Durability and Long Term Outcome of Enfortumab Vedotin + Pembrolizumab in the EV-103 Study in Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma – Terence W. Friedlander

July 29, 2021

In this discussion, Alicia Morgans and Terence Friedlander discuss updates from the EV-103 study. The EV-103 study is a phase one/two clinical trial that looked at the combination of enfortumab vedotin and pembrolizumab in, previously treated, patients with cisplatin-ineligible, metastatic urothelial cancer. Historically, cisplatin-ineligible metastatic urothelial cancer patients have had a very poor survival prognosis. However, the recent updates to the EV-103 trial data show a 73% response (partial and complete response) rate for patients with cisplatin-ineligible metastatic urothelial cancer. This 73% response rate far outshines response rates in past urothelial cancer studies, with it being a rarity to see response rates over 50%. The updates to this study go even further than response rate, with data that patients showed a median duration of response of over twenty-five months. As the conversation continued, Dr. Friedlander discussed an ongoing study into the synergistic effects of the two drugs, stating that the EV-103 study does not precisely show the individual contribution from enfortumab vedotin. As the pair concluded their conversation, Dr. Friedlander discussed his excitement for the results of the phase three trial, stemming from the EV-103 study.


Terence W. Friedlander, MD, Medical Oncologists, University of California San Francisco Medical Center, San Francisco, CA

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans, and I am an Associate Professor of Medicine and a GU Medical Oncologist at Northwestern University. I'm so excited to have here with me today, Dr. Terry Friedlander, who is the Chief of Hematology-Oncology at The Zuckerberg San Francisco General Hospital, as well as being an Associate Professor of Medicine at UCSF and the Associate Director of the Helen Diller Comprehensive Cancer Center, also at UCSF. Thank you so much for being here with me today, Dr. Friedlander.

Terence Friedlander: Thanks. It's my pleasure to be here.

Alicia Morgans: Wonderful. I wanted to talk with you about an amazing presentation that you had at ASCO 2021, where we really heard some updated results on EV-103. Can you share a little bit about what you discussed?

Terence Friedlander: Sure. So the EV-103 study is a clinical trial, basically, phase one/two clinical trial, looking at the combination of enfortumab vedotin, which is an antibody-drug conjugate recently FDA approved for metastatic urothelial cancer. Together with pembrolizumab, which is a PD-1 inhibitor and immune therapy, for patients who have cisplatin-ineligible, metastatic urothelial cancer, who are essentially treatment naive in the metastatic setting. And in this trial, we had a dose-escalation cohort as well as a dose-expansion cohort. And that is what the poster presentation covered at ASCO 2021. It was a total of 45 patients who received, basically drugged together as a three-week cycle, they got drugs on day one and day eight, you can refer to the poster to see the details. Overall, we accrued again, I said 45 patients, about a third of them, had liver metastases, and over 80% of them had visceral metastases.

So this was a fairly advanced population. And I should emphasize that these patients were cisplatin-ineligible, meaning they either had renal dysfunction or neurologic peripheral neuropathy, or other neurologic dysfunction that precluded the use of cisplatin. And this is traditionally a really poor prognosis group with median survivals of usually less than a year in this population. I think some of the most striking data was the response rate to this regimen. So the combination of EV and pembrolizumab had over 73% response rate, partial and complete response. Of that, 15% of patients had complete responses. So the [inaudible 00:02:16] type of disease entirely disappeared from scans by RECIST criteria. And that, to me, is very impressive. There are very few studies in urothelial cancer where we've seen response rates even above 50%, much less close to 75%.

Alicia Morgans: I completely agree. And I think the other metric that I also find really impressive is this disease control rate. So there were other patients who may not have met the criteria necessary for partial response, but who also had a disease that didn't seem to be progressive, right?

Terence Friedlander: Yeah. That's true. We had, as I said, almost 75% of patients had a partial response. 93% of patients had some tumor reduction on a scan, even if it wasn't [inaudible 00:02:58] burned by RECIST. In the poster we presented, the spider plot ... so we saw that almost all the responses happened early. So within the first imaging, in the first few months ... it was almost 90% of patients hadn't had their responses happen early. When we looked into the longer-term data, the patients who responded, which was the majority of patients on study, had a very long duration of response. So the median duration of response was over twenty-five months, over two years that patients were responding to this regimen and that is really unprecedented for urothelial cancer.

