Antitumor Activity of Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Cancer

Dr Rana McKay, a genitourinary medical oncologist at the University of California San Diego, discusses the results of EV-103 cohort K, which assessed the efficacy of enfortumab vedotin monotherapy or in combination with pembrolizumab in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.

Transcript: 

Dr Rana McKay: Rana McKay. I'm a genitourinary medical oncologist at the University of California in San Diego where I lead our genitourinary medical oncology team.

What is your reaction to the results of the EV-103 trial?

Dr McKay: So with regards to the EV-103 trial, just as a way of background, we know that patients who have locally advanced or metastatic urothelial carcinoma have a poor prognosis and their five-year survival rates are less than 10%. These patients can have high symptom burden and pain, which negatively impacts their quality of life and function. EV-103, and specifically cohort K of EV-103, was part of an open-label, multiple cohort phase 1b/2 study in patients with locally advanced metastatic urothelial carcinoma. Patients who were eligible for this study were cisplatin ineligible and this was a study that was enrolling patients in the frontline advanced setting.

Cohort K randomized patients to the combination of enfortumab vedotin plus pembrolizumab or enfortumab vedotin monotherapy and there was no formal statistical comparison between the two arms. The primary endpoint of the study was objective response rate and key secondary endpoints included other safety and efficacy parameters, and as an exploratory endpoint, there was an assessment of patient reported outcomes using the EORTC QLQ-C30, a brief pain inventory, and other pro instruments. With regards to the patients that were enrolled on this trial, the majority of individuals were male. The majority of individuals were of white race. With regards to reasons that they were not able to receive cisplatin, the bulk of individuals, it was because of low GFR or low creatinine clearance.

And then when with regards to liver metastases, there was about 17% of patients who enrolled in the trial that had liver metastases. The initial efficacy data were presented at ESMO in 2022 in Paris, demonstrating striking objective response rate with the combination of 64.5% and the median time to response really on the order of about two months and it was really exciting to see that data get presented. So at the 2023 Genitourinary Cancer Symposium, we saw data that got presented regarding the pro instruments and the quality of life from this study. And the big items that we're focused on were the EORTC QLQ-C30 and the brief pain inventory short form that were utilized to assess patient reported outcomes in this trial. Patients completed these questionnaires at baseline, prior to dosing, post randomization, weekly during cycles one through three and each cycle was 21 days, and then every cycle until end of treatment.

And when we look at the data from the trials, we actually observed that the pro data showed that EV plus pembro in cisplatin ineligible patients was associated with preserved or improved quality of life, functioning, and symptoms. There was transient worsening of some symptoms that was observed at week three, but this returned back to baseline within one to two weeks. In both treatment arms, there was similar trends in rapid improvement of pain that was demonstrated in the contents of the study. And EV pembro is the first regimen in the frontline setting to show clinically meaningful improvements in pain in cisplatin ineligible patients.

So it's really encouraging to see this data. There's actually currently a confirmatory randomized phase three trial called EV-302 that's currently ongoing that is actually looking at EV plus pembro versus cisplatin or carboplatin based regimens for patients with untreated locally advanced or metastatic urothelial carcinoma. So that study is being done in cis eligible and cis ineligible patients. And that study too will integrate patient reported outcomes, which will provide further data around the impact of this regimen on quality of life.

How might this data impact patient experiences and outcomes?

Dr McKay: Quality of life data is really important to integrate into trials. I think we have historically not done a great job of integrating it in. It's also quite difficult to do, analyze. We want to make sure that all the patients on the trial are completing the questionnaires as opposed to a select number that are completing the questionnaires. But I think this data is really important because I think the goals of therapy as I see them for patients with advanced disease a lot of times entail making people live longer, making people live better. And I think oftentimes we focus too much on the making people live longer, which is of course important, but we’ve got to make sure that our patients are feeling better. And I think this data highlights sort of the positive impact of an effective therapy with regards to symptom improvement.

How does this impact the management of patients with urothelial carcinoma?

Dr McKay: At the present time, this is still data from this phase one B2 study. We need that confirmatory phase three to really understand if this is going to be a regimen that's going to enter into the treatment landscape for this disease. Certainly the early data look very encouraging and hopefully we will get confirmatory results from the large phase three.