Pfizer submitted EMA application for enfortumab vedotin (Padcev) in combination with pembrolizumab (Keytruda) for first-line treatment of patients with locally advanced or metastatic urothelial cancer

Pfizer announced that the EMA validated the Type II Variation application for enfortumab vedotin (EV/Padcev; Nectin-4 ADC) in combination with pembrolizumab (P/Keytruda; anti-PD-1) for first-line treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC). Approval in EU is estimated in ~Q4 2024, although there is potential for faster approval.

EV’s expected continued movement up in the mUC treatment algorithm globally will create a unique opportunity to entrench in the 2L setting in countries where EV+P is reimbursed in 1L.

Key Highlights and Potential Implications:

• The application is based on data from the confirmatory P3 EV-302/KEYNOTEA39 trial in which EV+P demonstrated unprecedented efficacy vs platinum-based chemo in 1L ‘all-comer’ mUC, positioning the regimen as the future global 1L SOC
  • EV+P nearly doubled both PFS and OS versus platinum-based chemo, with HRs of 0.45 and 0.47, respectively
• This filing was expected in Q1 2024 and estimated approval in EU remains ~Q4 2024, although there is potential for faster approval given strength of the data
  • The FDA previously approved EV+P for 1L la/mUC in Dec 2023, just ~2 weeks after the sBLA filing was accepted under the FDA’s RTOR pilot program
    
    • Treatment selection following EV+P is an open question: HCPs have expressed willingness to sequence Trodelvy post EV+P but displaced 1L platinum-based chemo will also become a key 2L option and competitor 
    • Data demonstrating Trodelvy efficacy and safety following EV+P would help to inform 2L treatment selection vs platinum-based chemo

Additional Information

• In December 2023, Pfizer completed acquisition of Seagen
• In April 2023, the FDA granted accelerated approval for EV+P for treatment of cisplatin-ineligible la/mUC based on results from Dose Escalation Cohort/Cohort A and Cohort K of the Ph 1/2 EV-103 (KEYNOTE-869) trial, making it the first ADC + IO combination approved in this population
  • After several 1L mUC failures involving IOs (including restriction of Keytruda indication to platinum-ineligible), EV+P data lends evidence to the potential synergistic effects and clinical benefit of ADC + IO combination in the 1L setting
• P3 EV-302 serves as the confirmatory trial for the US AA and as the basis for global submissions for 1L all-comer mUC. Positive topline results were first reported in September 2023 with full results shared during a Presidential session at ESMO in October 2023(#LBA6)
• On Nov 30, 2023, Seagen/Astellas and Merck announced that the FDA granted priority review for the supplemental BLA of EV+P for la/mUC, and that the application would be reviewed using the Real-Time Oncology Review (RTOR) pilot program
• On Dec 15, 2023, the FDA approved EV+P for patients with la/mUC only two weeks after sBLA acceptance and well ahead of the PDUFA date of May 9, 2024
• Key data included in the updated Padcev and Keytruda USPI:
  • Efficacy (EV + P vs chemo)
    • mOS (mos): 31.5 vs 16.1 (HR 0.47)
    • mPFS (mos): 12.5 vs 6.3 (HR 0.45)
    • cORR: 68% vs 44%
      • CR: 29% vs 13%
    • Safety (EV + P vs chemo)
      • Median duration of exposure for Padcev: 7 months (range 0.3-31.9 mo)
      • Median duration of exposure for Keytruda: 8.5 months (range 9 d-28.5 mo)
      • Selected Gr 3-4 AEs / lab abnormalities:
        • Rash: 15% vs 0%
        • Peripheral neuropathy: 8% vs 0% (All grades: 67% vs 14%)
        • Diarrhea: 5% vs 1%
        • Hyperglycemia: 14% vs 5%
      • Fatal AEs: 4%
        • Acute respiratory failure 0.7%, pneumonia 0.5%, pneumonitis/ILD 0.2%
      • AEs leading to Padcev discontinuation: 35%, mainly due to peripheral neuropathy (15%), rash (4%), and pneumonitis/ILD (2%)
      • AEs leading to Padcev dose reduction: 42%, mainly due to rash (16%), peripheral neuropathy (13%), and fatigue (3%)
      • AEs leading to Padcev dose interruption: 73%, mainly due to peripheral neuropathy (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (5%), fatigue (4%), hyperglycemia (4%) and others