Alicia Morgans: Absolutely. Now tell me a little bit about how long, and perhaps you don't have this data ... how long out of those 25 months or whatever the duration was for an individual patient, how long did patients actually stay on therapy? And the reason I ask is that I have had some patients on EV who had to stop, for whatever the toxicity might be, that actually continued to have stable disease despite drug cessation. So I was just curious about that in this particular study.

Terence Friedlander: Yeah. So, the study allowed patients to get up to two years of therapy if they were able to tolerate it. But as you note, the major dose-limiting toxicity for most patients for enfortumab is actually peripheral neuropathy. It just sort of builds up over time and the payload ... I didn't mention this earlier, for EV is a drug called MMAE, monomethyl auristatin E, which is very similar to a taxane. So if you are using the drug, you can think of it like a taxane in many ways. So the neuropathy really limits dose, and in the study, the median cycle number received was nine cycles. So nine, three-week cycles. So just about half a year, but some patients were able to get up to 34 cycles. I think I actually had one of those patients myself who was able to stay on the study and that was very satisfying because the patient had a really excellent response.

So, a lot of patients in this study were able to continue the pembrolizumab as monotherapy, even after stopping the EV. So this sort of, to me, suggests that giving these two drugs together really makes us sort of a big bang at the beginning. And we may be able to sort of have that response sort of persisting over time. One thing the study doesn't tell us is what is the individual contribution of EV versus pembrolizumab? Is it one plus one equals two or is it a one plus one equals three? Are we getting synergy? And there is a currently accruing cohort to this study, cohort K, which is looking at trying to answer that question by accruing patients and randomizing them to either get EV alone as monotherapy or EV plus pembrolizumab, again for the same patient population in the frontline.

Alicia Morgans: And that will be so important because it seems almost like there is a synergy when I think about data for EV alone versus data for pembro. But of course, you can't know that unless you actually test. So I'm really glad that the team is moving that assessment forward. From your assessments and the work that you've done, are there any subgroups that seem to benefit more or less when you look at them within the context of this study? I know it's small. So....

Terence Friedlander: Yeah, so again, it is small. So it is a little hard to pick out specific subgroups from only 45 patients. We did see responses in patients with liver metastases, patients with visceral metastatic disease. I don't think we had enough patients to really say whether someone who had lymph node-only disease does much better with this combination than someone, for example, who has bone predominant disease. But I think that could be definitely explored in some of the bigger cohorts that are going to be presented. And certainly in the upcoming phase three study, the EV-302 study, which is looking at this combination, EV pembrolizumab compared to chemotherapy, standard of care platinum-based chemotherapy in the frontline setting.

Alicia Morgans: Great. Well, I certainly look forward to that. And as we wrap up just to confirm, were there any new safety signals, any concerns, AEs that were sort of new and newly identified in this report of this trial?

Terence Friedlander: Yeah, so there really weren't any new adverse events in this study that we've identified. And the safety profile seemed very consistent with what you would expect from each individual agent. So it doesn't seem like we are getting some kind of synergistic toxicity and that's good. This poster has been, or this study has been presented previously and we didn't really see new signals compared to that.

Alicia Morgans: Fantastic. Well, thank you so much. Just as we finalize here, I'd love to hear your summary or your message to the listeners as they think about this really exciting EV data.

Terence Friedlander: Sure. So, I think this study really shows the promising activity of this combination of really two novel agents in the frontline metastatic urothelial setting for patients who are cisplatin-ineligible. We're hoping that this data holds up and this really becomes an option for patients going forward in the future. And we are eagerly awaiting the phase three data as well. That may not come back for a year or maybe longer, but we'll see what that data shows. We are very excited about it.

Alicia Morgans: Absolutely. Well, congratulations to you, to your co-authors and collaborators. And certainly thanks to all the patients who participated in this work. I do think that this is a combination that we are all going to need to keep our eye on. And I look forward to hearing more. Thank you so much for your time today.

Terence Friedlander: Thank you. Really appreciate it.