Medicine Matters oncology

EV-201, Cohort 2, which are the data that I'm presenting at GU ASCO 2021, evaluated the role of enfortumab vedotin in patients with metastatic urothelial cancer that were cisplatin-ineligible and had previously received immunotherapy with either a PD-1 or PD-L1 antibody and then had disease progression and were treated with enfortumab vedotin. And these patients were specifically naive of platinum-based chemotherapy in the metastatic setting.

And the key clinical question that was being addressed in this trial that evaluated treatment in about 89 patients is, exactly, what is the role of enfortumab vedotin in the cisplatin-ineligible population that receive immunotherapy and are not good candidates for cisplatin-based therapy? And what we know about this population is that they generally have worse prognosis. They are not able to tolerate more aggressive therapies.

And the role of enfortumab vedotin is quickly evolving in advanced bladder cancer. We have tested it in the third-line setting, after both platinum-based chemotherapy and immunotherapy. We now have Level I evidence from a randomized study, EV-301, that demonstrated a survival benefit over a single-agent chemotherapy in the third-line setting and their provocative data looking at it in combination with immunotherapy in the first-line setting.

And so this particular trial really probes more into the role of enfortumab vedotin in metastatic urothelial cancer and specifically just after immunotherapy. And in the 89 patients who received at least one dose of study treatment, the objective response rate was 52%. The complete response rate was 20%. And when you look at the breadth of activity of this drug, 88% of post-treatment assessable patients-- meaning they have at least one post-treatment response evaluation-- 88% of those patients had at least some decrease in their tumors. 9% of patients had progressive disease as their best overall response to treatment.

When I take this in totality, what we see is that this drug is quite active, a breadth of responses, and beyond just objective responses. And a majority of patients achieved some measure of disease control with this drug. And so that was very provocative data. I think it's very important this, along with other trials, really tell us the activity of this drug in a metastatic disease.

Safety, obviously, was evaluated as part of this trial. Overall, the rates of grade 3 and 4 adverse events were relatively low. A majority of toxicities were quite manageable. The safety profile was very consistent with what we otherwise see in other studies of enfortumab vedotin-- namely, issues such as rash and hyperglycemia can occur early in the course of treatment, generally pretty manageable.

And neuropathy, which is a very on-target, expected toxicity for enfortumab based on the mechanism of action of its payload, monomethyl auristatin E, also was predictably developed in these patients several months into treatment. I think the median was around 2.4 or 2.5 months. And this was also manageable, with a majority of patients-- greater than half-- having improvement in neuropathy with either dose reductions, interruptions, and, also, physical therapy in my clinical practice is particularly helpful for these patients.

There were four treatment-related deaths as assessed by the treating investigators on this trial, three of which occurred early in the course of treatment, meaning within the first 30 days after the first dose of study treatment. And the common denominator in this population of patients who developed such severe toxicity and death appeared to be high BMI of 30 or greater. And this is something that, as investigators, we need to delve into deeper, like, you know, what are the risk factors, baseline, that associate with these early deaths? And it appears, so far, to be high BMI. And so this is something we need to investigate further. There was an additional death that occurred as a consequence of pneumonitis, but that occurred later in the course of treatment.

So, in totality, while there were these safety events we need to investigate further, overall, the response rates are quite promising. CRs are really, really promising. The median duration of response was 10.9 months. And so this, along with other studies, really highlight the role for enfortumab vedotin in metastatic urothelial cancer. And I think more studies, randomized trials that are currently ongoing are going to further refine the role for this drug in advanced disease.