Enfortumab Vedotin and Pembrolizumab Among Patients With Advanced Urothelial Cancer in the First-Line Setting

Results From the EV-302 Trial 

Thomas Powles, MBBS, MD, Barts Cancer Institute at Queen Mary University of London, UK, shares results from the EV-302 trial. This was a phase 3, global, open-label, comparing enfortumab vedotin and pembrolizumab with chemotherapy among patients with previously untreated advanced urothelial carcinoma.

In this trial, treatment with enfortumab vedotin resulted in significantly better progression-free survival (PFS) and overall survival (OS) than chemotherapy for this patient population, with a safety profile consistent to previous reports. 

Transcript:

Hello, I'm Tom Powles. I'm an oncologist from London at Bart’s Cancer Center. I'm going to talk to you today about the combination of enfortumab vedotin and pembrolizumab in urothelial cancer. We've combined the 2 drugs together to give, I think, transformative results in the frontline setting in metastatic disease. They're gonna be further studied in the muscle-invasive setting. It’s a very exciting time for this combination. 

Enfortumab vedotin is an antibody drug conjugate (ADC), targeting NECTIN4; MMAE [monomethyl auristatin] is the payload. It's a really active agent, with single-agent response rates in heavily pretreated patients of about 40%. Pembrolizumab is a PD-1 inhibitor. It's got response rates in pretreated patients of about 20%. When you combine the 2 drugs together, in the frontline setting in cisplatin-ineligible patients, the response is about 70%. Which is higher than we've seen for chemotherapy, gemcitabine-cisplatin, may be about 45%.

We did a randomized phase 3 trial of enfortumab vedotin plus pembrolizumab until progression vs chemotherapy, gemcitabine-cisplatin or gemcitabine-carboplatin, in frontline, metastatic urothelial cancer. It was all-comers, irrespective of histology, sites of disease, NECTIN biomarker, PD-L1 status. It was an all-comer trial, with about 880 patients.

The randomized phase 3 results showed a 55% reduction in the risk of progression and a 53% reduction in the risk of death, a hazard ratio of 0.45 and 0.47 respectively. These are highly statistically significant. The median progression-free survival, about 12 months., and median overall survival, 31 months at the moment. There’s some immaturity at the tail of that curve, and it is probably going to end up more like 35 months, I suspect, in later data cuts. The control arm performed well, as well as can be expected, 31% of patients in the control arm received maintenance avelumab, which is actually relatively high. 

Overall, we can say there's a lot of activity from a PFS and OS perspective, but also we had response rates of 68%, complete response rates of 29%. We've not seen that previously. The efficacy package is really impressive. 

When you look at adverse events, chemotherapy, grade 3/4 adverse events, about 70%. For enfortumab vedotin and pembrolizumab, 56%. Chemotherapy is not well tolerated and we know about neutropenic sepsis and nausea and other problems with that. Enfortumab vedotin and pembrolizumab, the toxicity profile is different. Skin rash, particularly during the first 3 or 4 cycles, peripheral neuropathy which can accumulate with time. It has other side effects as well, it can cause transaminitis, hypoglycemia. So there's lots of education and training required around the adverse events, particularly as we go on with the drug over a longer period of time. But overall, in my experience, the drug combination is relatively easy to give and particularly dealing with initial skin rash and subsequent peripheral neuropathy requires some training.

In conclusion, I think it's fair to say that these results are transformative. I don't think we're going to be using gemcitabine or gemcitabine-carboplatin that much in the future. I think patients are going to be getting enfortumab vedotin and pembrolizumab instead. I think the concept of cisplatin eligibility is going to become a lot less relevant in this setting. I think probably there'll be more patients who will want to have enfortumab vedotin and pembrolizumab than platinum-based chemotherapy. Many people feel gemcitabine-carboplatin wasn't that great and associated with toxicity. I think many patients will want to have enfortumab vedotin and pembrolizumab.

I think the next step of questions is EV-303 and EV-304, in the neoadjuvant setting, looking at enfortumab vedotin and pembrolizumab versus gemcitabine-cisplatin in the neoadjuvant setting, enfortumab vedotin and pembrolizumab versus cystectomy in the neoadjuvant setting, in cisplatin-eligible and -ineligible patients, respectively. My feeling is those results are probably going to be positive as well, I suspect. And then we looked at other ADCs and there are a whole series of other ADCs coming through in the future. 

It’s an incredibly exciting area in my opinion in urothelial cancer. I think we've transformed the frontline space — I think there's more to be done in the perioperative space. And I've started to use this as a standard treatment.

Source:

Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. Published online March 7, 2024. doi:10.1056/NEJMoa2312117