Regulatory Decision Summary for Keytruda (pembrolizumab)

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

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

Keytruda, in combination with enfortumab vedotin, 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 Keytruda Product Monograph for other authorised indications for urothelial cancer.

The authorization of Keytruda was based on the safety and efficacy results of a Phase 3 global, multi-centre, randomized, open-label, controlled clinical trial KEYNOTE-A39/EV-302. Patients (n = 886) with unresectable, locally advanced or metastatic disease received either enfortumab vedotin (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 KEYNOTE-A39/EV-302 met its primary endpoints, with statistically significant improvements in both PFS by BICR at the final analysis and OS at the pre-specified interim analysis.

The most common treatment-emergent adverse events (TEAEs) in patients (≥20% incidence) with Keytruda plus enfortumab vedotin 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) were: rash, peripheral neuropathy, hyperglycemia, anemia, diarrhea, fatigue, urinary tract infection, acute kidney injury, hyponatremia (5%), and neutropenia. These findings were consistent with previous observations and there were no new safety signals.

The risks associated with Keytruda plus enfortumab vedotin 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 TEAEs 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 and/or reductions as described in the product monograph. 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 Keytruda in combination with enfortumab vedotin for this indication is 200 mg every 3 weeks (or 400 mg every 6 weeks) administered intravenously over 30 minutes until unacceptable toxicity or disease progression.

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

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