EV-302 Subgroup Analysis: Improved Outcomes for Cisplatin-Ineligible Advanced Urothelial Cancer Patients - Michiel Van der Heijden

June 12, 2024

Zach Klaassen discusses the findings of the EV-302/KEYNOTE-A39 trial with Michiel Simon Van der Heijden. The trial addresses a critical gap in treatment for cisplatin-ineligible patients with advanced urothelial cancer. Historically, these patients, who often receive carboplatin-based chemotherapy, have faced poorer outcomes compared to those eligible for cisplatin. The EV-302 trial, however, treatment option. It evaluates the combination of enfortumab vedotin and pembrolizumab, showing significantly better results in terms of progression-free survival (PFS) and overall survival (OS) compared to standard chemotherapy, with hazard ratios for both endpoints below 0.5. Particularly for cisplatin-ineligible patients, the benefits are profound, with a hazard ratio of 0.43 for both PFS and OS, and a median OS not yet reached. These findings strongly support EV plus pembrolizumab as the preferred treatment, marking a pivotal advancement in managing this challenging patient population.


Michiel Simon Van der Heijden, MD, PhD, Trial Group Leader, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA

Read the Full Video Transcript

Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia, and we are live at ASCO 2024 in Chicago. I'm delighted today to be joined by Dr. Michiel Van der Heijden, a medical oncologist from the Netherlands Cancer Institute. Michiel, thanks so much for joining us today.

Michiel Van der Heijden: Thanks for having me.

Zach Klaassen: We're going to talk about a subgroup analysis of EV-302. Obviously, this was presented with much acclaim at ESMO 2023. So just by way of background, looking at the cisplatin-ineligible patients, which is the study presented at ASCO, what's the unmet need for these patients?

Michiel Van der Heijden: Yeah, so platinum-based chemotherapy has of course been the mainstay of treatment for decades in advanced urothelial cancer. And the choice of platinum agent has basically dominated treatment choice for us GU oncologists for all this time. So the first choice is cisplatin-based chemotherapy, which has quite good response rates, and also a small fraction of patients who have longer-term survival. However, for the cisplatin-ineligible patients, the outlook is a bit worse, so they can still receive carboplatin-based chemotherapy, but the outcomes in terms of response rates, progression-free survival, and overall survival are a little bit less than for cisplatin-eligible patients. Therefore, there's always been an unmet need for this patient population.

Now, we do have maintenance avelumab nowadays, but patients need to have a response, or at least stable disease, and be fit to start maintenance avelumab. If patients progress already on carboplatin-based chemotherapy, they will never reach this treatment. So it was an unmet need for many years.

Zach Klaassen: For sure. So before we get into the subgroup analysis, maybe just take us through the trial design of the EV-302/KEYNOTE-A39 trial. Like I said, it was published in the New England Journal, but just give us a high-level view of the study design and some of the intention-to-treat analysis before we get into the subgroup.

Michiel Van der Heijden: EV-302 is a study for patients with advanced urothelial cancer regardless of platinum eligibility. Patients in the standard arm had to receive the platinum agent that they could receive by widely accepted Galsky criteria. So if you're cisplatin-eligible, you should receive cisplatin. This is different from some of the other trials that have been done in the past.

Patients were then randomized to receive either enfortumab vedotin plus pembrolizumab, with both drugs continuing on with pembrolizumab for a maximum of two years, and the standard arm would receive platinum-based chemotherapy for a standard maximum of six cycles. I think, also importantly, patients were allowed to receive maintenance avelumab in this trial, and for progression-free survival, the start of a new treatment, so if you would start maintenance avelumab it would not be censored or seen as an event.

Zach Klaassen: Right. And then the intention-to-treat analysis, progression-free survival, overall survival, those data were presented. What were the highlights from those?

Michiel Van der Heijden: I think that when we saw the results, we were of course really excited because both primary endpoints, overall survival and progression-free survival, substantially improved with EV plus pembrolizumab, both with hazard ratios under 0.5. This was unheard of in advanced urothelial cancer.

Zach Klaassen: Yeah, absolutely. Let's fast forward now to this meeting where we're looking specifically at the cisplatin-ineligible patients. Walk us through that analysis and what results you found from that specific population.

Michiel Van der Heijden: Yeah, I think, especially for the US, EV plus pembrolizumab was already available based on previous single-arm studies for this patient group, and I think this trial really shows that that's justified. Because patients in the cisplatin-ineligible population had a hazard ratio for overall survival and progression-free survival of 0.43. So results were substantially better for the EV plus pembrolizumab arm. These results are of course also in line with the overall trial results.

Zach Klaassen: That's great. I mean, I think if somebody takes out bladders, and patients recur, and they've got kidney dysfunction, and they're comorbid, not just from their disease but from their big surgery, the cisplatin-ineligible patient population, roughly 50%, maybe higher than that even, what's the clinical context of these results now that we have a cisplatin-ineligible option?

Michiel Van der Heijden: Yeah, so I think for the overall population, in my view, EV plus pembrolizumab should be the first preferred choice as we've already also incorporated in guidelines like the ESMO and NCCN guidelines. But I think the argument is even more compelling for the cisplatin-ineligible population because the difference proportionally is more because the standard arm in this population performs worse compared to cisplatin-eligible patients. So I think, for some numbers, if you look at response rates, they were really substantially higher for EV plus pembrolizumab, as mentioned, OS and PFS, and if you look at OS, the median overall survival in this trial with this analysis has not even been reached yet.

Zach Klaassen: Yeah, it's exciting. I mean, the last year for this disease space has been really incredible. Thank you for sharing your thoughts on the cisplatin-ineligible cohort today.

Michiel Van der Heijden: Thank you for having me.

Zach Klaassen: Thanks.