Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here today with Dr. Jonathan Rosenberg, who is a professor and the Chief of the GU Oncology service at Memorial Sloan Kettering Cancer Center. Thank you so much for being here with me today.

Jonathan Rosenberg: It's my pleasure. Thank you so much for having me.

Alicia Morgans: Wonderful. So I wanted to talk with you, Jonathan, about EV-302, and the subgroup analyses that were presented at GU ASCO because I really think it's important for us to dig in and understand the effectiveness of the combination of enfortumab vedotin, or EV, and pembrolizumab across the different subgroups that we might face in clinical practice. Can you please tell us a little bit about this?

Jonathan Rosenberg: It's my pleasure to talk today about the pivotal data and subgroup analyses from EV-302. Just to refresh people's memories, EV-302 was a randomized Phase III trial in untreated metastatic urothelial cancer patients who were eligible for platinum-based chemotherapy. Patients were randomized one-to-one to EV/pembrolizumab as doublet therapy, or to gemcitabine and platinum chemotherapy, either cisplatin or carboplatin depending on what they were eligible for. The primary endpoints of the study were progression-free survival by blinded independent central review, as well as overall survival.

This study was regardless of cisplatin eligibility, and so, patients who were not cisplatin-eligible were enrolled and were randomized. The original data was presented at ESMO in 2023, prompting a standing ovation, showing a dramatic improvement in progression-free survival, with a risk of progression or death reduced by 55%. The hazard ratio was 0.45; you see the curves. EV/pembro in the dark purple or black, and chemotherapy in the gray line, showing a very high progression-free survival. In fact, doubling, 12.5 months versus 6.3 months.

And the results of overall survival were also shown, with chemotherapy almost doubling the overall survival of patients treated with chemotherapy by enfortumab. 31.5 months for EV/pembro, and 16.1 months for patients receiving chemotherapy.

These data have been transformative in combination with the fact that the response rate is very high, 67% with the combination, and 29% of patients with complete responses has really transformed the field and how we think about treating advanced urothelial cancer. However, one of the questions that remains is, are there people who really don't benefit the same way from EV/pembro compared to chemotherapy? And are there particular subgroups based on patient characteristics that should be treated differently? And so, this data was reported and updated at ASCO GU in 2024. And looking at overall survival, we saw that as far as cisplatin eligibility, which has been our benchmark for classifying patients with metastatic urothelial cancer for many years, that it really doesn't matter if you're cis-eligible or cisplatin-ineligible. And in fact, perhaps if you're cisplatin-ineligible, there may be even a little more benefit to receiving EV/pembro, probably because gemcitabine and carboplatin is inferior therapy compared to cisplatin. But the hazard ratio is 0.43, or 0.53, depending on whether you're cis-ineligible or cis-eligible.

Similarly, PD-L1 status, which we've been debating for several years in urothelial cancer with checkpoint inhibitor therapy, really doesn't matter in patients treated with EV/pembro. We see the hazard ratio of 0.49 for CPS high, and a hazard ratio of 0.44 for CPS low. Really breaking through these barriers, breaking through these boundaries that we thought were really written in stone in advanced urothelial cancer.

Moving on to sites of disease, we also see that the presence of liver metastasis in combination therapy with EV/pembro shows a substantially improved outcome in patients who have liver metastasis compared to those who don't. What we do see, though, is that when you look at the landmark survival analysis, the medians show that the overall survival is lower in patients who have liver metastasis compared to those who don't, showing that it is, in fact, still a negative prognostic feature, but that patients who receive EV/pembro do more than twice as well compared to those treated with chemotherapy.

Similarly, with visceral metastasis, although again, having visceral metastasis is a negative prognostic feature, there is a substantial improvement in overall survival, similar to the entire subgroup, and similar to the entire subset of patients, for patients if they receive EV/pembro, whether they have lymph node only or visceral metastasis.

And so, I think the take-home message here is that there really isn't a particular subset of patients that do not benefit. And the results for progression-free survival mimic this OS subgroup analysis, showing that progression-free survival has improved similarly in those patients.

And so, I wanted to stop there, and thank you for taking the time to see these slides.

Alicia Morgans: Thank you so much, Dr. Rosenberg, that was really, really helpful. And I think, as I think about all of the data you presented, about visceral metastasis, liver metastasis, specifically lymph node metastasis, it seems like this is really kind of a treatment for anyone. Are there any patients where you pause and say, "Maybe this is not the right therapy for you"?

Jonathan Rosenberg: I think the one group of patients which would have a problem are those who have severe peripheral neuropathy at baseline. And perhaps for those patients, the more conventional paradigm of gemcitabine and carboplatin followed by avelumab maintenance if they respond or have stable disease might be most appropriate.

