EV/Pembro and New Treatment Options for Metastatic Bladder Cancer

A roundtable moderated by Karine Tawagi, MD, of the University of Illinois, featured discussion on the treatment landscape of muscle invasive and non-muscle invasive bladder cancer.
Panelists Petros Grivas, MD, PhD, of Fred Hutchinson Cancer Center, and Vadim Koshkin, MD, of the University of California, San Francisco discussed some of the latest practice-changing trials in the treatment landscape, as well as the potential of bladder-sparing treatment approaches and the use of ctDNA.

In the final part of this roundtable, Drs. Koshkin and Grivas discuss what populations they believe are ineligible for treatment with enfortumab vedotin plus pembrolizumab, and discuss other new treatments for metastatic bladder cancer.

Watch this roundtable session from the beginning: The Evolving Treatment Landscape of MIBC and NMIBC

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Dr. Tawagi:
I know actually, when we were at ASCO GU, we were all on a panel together and we briefly talked about in the metastatic space, EV-302 has become the standard of care. In what populations do you think that somebody is ineligible for EV/pembro?

Dr. Koshkin:
Yeah. I mean, I would say the ability to use EV/pembro now that it’s approved, that it’s been approved in the US for almost a year now, full approval. It just now received approval in Europe, so it’s really going to be available in much of the world. I would say that it really expanded the proportion of patients that we can give it to. So relative to, for instance, cisplatin gemcitabine, which is probably about half or just under half of front-line metastatic patients that we can give it to. Really the major contraindication for me is significant neuropathy, right? So patients with grade 2 neuropathy, you really think twice about giving enfortumab and technically you probably shouldn’t. Now these patients are treatment naive. A lot of the patients we see who get neuropathy or who have neuropathy are those who have had it from prior platinum-based therapy.

But of course there are other reasons as well. So patients with significant and advanced diabetes obviously can have significant peripheral neuropathy as well. So that’s a population where I really maybe would be cautious about giving EV/pembro to. The other population that is often brought up is actually patients with diabetes and they are actually I think as long as you’re going to watch their sugars closely and have the diabetes under good control, I don’t think that EV/pembro is technically a contraindication. And then really poor risk or poor performance status, I should say patients so ECOG-III or sort of north of that, then yeah, you want to maybe consider also dose reduction enfortumab and consider whether you can give this combination. But really I think this combination treatment is so effective that even many patients with poor performance status, their poor performance status isn’t many frequently due to the cancer that they have.

And so actually you can actually improve it by giving them treatment that works and this is treatment that works. And yeah, you alluded to the UNITEs, our retrospective UNITEs study earlier. We do have data that patients, well, this is with single-agent EV, but even patients with performance status of three can get the drug and do reasonably well with it. So this is in the real-world setting. So yeah, so for me, yeah, it’s a pretty broad proportion of patients I would give this to. Really just those that maybe I wouldn’t consider for chemotherapy at all that we wouldn’t give the combination to.

Dr. Grivas:
I agree. I think it’s all this amazing discussion and I say amazing because it’s a good problem to have, to have options for the patients. And a few years ago we had, back when you started your fellowship, we had platinum-based chemotherapy and maybe a taxane and that was it. And now we have an embarrassment of riches. We have more salvage options in metastatic urothelial carcinoma maybe some colleagues in other cancers have, even more common cancers. So I think it’s amazing to see the progress made in the field. And as Vadim pointed out, pembrolizumab enfortumab is I think the most exciting and most effective regimen we have seen in metastatic disease. We’re awaiting date in the new adjuvant setting, I think the data from EV-103 and EV-302 are so strong.

Of course there are some caveats about the proportion of patients in the chemotherapy control group who many of them did not have access to enfortumab and that probably this huge delta in the OS case may have been smaller, but still it’s definitely practice changing trial, EV-302 and I have adopted using pembro/EV in the vast majority of my patients. As Vadim said, I think this is tremendous. The question is are there any patients who may not tolerate it? You pointed out Vadim grade 2 high neuropathy. That’s a challenge. So it’s a definite discussion with the patient quality of life considerations, uncontrolled diabetes, we don’t really know, to be honest, because these patients were excluded from the trial. That does not mean that they may not benefit, they may still do, but they need an extra close follow up. That’s a discussion with the patient and endocrinology, primary care provider, optimized diabetes control.

Ideally optimize that and give the patient the option if possible. But it’s an open question. We need data, and I will go back to UNITE that Vadim is leading. It’s a great registered perspective that discusses those questions and we saw some data from ESMO just a few weeks ago that patients with diabetes mellitus and neuropathy could receive EV/pembro and with very close follow up they can do well. We have to be very vigilant of course, and evaluate for any potential adverse events and be able to adjust. A couple of more points. I think the other question is patients with poor performance status, that’s a big question, whether they’re candidates for any therapy. Or sometimes you’re thinking very frail, occupiers of close two to three, could you do pembro alone? Could you sneak in a little bit lower dose of EV? Hard to tell, it’s a case by case discussion. The other population for extra attention is liver cirrhosis.

There’s some discussion about metabolism with those patients. Again, extra attention, extra discussion. I think we need consensus criteria that can be broadly discussed to have this dialogue, I think to develop those criteria. Vast majority of patients get it, and I mean pembro/EV. The last point I will make is we have some data from Dr. Petrylak at ASCO a few months ago that they saw that the higher dose, that 1.25 mg per kg, the standard dose I would say of EV starting correlates with higher response rate, but subsequent dose adjustments because of toxicity are okay and they should be done because of toxicity and did not compromise outcomes. So it gives reassurance that it’s okay to those adapt those reduce those hold if you need to discontinue EV because of toxicity.

Dr. Tawagi:
Right. I think that was really impactful data to be reassured that even if we encounter a situation where patients need to be dose reduced, we can still maintain some durability of responses in a lot of patients. Well, this was such a wonderful discussion. I really enjoyed speaking with both of you. I’m excited for all the Uromigos updates this weekend to hear more about bladder cancer updates and thanks for being here.