Christof Vulsteke, MD, PhD, breaks down findings, implications of KEYNOTE-905

Results from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895) were recently presented at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin, Germany, marking a major advance for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy.

The study evaluated enfortumab vedotin-ejfv (Padcev; EV) plus pembrolizumab (Keytruda; P) in the perioperative setting, building on the success of this combination in metastatic urothelial carcinoma. Overall, the findings demonstrated that perioperative EV+P improved event-free survival, overall survival, and pathological complete response rate compared with surgery alone in patients with cisplatin-ineligible MIBC.¹

These findings mark the first time that a perioperative regimen has shown a survival benefit in this patient population. The combination was recently granted priority review by the FDA based on the results from KEYNOTE-905, offering a potential new option in this setting.

In an interview with Urology Times®, Christof Vulsteke, MD, PhD, who presented results from the trial at the ESMO Congress, discussed the rationale for evaluating this combination in an earlier setting, the practice-changing nature of the results, and how urologists and medical oncologists can collaborate to enhance patient care. Vulsteke is the head of Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent, Belgium.

Urology Times: Could you describe the background/rationale for evaluating EV+P in this setting?

Vulsteke: Two years ago at ESMO, we presented transformative results on the combination of EV and pembrolizumab in the metastatic setting. In that setting, there was a doubling of overall survival...from 16 to 35 months. There were 30% of patients with a complete response, and after 2 years, 75% of these patients were still in complete response. But these are patients with metastatic disease, so [we thought], why don't we bring this promising combination to an earlier setting?

Urology Times: What were the key findings from this trial?

Vulsteke: There was a very strong hit for all of the end points, [including] the primary end point of event-free survival, and also the key secondary end points of overall survival and pathological complete response [CR] rate. Regarding event-free survival, there was a very early and sustained separation of the Kaplan-Meier curves, and this was translated into a statistically significant hazard ratio of 0.40 in favor of the intervention arm of enfortumab vedotin and pembrolizumab. If you looked at 2 years, the event-free survival in the control [arm] was 39% and in the intervention arm, it was 74.5%. So, this was quite striking.

Then for overall survival, it was also statistically significant, [with a] hazard ratio of 0.50. If you looked at 2 years, it was 63% in the control arm and 80% in the intervention arm. So, in this first interim analysis, overall survival was already a very strong hit. This is the first trial to show an overall survival benefit in this population.

If you look at pathological CR, and remember, we used the denominator very honestly, all the patients had an excellent response. [Patients who had] neoadjuvant chemotherapy but refused to go to surgery were considered nonresponders because we didn't have a specimen to analyze. So, the denominator is all the [intent-to-treat] population. By doing this analysis, we ended up with a path[ological] CR of 57.1%.

Urology Times: What are the safety considerations with this regimen?

Vulsteke: When you have great power, such as with this regimen, you also have big responsibility. I think it’s the responsibility of the doctor to have experience with EV. With EV, it's very important [to consider] skin toxicity in the first 2 cycles. Your doctor should look for signs of SDRIFE [symmetrical drug-related intertriginous and flexural exanthema]; that's a kind of skin toxicity that is typical for this drug. They should also look for [things like] fever [or] painful itching. If you know [about these toxicities,] you can easily handle [them]. If you're in the third cycle, then you can be reassured that you’re past the skin toxicity.

In the long term, it's all about polyneuropathy. Give drug holidays. In this trial, it was like we saw in prior experiences with EV+P in the metastatic setting; skin toxicity and polyneuropathy were the predominant toxicities.

Urology Times: Based on these results, which patients may be best suited for perioperative EV+P?

Vulsteke: These are patients who are not amenable for cisplatin-based chemotherapy. We prove here that these patients can receive systemic therapy, and we can even improve [their outcomes]. I think there are very few reasons why you should not give this regimen, except, for example, polyneuropathy. If you have already grade 2 or higher polyneuropathy at baseline, then you can think about not giving this regimen because it can dramatically worsen that in these patients. Another consideration is if you already have a contraindication with checkpoint inhibition, but [medical oncologists] are very used to this in the metastatic setting.

Urology Times: What is the potential significance of this regimen for the cisplatin-ineligible population?

Vulsteke: I think this is practice-changing for cisplatin-ineligible MIBC. It proves that this regimen, which was so active in the metastatic setting, is also very active in an earlier setting. This paves the way for [next-generation] trials to potentially create a surgery-free future for these patients, but also for the cisplatin-eligible patients. [Data from that population] will hopefully be reported soon in the [KEYNOTE] B-15 trial, so [I am] looking forward to that.

Urology Times: These findings have implications for multidisciplinary collaboration. How should urologists and medical oncologists collaborate on a treatment pathway for these patients?

Vulsteke: Indeed, there's a very strong collaboration between both [urologists and medical oncologists.] You need to work very strongly together. It will be good if all of these patients are also seen by the [medical oncologists], so the [medical oncologist] can decide on whether this treatment is feasible for this patient. A lot of times, it can be said that these patients are not amenable to systemic therapy. I think with this regimen, you can even treat very poor patients, and you can improve on them also, but I think a [medical oncologist] has responsibility to act on that.

Urology Times: What role will EV+P play across the disease spectrum in the coming years, and what remains unknown?

Vulsteke: I think [we’ve entered] a new chapter with the combination of ADCs [antibody-drug conjugates] and checkpoint inhibition in this setting. The ultimate goal is to get a path CR of 100%, so there are still patients here who do not respond.

The study is 1 year based on [what we saw in] the metastatic setting. All the pembro studies are 1 year, and EV was [given for] a median of 9 cycles. It can be argued that 9 cycles are too much, but de-escalation has to be tested. Also, other antibody-drug combinations will [be explored] in this space. We have enfortumab vedotin, but you can also act on other targets and other payloads. I think it will be a hard regimen to beat in the near future, but in the long run, I think we have to aim for total cure.

REFERENCE

1. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: the phase III KEYNOTE-905 study. Presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA2. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA2.html.pdf