Enfortumab Vedotin Plus Pembrolizumab: Results of the EV-302 Trial With Thomas Powles, MD, MBBS, MRCP

In this interview, Thomas Powles, MD, MBBS, MRCP, Director of the Barts Cancer Center in London, sat down with Oncology Data Advisor to discuss the results of the EV-302 trial, a phase 3, open-label investigation of enfortumab vedotin plus pembrolizumab for previously untreated locally advanced or metastatic urothelial cancer.  

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, I have the honor of being joined by Dr. Thomas Powles to discuss the results of the EV-302 trial. Dr. Powles, thank you so much for coming on today.

Thomas Powles, MD, MBBS, MRCP: Thank you for inviting me.

Oncology Data Advisor: To start off, would you like to introduce yourself and tell us about what your work and your research focus on?

Dr. Powles: I’m Tom Powles. I’m a Professor of Urology Cancer and I’m the Director of the Barts Cancer Center in London, and I do clinical trials in urology cancers, particularly urothelial and kidney cancer.

Oncology Data Advisor: Awesome. I’m excited to talk with you today.

Dr. Powles: Nice to talk to you too.

Oncology Data Advisor: For background, how has enfortumab vedotin been used in urothelial carcinoma previously, and what is the EV-302 trial investigating?

Dr. Powles: Enfortumab vedotin is an antibody-drug conjugate. Antibody-drug conjugates are a new class of cancer drugs. Essentially there are three components: there’s an antibody, a linker molecule, and a payload. Cancer cells overexpress a number of proteins. The antibody targets those proteins and therefore attaches itself specifically to the cancer cell, a bit like a homing missile. The molecule is then internalized and the linker molecule then removes the antibody from the payload, which releases the payload into the cancer cell. That payload then destroys the cancer cell by different mechanisms depending on how that works. Enfortumab vedotin is a great example of an antibody-drug conjugate. It targets Nectin-4. Nectin-4 is overexpressed in 98% of urothelial cancers, and MMAE is the payload, which is a microtubule-disrupting agent. So, essentially you are delivering high concentrations of MMAE into bladder cancer cells and sparing the vast majority of the rest of the body.

Now, MMAE is also expressed in other areas like skin, and therefore the toxicity profile of antibody-drug conjugates often follows the distribution of where the antibody is targeting. The drug is in development.I’m going to talk today about a big, randomized phase 3 that was positive, but enfortumab vedotin has been explored in a number of trials previously in urothelial cancer. Previously it’s been explored predominantly in an area of heavily pretreated patients, and those patients have been pretreated with chemotherapy and immune therapy, which is a standard-of-care. Classic chemotherapy, historically, is associated with about 10% response rates in those heavily pretreated patients. Phase 1 and phase 2 trials showed that enfortumab vedotin was associated with a 40% response rate. That’s much higher than we expected. The toxicity profile was manageable. The toxicity profile focused on skin toxicity, peripheral neuropathy, and hyperglycemia as three adverse events of special interest, and they continue to be adverse events of special interest. That prompted a randomized phase 3 trial of enfortumab vedotin versus chemotherapy in this heavily pretreated population.

The results of that randomized phase 3 trial showed a 30% reduction in the risk of death and confirmed that 40% response rate. Therefore, enfortumab vedotin as a single agent became a standard-of-care. Intriguingly, in parallel, the drug was being combined with pembrolizumab, which is an immune checkpoint inhibitor. Pembrolizumab also has activity in urothelial cancer. It’s well tolerated, and it appears that when you combine these two drugs together, unlike when you combine chemotherapy in bladder cancer, you don’t get antagonism. The two drugs seem to play well together, and you don’t get any immune suppression from the enfortumab vedotin with the pembrolizumab. Therefore, the two together have response rates in the frontline setting in previously untreated patients of 68%. This was much higher than chemotherapy. Classic chemotherapy had response rates of about 45%. So, looking at this 68% versus 45%, we hypothesized that we could beat front-line chemotherapy with a combination of enfortumab vedotin and pembrolizumab.

We did one more experiment before we launched the randomized phase 3 trial, and that’s a study called Cohort K which Jonathan Rosenberg led. In that trial we tested single-agent enfortumab vedotin versus the combination of enfortumab vedotin and pembrolizumab in previously untreated patients to prove that you needed to add the second drug. Otherwise, you’d say, why not just give them enfortumab vedotin and maybe pembrolizumab at some point in the future? In that randomized phase 2 trial, we clearly showed a higher response rate and more durable responses with a combination of the immune checkpoint inhibitor and enfortumab vedotin versus enfortumab vedotin alone.

In summary, we have a really active single agent in heavily pretreated patients. We have proof that the addition of pembrolizumab, which is also active, to enfortumab vedotin is better than the drugs by themselves. Therefore, we hypothesized that if you compare enfortumab vedotin plus pembrolizumab to standard chemotherapy, which is the current standard-of-care, gemcitabine/cisplatin or gemcitabine/carboplatin with or without maintenance of avelumab, we would have higher response rates, longer progression-free survival, and longer overall survival. That is the crux of EV-302.

Oncology Data Advisor: Fantastic. Thank you so much. That was really helpful for understanding the mechanism of action and how enfortumab has been used. What were the efficacy results of the EV-302 trial that were just announced in the press release this week?

