-label, controlled clinical trial EV-301.

Adult patients previously treated with both platinum-based chemotherapy and immunotherapy (either anti-PD-1 or anti-PD-L1) with inoperable locally advanced or metastatic urothelial cancer received either Padcev (1.25 mg/kg on days 1, 8 and 15 of each 28-day cycle) (n = 301) or chemotherapy (either docetaxel, paclitaxel or vinflunine (the latter where authorized), on day 1 of every 21-day cycle) (n = 307). 

The primary efficacy endpoint was overall survival (OS). At a pre-planned interim analysis, the pre-specified efficacy boundary for OS was crossed and the EV-301 trial was stopped for efficacy on the recommendation of an independent data monitoring committee. The enfortumab vedotin treatment arm demonstrated clinically and statistically significant OS results in adult patients with inoperable locally advanced or metastatic urothelial over those treated with one of three chemotherapies in the comparator arm.

The most common adverse treatment-emergent adverse events (>10%) were: alopecia, decreased appetite, fatigue, diarrhea, peripheral sensory neuropathy, pruritus, nausea, constipation, dysgeusia, pyrexia, anemia, dry skin, rash, rash maculopapular, weight decreased, asthenia, vomiting, abdominal pain, aspartate aminotransferase increased, hematuria, neutrophil count decreased, hyperglycemia, insomnia and lacrimation increased.  The most common Grade 3+ TEAEs (>5%) reported in the enfortumab vedotin arm were rash maculopapular, hyperglycemia, neutrophil count decreased, fatigue, anemia and decreased appetite.

There are different risks associated with enfortumab vedotin treatment than with either of the chemotherapy treatments used in the clinical trial due to the targeted nature of this therapy. Skin reactions, hyperglycemia, peripheral neuropathy, ocular disorders, pneumonitis and infusion site extravasation were identified as serious adverse events. Fatal events due to pneumonitis, hyperglycemia, sepsis and multiple organ dysfunction syndrome were reported in the clinical trials. In the post-market setting in the United States, severe cutaneous adverse reactions were reported. Thus, a Serious Warning and Precautions Box was added to the warn prescribers of the fatal events linked to Steven-Johnson syndrome, toxic epidermal necrolysis, hyperglycemia and diabetic ketoacidosis.

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 and/or reductions as described in the product monograph. The overall risk/benefit is considered positive for this target population that currently has few other treatment options.

The recommended dose 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, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

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

For more information on Health Canada’s decision, please view the Summary Basis of Decision.