EV-302 Supports Enfortumab Vedotin Plus Pembrolizumab as Bladder Cancer SOC

Thomas Powles, MBBS, MRCP, MD

Barts Cancer Institute at St. Bartholomew’s Hospital, Queen Mary University of London

Enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) supersedes all other strategies in the frontline treatment of patients with locally advanced or metastatic urothelial carcinoma, according to Thomas Powles, MBBS, MRCP, MD.

Powles spoke with CancerNetwork^® at the 2025 ASCO Genitourinary Cancer Symposium about his presentation on updated findings from the phase 3 EV-302 trial (NCT04223856) assessing the first-line enfortumab vedotin combination vs chemotherapy in the aforementioned urothelial carcinoma population.¹ With a median follow-up of 29.1 months (95% CI, 28.5-29.9), combining enfortumab vedotin with pembrolizumab produced sustained, statistically significant improvements in progression-free survival (PFS; HR, 0.48; 95% CI, 0.41-0.57; 2-sided P <.00001) and overall survival (OS; HR, 0.51; 95% CI, 0.43-0.61; 2-sided P <.00001).

According to Powles, these outcomes are “transformative” for the vast majority of patients with locally advanced or metastatic urothelial carcinoma.

“We have managed, with a further 12 months of follow-up in this area of huge unmet need, to underpin this as the preferable regimen from a global perspective,” Powles stated regarding the enfortumab vedotin combination.

Powles detailed other results from the updated EV-302 trial analysis, which included a review of the most common toxicities associated with the enfortumab vedotin combination and an assessment of how confirmed complete responses (CRs) impacted other treatment outcomes. Additionally, he highlighted the potential next steps for evaluating similar treatment regimens as neoadjuvant therapy and in other earlier settings.

Powles is 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.

CancerNetwork: What is the background for this updated analysis of findings from the phase 3 EV-302 trial?

Powles: Platinum-based chemotherapy has been the standard of care for a generation-- 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 [ADC] targeting Nectin-4 with monomethyl auristatin E, 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.²

At that point, there were about 12 months of median follow-up in the trial. The OS, historically, of urothelial cancer has only been between 12 and 14 months. Although it sounds short, I’m afraid, historically, these [treatments] haven’t done very well.

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 PFS doubled with the new regimen, and we managed to double 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.

At this point, it’s also important to say that [enfortumab vedotin] is associated with a significant toxicity profile, as is platinum-based chemotherapy, but it’s distinct from platinum-based chemotherapy. [There is] less nausea and myelosuppression, and more skin rash and more neuropathy.

What were the most significant efficacy findings associated with the enfortumab vedotin combination in this updated analysis?

The updated results, which we showed at the ASCO Genitourinary Cancer Symposium, [had] 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 CR, so the cancer appeared to disappear altogether. We also looked at those responses, we looked for the duration of response [DOR], and we showed that the DOR 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 [at 1 year], 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 PFS. The hazard ratio remains at approximately 0.5, [representing a] doubling in PFS. The median OS is now 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 [with] no new toxicity signals seen. In fact, most of the toxicity appears to occur during the beginning of treatment.

What were the most common toxicities observed with the combination, and how were they best managed?

The most significant toxicity associated with enfortumab vedotin plus pembrolizumab is different from chemotherapy [in 3 ways]. Yes, it’s associated with some fatigue. It’s associated with some nausea, but it does have the skin rash: a red skin rash sitting on the flexor surfaces that occurs during the initial period of therapy—during the first 3 or 4 cycles. That’s quite common, and that requires dose interruptions and dose reductions.

After 6 or more cycles, patients tend to get peripheral neuropathy, [which feels like] pins and needles in their feet. If you do not intervene, that can be progressive and problematic. [Treatment] can also cause some hyperglycemia, and that hyperglycemia [occurs] only in 1% to 2% of patients who require intervention. Some patients indeed require diabetic-type treatment.

Those are 3 key areas of toxicity. [Treatment] is not associated, particularly, with interstitial lung disease as some of the other ADCs. There are some corneal abnormalities, but the eye toxicity with this particular regimen is particularly minimal.

Regarding the exploratory analysis, how does the occurrence of a confirmed CR impact other treatment outcomes with enfortumab vedotin plus pembrolizumab?

Those patients who responded did well, and that’s one of the striking features of this result. What we saw with chemotherapy was many patients initially responding, but the cancer coming back quite quickly. Here, we show durable responses. At 2 years, in [67.5%] of patients who responded to therapy, 50% haven’t progressed at 2 years. That’s really impressive. Then, of course, the second piece around the patients is that, of 30% who had a CR, 95% of those patients were alive at 2 years. That’s, in my opinion and others, transformative compared to what we saw previously.

Considering how these data support enfortumab vedotin plus pembrolizumab as a first-line standard of care in this population, what factors should be considered when sequencing this combination with other options during treatment?

Enfortumab vedotin plus pembrolizumab supersedes other approaches in this environment. I don’t think [gemcitabine/cisplatin] or [gemcitabine/carboplatin] with either nivolumab [Opdivo] or maintenance durvalumab [Imfinzi] has a major population where you would choose them instead. There are patients who are not fit enough for systemic therapy, of course, and there are [certain] patients who have contraindications to immune checkpoint inhibition [and may have] active arthritis on immunosuppressive therapy. But as a rule, this [combination] supersedes previous chemotherapy.

We still need to do better in urothelial cancer. We need to group these regimens earlier in the disease, where I believe it to be more curable. We need to look at the results of the perioperative trials in that space, and that’s going to be exciting. There are neoadjuvant trials with enfortumab vedotin plus pembrolizumab and enfortumab vedotin plus durvalumab and tremelimumab [Imjudo]. I expect to see similar results. I hope what we might even do is be able to cure patients in the perioperative space without surgery. It’s a very exciting time in urothelial cancer.

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. doi:10.1016/j.annonc.2023.10.106