Dr. Powles: EV-302 is a large, randomized phase 3 study. It enrolled a large number of patients, as you would expect in a big, randomized phase 3 of patients who were previously untreated in the frontline metastatic or advanced setting with urothelial cancer. All patients had to have a histologically proven component of urothelial cancer, often known as bladder cancer. They also had to have a good performance status. They could not have had previous chemotherapy or immune therapy in the metastatic setting, although some patients were allowed to have chemotherapy in the perioperative setting at the time of surgery. These patients had no contraindications for enfortumab vedotin, pembrolizumab, or chemotherapy. We enrolled over 800 patients in a 1:1 manner. We had primary end points of progression-free survival and overall survival. We also tested response rate.

The trial recruited over a number of years; it’s a multi-site, so over 200 sites around the world, and the results of the trial showed a striking progression-free and overall survival advantage, which are clinically meaningful. We also showed higher response rates. The data showed that the combination was tolerable and in line with expectations from previous combinations, which I described previously. We focus on these adverse events of special interest. The combination was active, and we feel it’s practice-changing.

Oncology Data Advisor: That’s amazing. Thanks so much for explaining the results. So, you mentioned it’s practice changing. What do you think these results will mean for the continued use of enfortumab as time goes on?

Dr. Powles: So, my feeling is, and the feeling of my co-investigators, that these results are transformative. The historical treatment with gemcitabine and platinum-based chemotherapy has been around for a generation—since 40 years ago—and it hasn’t been beaten previously. This is the first time that a new combination in unselected patients has an overall survival advantage in the first-line metastatic setting that’s not been done previously. We’ve used immune checkpoint inhibition; currently the standard is as a maintenance therapy after chemotherapy. It’s important to recognize a high proportion of patients who took part in this trial in the control arm also had that maintenance therapy. Even with that, we showed significant overall survival and progression-free survival with tolerable results. Overall, these transformative results will supersede chemotherapy in the relatively near future, in my opinion.

Oncology Data Advisor: That’s amazing. Are there any next steps for the trial or are there further analyses planned?

Dr. Powles: The answer is there are a number of next steps to the study, and in the data which we plan to present, we’ll look at the patients’ characteristics, of course, the primary end points of the trials, but there are other end points where we can look at subsets of patients. That includes those patients with immune-type biomarkers, also subsets of bone metastasis or visceral metastasis to see how they got on with the combination versus chemotherapy. There’s a whole string of biomarker data which we can look at to try and identify the patients who benefit the most. Although, I have to say, as I said previously, this was a trial which benefited broad subgroups of patients. And then, of course, it’s important to recognize that there are a number of other trials within enfortumab vedotin and pembrolizumab. The trials that I’m particularly excited about are those in the perioperative space.

So, I’ve talked about frontline metastatic disease, but there are also patients, at the time of having their cystectomy and operation, who also can have neoadjuvant therapy, and there are trials comparing neoadjuvant chemotherapy with enfortumab vedotin and pembrolizumab. If those trials reproduce the results of EV-302, it’s likely that this combination will not just supersede chemotherapy in the metastatic space but will also supersede chemotherapy in the perioperative space. Also, I have to tell you that there are early phase 1 trials looking at enfortumab vedotin intravesically, so being squirted into the bladder, and those trials are also really exciting. So, there’s a plethora of different studies exploring the combination, and I think this is transformative in metastatic disease, but I think it will translate earlier in the disease setting as well.

Oncology Data Advisor: Great. That’s really exciting to hear about all these avenues being explored, and I look forward to hearing results as time goes on.

Dr. Powles: Fabulous.

Oncology Data Advisor: Thank you so much again for coming on today. It was wonderful to hear about these results of the trial and thank you again for your time.

Dr. Powles: It was kind of you to invite me. Thank you.

About Dr. Powles

Thomas Powles, MD, MBBS, MRCP, is a Professor of Genitourinary Oncology and the Director of Barts Cancer Centre at St. Bartholomew’s Hospital, in London. Dr. Powles is also the Lead for Solid Tumor Research at Barts Cancer Center. His main research interests revolve around determining correlation of novel biomarkers in genital and urinary cancers, where he takes an active role in phase 1 to phase 3 clinical trials, of which he has over 100 peer-reviewed papers on these topics.

For More Information

Hoimes CJ, Flaig TW, Milowsky MI, et al (2023). Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol, 41(1):22-31. DOI:10.1200/JCO.22.01643

Seagen (2023). Padcev® (enfortumab vedotin-ejfv) and Keytruda® (pembrolizumab) significantly improve overall survival and progression-free survival in patients with previously untreated advanced bladder cancer in pivotal phase 3 EV-302 trial [news release]. Available at: https://investor.seagen.com/press-releases/news-details/2023/PADCEV-enfortumab-vedotin-ejfv-and-KEYTRUDA-pembrolizumab-Significantly-Improve-Overall-Survival-and-Progression-Free-Survival-in-Patients-With-Previously-Untreated-Advanced-Bladder-Cancer-in-Pivotal-Phase-3-EV-302-Trial/default.aspx

Transcript edited for clarity. Any views expressed above are the speakers’ own and do not necessarily reflect those of Oncology Data Advisor. 

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