And perhaps similarly, patients with poorly controlled diabetes who are at risk for more severe complications from EV/pembro due to hyperglycemia might also be another group where I might consider platinum-based chemotherapy. Although with the use of corticosteroids as part of antiemetic regimens, that can also be somewhat problematic in patients with diabetes that's poorly controlled. So for those patients, I probably would avoid EV/pembro as well, but it's not without risk otherwise.

Alicia Morgans: So essentially, just to boil it down, for the majority of patients, this is the right path forward rather than chemotherapy. And part of that is because at least the JAVELIN data required stable disease or better before we get the maintenance. And our newer data required cisplatin and gemcitabine versus, or with a checkpoint. And so these sort of stipulations are not required in this current algorithm, and may help more patients actually benefit from the combination. Is that what I understand?

Jonathan Rosenberg: That's very fair. I think the combination of gemcitabine/cisplatin/nivolumab is very interesting, in that the patients who have complete responses do extraordinarily well. The problem is, you can't pick those patients out in advance, so you have to treat everybody. The majority of patients will have outcomes that are worse than you might expect with gemcitabine, but then with enfortumab and pembrolizumab, and you don't get a do-over when you're treating metastatic urothelial cancer. And so, I think until we have better options, enfortumab vedotin and pembrolizumab is the best option for patients who have this very difficult to treat disease. And again, it appears to blow apart our traditional categories, in terms of prognostic features for patients with advanced disease.

Alicia Morgans: Really important. And I think as future information helps us understand, perhaps via biomarkers, that this patient population is going to do extraordinarily well on gem/cis/nivolumab, this might be an option. And also, of course, in Europe, where we don't actually have the combination approved, or in other parts of the world, that combination of gem/cis/nivolumab may still be a great option, as the JAVELIN regimen also may be a really important option. So if you had to talk about clinical implications, in the clinic tomorrow, what would your message be to listeners as you're thinking about subgroups and sort of making those clinical choices?

Jonathan Rosenberg: I think it's pretty easy in many ways, right? There's not a subgroup that particularly does better or worse per se with EV/pembro, compared to any other subset of patients with advanced urothelial cancer. And so, for those patients who are eligible for EV, again, people without severe peripheral neuropathy, probably without poorly controlled diabetes, anyone else is a good candidate. There are risks of very severe early toxicities with enfortumab, very small risks, but they're real. In terms of severe skin rashes, hyperglycemia that's difficult to manage, and even very rare cases of things like metabolic acidosis, which are often life-threatening and have been occasionally fatal.

But we also know that the toxic death rate from chemotherapy is about 1%, and probably not very different with enfortumab and pembrolizumab. It's just that the spectrum of side effects is different between the two regimens. And something we didn't talk about so much is really understanding how to manage the side effects of EV and pembro is very important as you're taking care of these patients. And seeing patients regularly early in therapy really provides an opportunity to intervene if you see toxicities, such as significant skin toxicity, arising in those patients.

Alicia Morgans: Well, and just to that point in the minute we have left. I have found, especially when we talk about skin toxicities and neuropathy, these are things that we want to be really proactive about. Any guidance there for clinicians who are trying to even newly integrate EV into their treatment plans?

Jonathan Rosenberg: A few pieces of advice I think are notable. First, it's okay to skip a dose or lower the dose of EV if you are concerned about a patient. And that may be a way to forestall more serious toxicity. Making a good friend of a dermatologist is also helpful. Liberal use of topical steroids for rashes is important. We see a lot of skin rashes, most of which are very minor, but once in a while can be much more difficult to manage. And you really have to be able to access someone who has some expertise in dealing with this if you can.

In addition, the neuropathy is something that's cumulative over time, and many patients who experience it are actually the ones who are responding. We do know that the median number of cycles received with enfortumab in the study was about seven to eight. And so, people don't necessarily need to be maintained on enfortumab forever, although still, the optimal duration of enfortumab therapy is unclear. There are some patients who are able to tolerate it for very long periods, either by minimizing the neuropathy they have, or not developing it, if they're lucky. And so, understanding who's at risk for that, I think, is an important research question for the future.

I find that physical therapy for patients is often helpful in minimizing the negative effects of neuropathy. It doesn't eliminate the problem, but it helps with balance, gait, and strength in their lower extremities, such that they don't become debilitated by the negative side effects of enfortumab.

Alicia Morgans: I couldn't agree more. And I think, should they experience these effects, sometimes it can be really helpful in reversing some of them as well.

I so appreciate your time and your expertise. Final words before we close?

Jonathan Rosenberg: I think we're in exciting times in bladder cancer. We now have to figure out what we do next and how we improve on the success we've already seen, and figure out the optimal sequencing of therapy. So more to come in future talks.

Alicia Morgans: Wonderful. Well, we love having future opportunities to talk with you, Dr. Rosenberg, and so much appreciate the time and expertise you've spent today. Thank you.

Jonathan Rosenberg: My pleasure.