Dr. Jonathan Rosenberg on Whether EV Should Be a New Standard of Care for mUC

Jonathan Rosenberg, MD, Memorial Sloan Kettering Cancer Center, explains the data that has led to FDA accelerated approval of enfortumab vedotin in combination with pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma, how the combination is being investigated in clinical trials today, and how its toxicity profile compares to the current standard of care.

Prior to the EV-plus-pembrolizumab approval, what treatment options were available for patients newly diagnosed with metastatic urothelial carcinoma who were ineligible for cisplatin-based chemotherapy?

Dr. Rosenberg: For patients who had metastatic disease when they were diagnosed, the standard option would be gemcitabine and carboplatin for almost all patients who were not eligible to get cisplatin-based chemotherapy. The historical data goes back to a study from Europe where the median survival was about 9 months, and the response rate was in the mid-thirties in terms of objective responses. These were really not very good outcomes for those patients who tend to be a little frailer with some more comorbidities.

More recent studies have shown that gemcitabine and carboplatin with modern supportive care and maybe just better care overall, might be a little longer than that, maybe 12 to 14 months. But even so, still not a great number. Most patients would be falling into about a year range in terms of longevity. With maintenance therapies, with immunotherapy, that number’s probably now longer than that because of the introduction to maintenance avelumab, but still maybe in the 18 to 20 month range at the most is my guess.

What does the data tell us about outcomes for patients receiving the new combination?

Dr. Rosenberg: The first trials that got enfortumab vedotin approved were based on phase 1, 2, and then ultimately phase 3 data, in patients who had PD-1, PD-L1 refractory and platinum refractory disease or platinum experienced and PD1 experienced. In this context, the response rate was in the low-forties, which in a refractory setting is pretty impressive. The median survival was a little over a year or maybe 13 months in those studies. The randomized phase 3 trial, EV-301, showed that in fact it was better than standard chemotherapy in that setting, in the refractory setting. And all of that data plus data understanding the interaction of the immune system with antibody drug conjugates led to the design of EV103, which is the study that led to the accelerated approval of the combination of EV plus pembro.

It was a multi cohort study looking at different combinations of treatments, not just EV and pembro, but in some cohorts, adding chemotherapy to that combination or EV plus chemo without pembro. But the real winner in all of that was the enfortumab and pembrolizumab combination where the first cohort of that study, cohort A, along with the phase 2 dose of the phase 1 part of it, dose escalation/cohort A, showed that 73% response rate, which really blew all of our minds at the time. The follow-up data has shown that this appears to be quite durable, that the median and duration response was 25 months in 73% of patients. So, 73% of patients had not progressed, half of them had not progressed until 25 months, which is an extraordinary number.

The median survival was 22 months compared to 9 to 12. And so that led to cohort K, which was the randomized study that led to the FDA approval, which was for the accelerated approval of EV pembro or EV monotherapy in metastatic cisplatin-ineligible, untreated metastatic disease, with urothelial cancer and showed very similar results with a response rate of 64.5%. The duration of response was not reached, and the median survival data’s not mature, but over 20 months. When combining cohort A and cohort K, you get a response rate of 68.5%, which again, in a cisplatin-ineligible population who might not get really great therapy, appears to be quite an improved outcome compared to historical data.

How is this combination being further investigated in clinical trials today?

Dr. Rosenberg: There’s a large randomized phase 3 study called EV302, which is comparing EV pembro to gemcitabine and platinum, either cisplatin or carboplatin, depending on what the patient’s a candidate for. That study is to confirm the results and hopefully to lead to full approval as opposed to accelerated approval and also lead to worldwide approval of the combination. We’re hoping to see those results in the next year, year and a half. My expectation is that the data will support the full approval based on what we’ve seen in a sicker, less fit patient population, though we haven’t beaten cisplatin yet in advanced bladder cancer. We’ll see where this study ends up reading out.

In addition to that, there are two other phase 3 trials that are ongoing. One of them is in cisplatin-eligible patients who have muscle invasive bladder cancer. This is locally advanced disease or locally invasive disease, randomizing them to either chemotherapy with gemcitabine and cisplatin or enfortumab vedotin and pembrolizumab as neoadjuvant combination therapy. There is a postoperative adjuvant period for patients who are getting the experimental arm. The second study is for patients who can’t get cisplatin in the perioperative setting. They’re randomized to either EV plus pembro followed by surgery are just going straight to surgery.

Those two trials might extend the indication all the way to locally advanced muscle invasive disease that is resectable. In fact, before the first line setting, this could increase cure rates, preventing people from developing metastases. It may eventually be that this is a treatment for stage 2 and 3 disease in addition to stage 4 disease.

How does the combination’s toxicity profile compare to the current standard of care?

Dr. Rosenberg: It’s a very different type of toxicity profile, and I don’t want to minimize the toxicity of EV and pembro. I think that at times, it can be a very difficult regimen. There’s a fair amount of skin toxicity with skin rashes. Very rarely, you get life-threatening skin reactions. With EV alone, and probably not more with EV pembro, but still because enfortumab is in the mix, it happens. You have a little bit more pneumonitis than perhaps with enfortumab alone or pembro alone, but you don’t have a lot of cytopenias, low blood counts, that you get with gemcitabine and carboplatin, which reduces the ability to give the treatment. Patients often are able to stay more on schedule from a blood-count perspective with EV plus pembro, but they may encounter other sort of immune-related toxicities or enfortumab-related toxicities.

One of the issues that might preclude someone who is cisplatin-ineligible from receiving enfortumab is that if they have significant peripheral neuropathy. Enfortumab will probably make that a lot worse, as time goes on. Those patients may not be the optimal candidates. There is some evidence that people with very poorly controlled diabetes may not do that well within enfortumab until you control their diabetes, and then it may be safe. But, we know that enfortumab and enfortumab and pembro can cause some serious hyperglycemia, once in a blue moon, requiring an ICU stay.

There are some patient categories that gemcitabine and carboplatin might be better suited, at least initially. But, the toxicity profile is probably simply different rather than necessarily easier.