Thomas Powles, MD, MBBS, Barts Cancer Institute, London, United Kingdom, discusses the updated analysis of the EV-302/KEYNOTE-A39 trial presented at the 2025 American Society for Clinical Oncology (ASCO) Genitourinary Cancers Symposium. According to these data, enfortumab vedotin plus pembrolizumab showed continued efficacy against chemotherapy among patients with locally advanced or metastatic urothelial carcinoma. 

Transcript:

At ASCO GU 2025 I presented the updated analysis of the EV-302 study, which compares enfortumab vedotin with pembrolizumab and chemotherapy in front-line advanced urothelial cancer. It's a large, randomized, phase 3 study which previously reported as being positive for all of its end points and now we're presenting an additional 12 months of follow up. 

The design of the trial has been well reported. Its front-line metastatic urothelial cancer, platinum, gem[citabine]-cis[platin] or gem[citabine]-carbo[platin]. It's about 880 patients randomized 1-to-1 to receive enfortumab vedotin and pembrolizumab until progression or gem-cis/gem-carbo, about 30% of patients in the control arm got maintenance durvalumab. We previously described the primary end point with a 50% reduction in the risk of progression, a 50% reduction in the risk of death, also a 68% versus 44% response rate and a 29% CR [complete response] rate. The adverse event profile was also well-reported with approximately similar numbers in grade 3/4 toxicity. I'll talk a bit more about that in a minute. 

This updated analysis with a further 12 months of follow up shows really consistent results with the previous results. It shows the response rates are about the same, the CR rate is now 30%, and when we looked at durability of these responses, we could show that the results were excellent. The results showed that at 24 months about 50% of patients were still in response. When one looks back in time, the median survival with chemotherapy was only 12 to 14 months and here we have 70% of patients responding and 50% of those alive at 2 years. That gives an indication of the transformative nature of these results. But if you look at the CR rate, now that's 30%, what you see is 75% with durable CR at 2 years and about 95% of those patients alive at 2 years. This translates into the progression-free survival and overall survival data, and these results are reassuringly consistent with the original data with this additional 12 months of follow up. 

We still have a 50% reduction in the risk of progression and a 50% reduction in the risk of death. The hazard ratio is 0.48 and 0.51, respectively. Landmark analysis shows at 2 years, 60% of patients were alive and about 40% were progression-free. When one looks at these data in context with what we had before with platinum-based chemotherapy, irrespective of concurrent or sequenced immune therapy, these results from an efficacy perspective look much, much better. 

The adverse event profile continues to show similar results. Most of the toxicity of both of these regimens occurs at the beginning of treatment. What we showed was grade 3/4 were in both arms, different toxicity profiles of chemotherapy with more neutropenia, more nausea, more pancytopenia and we saw more neuropathy and more skin rash associated with enfortumab vedotin. There were no new safety signals or dynamic changes there.

Overall, I think it's fair to say that EV[enfortumab vedotin]-pembrolizumab is now the standard of care in this setting. It's widely approved and adopted by guidelines from a global perspective, and these data reassure that and give us more confidence. The median overall survival of 34 months, when one looks historically back in time where we had 12 to 14 months, is a huge change.

Source:

Powles T, Van der Heijden M, 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). Presented at 2025 ASCO Genitourinary Cancers Symposium. February 13-15, 2025; San Francisco, CA. Abstract 664.