Seagen/Astellas and Merck announced positive results from Phase 3 trial investigating enfortumab vedotin (Padcev) + pembrolizumab (Keytruda) in 1 Line mUC all-comers

Seagen/Astellas and Merck announced positive topline results from the global confirmatory P3 EV-302/KEYNOTE-A39 trial investigating enfortumab vedotin (EV, Padcev; nectin-4 ADC) + pembrolizumab (Keytruda; PD-1) versus chemotherapy in 1L all-comer mUC, which met the dual primary endpoints of PFS and OS.

Detailed data are anticipated at ESMO 2023.

EV-302 results confirm the US accelerated approval of EV + Pembro in 1L cis-ineligible mUC and will support global filings in an expanded 1L all-comer population, where it is expected to become a standard of care regimen. Estimated full US approval ~Q3’24 and EU approval ~Q1’25.

As EV moves up in the mUC treatment algorithm, Trodelvy has a unique opportunity to entrench as a 2L choice in patients meeting eligibility criteria. However, EV-302 will also establish the ADC class benchmark in the 1L setting, creating a high bar for future 1L ADC combinations to beat.

Key Highlights and Potential Implications:

• The P3 EV-302 study of EV + Pembro versus chemotherapy in 1L all-comer mUC met its dual primary endpoints of PFS and OS and key secondary endpoint of ORR, solidifying EV’s opportunity in a broad 1L setting

  • Numerical data were not provided but OS (crossed pre-specified efficacy boundary at interim analysis) and PFS results were described as both “statistically significant” and “clinically meaningful” versus chemotherapy

  • Safety results were noted as consistent with data previously reported in 1L cis-ineligible patients (P1/2 EV-103). Skin rash and peripheral neuropathy expected to remain key concerns with this regimen; no mention of Gr 5+ TRAEs in the press release, although 5% seen in P1/2 EV-103

  • Of particular interest will be how EV + Pembro performed in subgroups including in cisplatin eligible vs ineligible patients and compared to patients treated with maintenance avelumab (expected to be relative minority of pts) vs without in the reference arm

• EV-302 serves as the confirmatory trial for EV + Pembro’s current US accelerated approval for 1L cis-ineligible la/mUC (Apr 2023; based on P1/2 EV-103 Cohorts A & K) and will also serve as the basis for global submissions for 1L all-comer mUC

• Label expansion to include the 1L cis-eligible segment will effectively double the size of EV + Pembro’s addressable patient population (est. ~55% cis-eligible)

  • Global insights suggest EV + Pembro will become a 1L SOC following prospective all-comer approval. Physicians do not appear to have concerns in sequencing ADCs that have different targets and limited AE overlap for mUC, and thus EV moving up in the algorithm is expected to also help Trodelvy move forward

    • ​​​​​​​​​​​​​​Displaced 1L platinum-based chemotherapy could become a relevant 2L competitor to Trodelvy; data demonstrating Trodelvy efficacy and safety following EV + Pembro would help to inform 2L treatment selection vs platinum

  • Despite expected high adoption of the combination in 1L mUC, EV +/- Pembro is expected to remain a relevant 2L competitor to Trodelvy in patients continuing to receive 1L platinum-based chemotherapies​​​​