EV-302 Results and How They Compare to the JAVELIN Paradigm

A roundtable discussion, moderated by Peter O’Donnell, MD, discussed the advanced urothelial treatment landscape, as well as recent trial data from ESMO 2023. Dr. O’Donnell was joined by Terence Friedlander, MD; Matthew Galsky, MD; and Jonathan Rosenberg, MD.

In the next segment of the roundtable series, the panel discussed how the EV-302 data compare to the previous JAVELIN paradigm in patients with bladder cancer.

Watch the next segment in this series.

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Dr. O’Donnell: It’s hard to argue with the data, so I’m trying to find ways to maybe have something to debate here. There have been some analyses prior looking at the JAVELIN data set, which was our paradigm up until 2 weeks ago. Where the JAVELIN paradigm looked like it was maybe getting to 29 months from the initiation of all therapy for those patients. This EV [enfortumab vedotin]/pembrolizumab is sort of close to that 31 months. Is there any argument to be made about that or can we comment on… People may be making that comparison that maybe we’re in a similar ballpark to where we were and it’s not transformative. Matt, maybe I’ll start with you.

Dr. Galsky: Yeah, I think that whenever we’re comparing a maintenance strategy to an upfront strategy, it’s comparing apples and oranges. I would hesitate to make those comparisons, because once someone has reached the point of maintenance, that’s probably the most favorable prognostic factor that you can imagine in the frontline setting, because it happens retrospectively. We can look at baseline prognostic factors in terms of getting to that point, but nothing as good as actually getting to that point, and that just predicts for better outcomes. I think we need to compare apples to apples, what happens from the start with different regimens. That’s not to negate the potential effects of an inadequate control arm that incorporates switch maintenance therapy, but I think that is a little bit of muddy waters, because we don’t precisely know how many patients that should be in the real world, or on the control arm of trials from the start, how many patients really should be getting switch maintenance treatment or could be getting it, rather.

Dr. O’Donnell: Terry, do you want to comment on that as well? This idea of JAVELIN paradigm, have we shattered it?

Dr. Friedlander: Yeah. I think JAVELIN was a really interesting study. What I took home from JAVELIN was that giving a checkpoint inhibitor earlier in the treatment paradigm is better than waiting for patients to relapse. If you wait for patients to progress after getting frontline platinum, you lose patients, they present with bad disease—PEs [pulmonary emboli], brain metastases, bad things that prohibit them from getting treated. That analysis that showed that patients who were on JAVELIN had a median OS [overall survival] of 29 months, as Matt has said, really excludes all the patients who never made it to stable disease or better to get on the study. It is really a tough comparison to do.

I think as you look at EV-302, if you take the lesson from JAVELIN that says giving checkpoint inhibitors earlier is better and not waiting for patients to progress, or not making patients jump through hoops to get a checkpoint inhibitor, it makes a lot more sense just clinically to be giving the checkpoint inhibitor earlier. That’s true not just for EV-302, but also for the CheckMate 901, the gemcitabine/nivolumab regimen as well. I think that if you just step back for a second and look at trends across bladder cancer, it’s really been moving checkpoint inhibitors up. I don’t think it’s necessarily about saying, “Oh, the OS here is 2 months different than the OS here.” It’s really thinking about where this trend is going. It really makes me wonder what the future of maintenance therapy is for patients, because most patients will be starting with a checkpoint inhibitor. But I think there may still be a role in it, perhaps we can talk about that in a little bit.

Dr. O’Donnell: Yeah, we’ll get to the 901 data in a little bit. All right, Jonathan, I’m going to ask you 1 final question about the EV/pembrolizumab paradigm now, which we anticipate it’s going to probably have pretty heavy adoption here. In the United States, right? It’s essentially going to lead to a label expansion, right? We’ve already been giving this regimen in cisplatin-ineligible patients and now we could give it to everybody. We know that trial patients are not the real world; the data are very impressive. But are there patients where you’d have a pause about maybe using EV/pembrolizumab? Or are there considerations about patient groups that you want to really emphasize that we have to use this regimen with caution or think about some preventative management steps?

Dr. Rosenberg: I think patients who have baseline uncontrolled hyperglycemia are people that you have to either watch carefully or else pick a different treatment, get it managed. Often, you don’t have enough time to get that happening before you have to start therapy in a metastatic patient. People with very severe peripheral neuropathy at baseline are people where EV is probably prohibited. Maybe you might get a dose or 2 in, but you might probably have to stop very quickly. I think those are 2 obvious patient populations where you would have to think twice about giving EV/pembrolizumab. For those people, the maintenance strategy is not a bad approach. It’s not that you’re saying they can’t get treatment; it’s just that they may be better off served by treatment that may not have as much risk to them.

But I do think that early monitoring of patients on EV, either as single agent or in combination, is really important. I think in a lot of practices, maybe people don’t get seen on day 8 when they’re getting their EV or they don’t get seen on cycle 2 day 8. During that time, bad things sometimes happen; it’s not common. But my feeling is, early management of rashes can abort something more serious either by dose reduction or skipping doses. Or if you have a good dermatologist, having them see a dermatologist and come up with a treatment strategy for the rashes. I actually think that we need some real investigation about what’s the underlying mechanism of the rash beyond Nectin-4 in the skin and MMAE [monomethyl auristatin E] deposition, whether there’s other certain cytokines that can tell you should pursue this treatment strategy or a different way. None of that is really happening in a systematic way at the moment, unfortunately. Early intervention, I do think can save lives from toxicity with EV.

Dr. O’Donnell: Great points.