Enfortumab Vedotin Combo Yields ‘Transformative’ Urothelial Cancer Outcomes

In a conversation with CancerNetwork^® at the 2025 ASCO Genitourinary Cancer Symposium, Thomas Powles, MBBS, MRCP, MD, highlighted updated results that he presented on the phase 3 EV-302 trial (NCT04223856).¹ He described how additional follow-up in the EV-302 trial has demonstrated “transformative” outcomes with enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in those with advanced or metastatic urothelial carcinoma.

Powles, a professor of genitourinary oncology, lead for Solid Tumor Research, and director of Barts Cancer Institute at St. Bartholomew’s Hospital, Queen Mary University of London, in London, United Kingdom, first outlined the context for the EV-302 trial. Investigators assessed how the Nectin-4–targeting antibody drug conjugate enfortumab vedotin administered in combination with immune checkpoint therapy could improve upon outcomes achieved with the prior standard of care, platinum-containing chemotherapy.

Building upon previously reported results from the EV-302 trial,² Powles detailed how the findings presented at the ASCO Genitourinary Cancers Symposium demonstrated sustained improvements with enfortumab vedotin plus pembrolizumab vs platinum-containing chemotherapy after 12 additional months of follow-up.

Transcript:

Platinum-based chemotherapy has been the standard of care for a generation, for 40 years in first-line advanced urothelial cancer. Things have been static for a long period of time, and it became apparent that both immune checkpoint inhibition and this drug, enfortumab vedotin, which is an antibody drug conjugate targeting Nectin-4 with MMAE, were active in the disease. The hypothesis was, if we combine those 2 drugs together, can we beat platinum-based chemotherapy? That was tested in a big, frontline randomized phase 3 study. We presented it for the first time [approximately] a year and 3 or 4 months ago, and we published it at that time.

What we showed in the trial were transformative results. We showed response rates of 67% to 68% [with enfortumab vedotin plus pembrolizumab] vs 44% [with chemotherapy]. We showed progression-free survival [PFS] doubled with the new regimen, and we managed to double overall survival [OS]. The survival was so good in the study arm that, in fact, it looked quite immature at that time. The key was to go on from there and do a further 12 months of follow-up to see if the initial results could be duplicated and consistent with what we have shown previously.

The updated results, which we showed [at the ASCO Genitourinary Cancer Symposium], was a further 12 months of follow-up. The good news is that we showed 2 important things. First, the response rate, as you would expect, remains the same. Also, 30% of patients had a complete response, so the cancer appeared to disappear altogether. We also looked at those responses, we looked for the duration of response, and we showed that duration of response was great. [Approximately] 50% of patients continued to respond after 2 years. If you go back in time and remember, 68% of patients were responding, and 50% continued to respond at 2 years. OS was only 12 to 14 months before we did this, so that’s a huge difference. In the completely responding patients—that 30% of patients—[78%] were progression-free at 2 years.

These [outcomes] are transformative for the vast majority of patients. That translated into the progression-free survival. The hazard ratio remains at about 0.5, [representing a] doubling in PFS and, indeed, OS. The median OS now is more mature; it is 34 months. You can see that 60% are alive at 2 years, and the hazard ratio for that is still 0.5; a doubling in OS, but no new toxicity signals seen. In fact, most of the toxicity appears to occur during the beginning of treatment.

References

1. Powles TB, Van der Heijden MS, Loriot Y, et al. EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). J Clin Oncol. 2025;43(suppl 5):664. doi:10.1200/JCO.2025.43.5_suppl.664
2. Powles TB, Valderrama BP, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340.