FDA granted priority review for enfortumab vedotin (EV/Padcev) in combination with pembrolizumab (P/Keytruda) in first line ( 1L) treatment of locally advanced or metastatic urothelial cancer (la/mUC)

Seagen/Astellas and Merck announced that the FDA granted priority review for the supplemental BLA of 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).

The application is being reviewed under the Real-Time Oncology Review (RTOR) program and the FDA has set a PDUFA date of May 9, 2024. However, under RTOR we expect approval earlier, potentially in Q1’24.

EV’s continued movement up in the mUC treatment algorithm creates a unique opportunity to entrench Trodelvy in the 2L setting.

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 1L SOC and raising the bar for future 1L regimens

• • EV+P nearly doubled both PFS and OS versus platinum-based chemo, with HRs of 0.45 and 0.47, respectively
• Fast US filing and RTOR were expected based on strength of EV-302 data and Astellas’ recent guidance of planned US submission in Q4’24. Under RTOR, Gilead CI expects approval will likely come ahead of the target action date, potentially in Q1’24
  • EU filing and approval are expected Q1’24 and ~Q4’24, respectively
• If approved, the application will convert the current US accelerated approval of EV+P in 1L cis-ineligible la/mUC to standard approval for all 1L la/mUC patients regardless of cisplatin eligibility, effectively doubling the size of EV+P’s addressable patient population (est. ~55% cis-eligible)
• EV has served as a direct competitor to Trodelvy in the 2L+ setting; however, with the expected approval of EV in a broad 1L setting, there is opportunity for Trodelvy to entrench as a 2L treatment of choice
  • 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 to Trodelvy
  • Data demonstrating Trodelvy efficacy and safety following EV+P would help to inform 2L treatment selection vs platinum-based chemo

Additional Information

• The FDA granted accelerated approval for EV+P for treatment of cisplatin-ineligible la/mUC in April 2023 based on results from Dose Escalation Cohort/Cohort A and Cohort K of the Phase 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 with full results (outlined below) shared during a Presidential session at ESMO in October (#LBA6)
  • Study Information
    • P3 EV-302 (NCT04223856): enfortumab vedotin (EV) + pembro (P) in 1L cis-eligible and cis-ineligible (‘all-comer’) mUC
    • N=886 (EV+P: 442)
    • 1EP: PFS, OS
    • 2EP: ORR, Safety, DOR
    • Median follow up (mo): 17.2
    • Median number of treatment cycles (mo): EV + P = 12; Chemo = 6
  • Efficacy (EV + P vs chemo)
    • mPFS (mos): 12.5 vs 6.3 (HR 0.45)
      • Cis-eligible HR: 0.48
      • Cis-ineligible HR: 0.43
    • mOS (mos): 31.5 vs 16.1 (HR 0.47)
      • Cis-eligible HR: 0.53
      • Cis-ineligible HR: 0.43
    • cORR: 68% vs 44%
      • CR: 29% vs 13%
    • mDOR (mo): NR (20.2, NR) vs 7.0
  • Safety (EV + P vs chemo)
    • Gr3+ TRAEs: 56% vs 70%
    • Key most common Gr 3+ TRAEs for EV + P:
      • Maculopapular rash: 8%
      • Neutropenia: 5%
      • Peripheral neuropathy: 4%
    • Gr3+ EV treatment-related AESI:
      • Skin reactions: 16%
      • Peripheral neuropathy: 7%
      • Hyperglycemia: 6%
    • Gr 5 TRAEs: 1% (asthenia, diarrhea, immune-mediated lung disease, multiple organ dysfunction syndrome)