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Sam Chang: Hello, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, and we are at GU ASCO 2024, and we have the pleasure and honor to have Dr. Michiel Van der Heijden from Europe actually giving us a late-breaking abstract looking at the combination therapy of EV and pembro. Tell us about the results and the deep dive into what was shown with the data.

Michiel Van der Heijden: Yeah, thanks for having me in this interview. So EV-302 is a trial that examines enfortumab vedotin plus pembrolizumab versus chemotherapy. And as a bit of background, for decades, we've used chemotherapy as the mainstay of treatment for advanced urothelial cancer. And cisplatin eligibility has defined therapy choice for as long as I can remember.

Sam Chang: Sure.

Michiel Van der Heijden: In this trial, we compared EVP with chemotherapy in previously untreated patients with advanced urothelial cancer who were eligible for all of the study drugs and who had a maximum performance status of two. They were randomized to either enfortumab vedotin and pembrolizumab or standard platinum-based chemotherapy. And the choice of platinum agent was determined by the protocol by the commonly used Galsky criteria.

Also important in this trial, patients were allowed to have maintenance immunotherapy in the control arm, and this would not constitute a PFS event. So the main results were already presented at ESMO, and I think were quite astonishing that-

Sam Chang: Game-changing.

Michiel Van der Heijden: Game-changing.

Sam Chang: Yes.

Michiel Van der Heijden: ... That both in PFS and OS, the two primary endpoints, the trial already met these endpoints at the first interim analysis, and not only met them, the hazard ratios for progression-free survival and overall survival were both below 0.5, which is really unheard of in bladder cancer.

So this was already presented, we already saw a glimpse of clinical subgroups, but the presentation at this meeting is about a more in-depth look at certain clinical subgroups that are relevant for clinicians. One of the clinical subgroups was cisplatin eligibility. So patients would be either cisplatin-eligible and would receive in the control arm cisplatin, cisplatin gemcitabine, or cisplatin-ineligible and would receive carboplatin gemcitabine.

Sam Chang: Sure.

Michiel Van der Heijden: And in both these groups, the results for both PFS and OS were very consistent with the overall results of the trial. Same for PD-L1 expression; there was no difference, both clearly showed EVP to do better in either PD-L1 positive or negative patients.

Some of the other subgroups that we looked at were, for example, liver metastasis. That's, of course, a known adverse prognostic factor-

Sam Chang: Poor prognostic factor. Sure.

Michiel Van der Heijden: Poor prognostic factor. And also in this trial, these patients did worse, but still, EVP performed much better than chemotherapy both in progression-free survival and overall survival. I think one of the subgroups that was also of interest to look at is the lymph node-only disease. So that's the other end of the spectrum, the much more favorable prognostic factor. And these patients did really well. So here again, there was a hazard ratio under 0.5 for EVP, and the median progression-free survival was not even reached in patients with lymph node metastasis, and the overall survival also-

Sam Chang: Big advantage as well. Or still not reached, maybe still not reached?

Michiel Van der Heijden: Not reached, and the tail of the curve for the lymph node metastasis only group sort of settled at this moment in time at 70%. So, even the further out part of the curve.

Sam Chang: And then remind me of the length of follow-up, then. Median time of follow-up was how long for this trial?

Michiel Van der Heijden: Yes, so that's absolutely an important point. The median follow-up for survival is 17.2 months. We're here talking about much later parts of the curve, so after two and a half years and further. And at this point, it settled at about 70% in the last part.

Sam Chang: So was there any subgroup where there wasn't a big advantage in favor of the combination of EV and pembro? Not yet.

Michiel Van der Heijden: There was not. No, it was, in that way, a very boring presentation. All of these subgroups showed that EVP did much better than chemotherapy.

Sam Chang: And then, as you broke down the carbo gem group versus the, I know they were not directly compared, but were there differences between the success between the carbo gem and the cis gem? You would assume that there'd be an advantage for the cisplatinum as opposed to the cisplatinum-ineligible group. Did you guys actually look at that within your control arm?

Michiel Van der Heijden: The hazard ratios for overall survival were slightly better in the cis-ineligible group, but still, yeah, the hazard ratio—

Sam Chang: Overlaps—

Michiel Van der Heijden: The cisplatin-eligible group was still really good in favor of EVP.

Sam Chang: So, the take-home message then, overall in terms of the success, clearly, like I said, game-changing, practice-changing. But even when diving down into those factors that can influence choices, visceral mat, nodal disease, etc., there seemed to be an advantage for this combination of EV pembro vis-à-vis platinum-based chemotherapy.

Michiel Van der Heijden: Exactly. I think in every group that we examined, EVP did better.

Sam Chang: So you said boring, not surprising. Any surprises at all then when you guys dove down and looked at these subgroups? Not really then.

Michiel Van der Heijden: No. I don't know if you by now can still call it a surprise, but I'm still amazed when I see this data in front of me. I also treat a lot of patients in the study, so this is what I also actually saw in my patients. But to give you just some numbers, we also looked at objective response rates in patients with liver metastasis. It was 60% for EVP. 60% of patients responding.

Sam Chang: So almost two out of three. Wow, okay.

Michiel Van der Heijden: For lymph nodes-only disease, 77 and a half percent of patients had an objective response, which I think is incredible.

Sam Chang: What about, and you may not have this data, we know that the efficacy seems to be maintained throughout the subgroups. What about, were there any subgroups that tended to have more side effects associated with the combination therapy versus the platinum-based chemotherapy?

Michiel Van der Heijden: Well, that's an interesting question. We didn't really look at that specifically, if there was a difference in toxicity. In itself, I wouldn't really expect that. I think in general, we know the combination that both components of the combination have certain side effects, and I think the side effects that we observed in the study are consistent with those side effects. I think in general, the overall safety was manageable and no new safety signals arose. I don't think there's any specific group where we see more side effects.

Sam Chang: Great. Well, Dr. Van der Heijden, thank you so much for spending some time with us. I know you've just flown nine and a half hours to get here, but really important for folks, at least within the US, obviously the oncologists have a good idea, but for the urologists, radiation oncologists, those that may not have followed the data from ESMO to get the verification of not only the big response but within the subgroups, to see that maintained is a really important change in our practice. Thanks again for spending some time with us and we look forward to further long-term data with this cohort of patients.

Michiel Van der Heijden: Thank you for having me here.