EV-302 Follow-Up Reinforces Shift in Frontline Urothelial Cancer Pathways

In this interview, Dr Thomas Powles discusses how updated results from the EV-302 trial confirm that enfortumab vedotin plus pembrolizumab significantly improves survival and response rates compared to standard chemotherapy in first-line metastatic urothelial cancer, establishing a new standard of care.

Thomas Powles, MBBS, MD: I'm Dr Thomas Powles. I'm an oncologist from Barts Cancer Institute in London. What were the key objectives and outcomes of this study?

Dr Powles: The EV-302 study is a randomized phase 3 trial comparing the combination of enfortumab vedotin (EV) and pembrolizumab with standard platinum-based chemotherapy in frontline metastatic urothelial cancer.

The background and purpose of the trial were to try to see if this combination could outperform standard chemotherapy, which had been the standard of care for 40 years.  Enfortumab vedotin is a Nectin-4-targeted antibody-drug conjugate (ADC). It has monomethyl auristatin E (MMAE) as the payload and has exceptional single-agent activity in urothelial cancer.

Pembrolizumab is a PD-1 inhibitor, an immune checkpoint inhibitor used widely across different cancers. The phase 2 data suggested great response rates, so we designed a trial with progression-free survival and overall survival as the primary end points. We randomized approximately 900 patients with first-line metastatic urothelial cancer—meeting all the standard criteria, adequate renal function, etc, classic first line metastatic urothelial cancer—to receive, in a 1:1 manner, either EV plus pembrolizumab or standard chemotherapy. EV plus pembrolizumab was continued until progression. Six cycles of chemotherapy were given, and about 30% of patients got maintenance avelumab after that.

The trial hit its primary end points to progression-free and overall survival. These data were presented about a year ago after about 13 months of follow-up. Here at American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, we gave updated survival data with 26 months of follow-up, an extra year of follow-up.

It's important to remember that standard-of-care median overall survival back in the day was about 12 months. In the control arm here, we showed 16 months, which is a longer period of time, obviously, so 26 months of median follow-up for this sort of trial is actually quite mature now. What we showed in this trial were results very consistent with the initial results. We showed progression-free survival hazard ratio with 0.47, 50% reduction in risk of progression, and hazard ratio for overall survival of 0.51, 50% reduction in the risk of death.

We showed a median overall survival of 34 months, nearly 3 years. When I started treating this disease, it was only 12 months. We've made huge progress in that respect. We showed complete response rates of 30%, which is unheard of in this disease previously, and response rates of 68% compared to 44% for chemotherapy. Subset analysis showed that EV plus pembrolizumab outperformed chemotherapy in all of the key subgroups, [including] platinum eligibility, visceral metastasis, and PD-L1 status, which is very reassuring.

We went on and looked at 2 subsets we haven't looked at before. We looked at duration of response and we showed that those responders—remember, it's 70% of patients who are responding—are progression free at 2 years. There is great durability for EV pembro. The complete responders, that 30% of patients, duration response is 75% of patients who are maintaining their response at 2 years. This is so different from what we saw before with chemotherapy, where patients initially responded and then they progressed.

We looked at some detail of the efficacy profile, but also the safety profile. What we showed from a safety perspective was consistent data with the initial data. We didn't show any new safety signals, and actually what we showed is that almost all the toxicities occurred during the first follow-up period.

It's fair to say that EV plus pembrolizumab until progression is associated with adverse events, but not more adverse events than chemotherapy. I don't think it's more difficult to give than chemotherapy; it's probably easier, 1 to 6 cycles, while one goes on for a longer period of time. Additionally, because the adverse events are different, early skin toxicity, for example, later peripheral neuropathy, less neutropenic sepsis, there's education and training associated with it.

Overall, it's fair to say that these additional 12 months of follow-up have made a big difference because we are now even more confident that EV plus pembrolizumab is significantly better across broad efficacy parameters than standard chemotherapy. Indeed, some may say twice as good—the new standard of care. Since the original presentation, it's received various approvals across the globe, and when I travel around the world and I speak to colleagues, they tell me what a big difference it's making for their patients.

How do these findings influence the long-term treatment strategy for patients with locally advanced or metastatic urothelial carcinoma?

Dr Powles: These data have an important role in informing patients on their long-term strategy. It's very clear that, given the choice, this would be the regimen under almost all circumstances that you would want to reach for. If you had a patient with extensive peripheral neuropathy, then perhaps it would be contraindicated. But the reality is, platinum-based chemotherapy as an alternative is not great for patients with neuropathy. That's pretty challenging.

Absolute contraindication to pembrolizumab is advanced liver dysfunction. EV is metabolized by the liver. So, there are some specific criteria you might look at and say, "Those patients should be looking at something else." But, again, for patients with poor performance status, patients with advanced liver problems, gemcitabine-cisplatin and gemcitabine-carboplatin are not really attractive options either. I don't think there are patients, from my perspective, where I'd be reaching for gemcitabine-carboplatin.

There are some criteria that have been described before, looking at trying to define patients that can't have EV plus pembrolizumab. Those criteria talk about things like renal dysfunction, other issues such as cardiac issues, or a history of corneal problems. They're not contraindications, in my experience, for EV or pembrolizumab, and I don't think those criteria are that helpful moving forward. It's more of a clinical decision. Indeed, for things like diabetes—dare I say it—at baseline, you probably have a better idea of controlling your blood sugar than if you don't. If you had unstable diabetes at baseline, yes, of course you might not want to give that patient EV plus pembrolizumab, but you wouldn't want to give them  gemcitabine-cisplatin either and put them into neutropenic sepsis with poorly controlled diabetes. That sounds dangerous as well.

It's about education, training, and management of toxicity—not predefining patients that can't have treatment at baseline. Again, as I travel around the world, when I speak to people and they change from chemotherapy to EV plus pembrolizumab, the feedback I'm getting is that it's well-tolerated in the vast majority of patients. It's preferable compared to platinum-based chemotherapy, which I see as becoming part of the past. That is really exciting.

Are there any other takeaways from this study that you would like to highlight?

Dr Powles: Some people say to me, "What do we do next with the study?" There are 2 or 3 things. We could get further clarity around subsequent therapies, which is important. We need to explore those patients whose cancers progressed after perioperative immune therapy. Is rechallenging with immune therapy in the context of EV plus pembrolizumab warranted? Those are 2 important questions.

The third question, which I'm often asked about, is, what about the rarer subgroups and the pure squamous? We need to learn more about that subgroup of patients, for example. Finally, how long should we keep going with therapy for? I feel that this is a very difficult question. I don't think we'll ever be able to do discontinuation trials, in my opinion. I feel that a year of therapy is too short, but I do feel that 5 years feels much too long.

There are some patients who want to keep going. Other patients seem to want to get into a deep, durable response and then stop coming to therapy for drugs because it's a day 1, day 8 regime and a 21-day cycle. It's a commitment, but when you look at that commitment in the context of the previous treatment being associated with median survivals between 12 to 14 months, then you look at that commitment and say, "That's probably worthwhile."

Overall, it’s a practice-changing, transformative regimen, consistent data with further follow up. Bits and pieces still to do, but we're moving the regimen into the perioperative setting. We're going to move it to muscle-invasive bladder cancer. We're going to cure a lot of patients there. It's a really exciting time in urothelial cancer.