Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we're discussing the EV-301 trial examining enfortumab vedotin in previously treated advanced urothelial carcinoma. I'm Chris Wallis, a fellow in urologic oncology at Vanderbilt, and with me today is Zach Klaassen, assistant professor in the division of urology at the Medical College of Georgia

This study was presented at GU ASCO and concurrently published in the New England Journal of Medicine, and this is the citation here of the EV-301 study led by Tom Powles. For background, most UroToday readers and viewers will know that the revolution in immuno-oncology has not spared bladder cancer, so this is a highlight of the approvals of treatment approaches in advanced bladder cancer over the last 5 years or so. And as we can see, there were five different IO regimes that were approved. Then starting in 2019, we now have a targeted therapy, both with erdafitinib and then with enfortumab vedotin, And so we'll talk a little bit about the mechanism.

What we see here is the schematic of how enfortumab is trafficked within the cell. Nectin-4 is a cell adhesion molecule that's fairly specifically expressed in bladder cancer and allows targeting of tumor cells with fairly high specificity. Enfortumab is a combination of a human monoclonal antibody to nectin-4, as well as a microtubule disrupting chemotherapeutic agent.

In the EV-301 study, the authors enrolled adult patients with histologically or cytologically confirmed urothelial cancer who had radiologically documented metastatic or unresectable locally advanced disease. Patients had to have an ECOG 0 to 1, and have had previous immunotherapy as well as prior platinum therapy. Key exclusion criteria included pre-existing sensory or motor neuropathy, clinically significant to toxic effects of prior therapies, active brain metastasis, uncontrolled diabetes, active keratitis or corneal ulceration, as well as more than one prior line of chemotherapy.

They performed a randomized, open-label study with 1:1 randomization to enfortumab vedotin versus chemotherapy, and stratification was performed according to ECOG performance status, geographic region, and the presence of liver metastasis. Notably, investigator choice chemotherapy could include any of docetaxel, paclitaxel, or vinflunine, however, a maximum of 35% of the cohort was allowed to be allocated to vinflunine.

The key endpoints here, primary endpoint was overall survival and secondary endpoints included progression-free survival as assessed by the investigator, clinical response, as well as safety. Assessment was performed with radiographic imaging at baseline, and then every 8 weeks a bone scan was performed at baseline, and then repeated only among those with positive scans. Brain imaging was performed as clinically indicated.

This is the schematic of the study, highlighting key points that we've just discussed. In terms of statistical analysis, overall and progression-free survival were assessed using the Kaplan-Meier method and compared with log rank tests, and then subsequently Cox proportional hazard models were used to estimate hazard ratios. Efficacy analyses were conducted among all randomized patients and safety analyses among all patients who received any dose of the study drug. The authors used a group sequential design with planned interim and final analysis, and this is a report of the interim analysis, at which time overall survival was tested at a one-sided alpha of 0.00541 for efficacy. This was then down adjusted to a 0.00679. On that, I'll pass it over to Dr. Klaassen to talk us through the results of the EV-301 study.

Zachary Klaassen: Thanks, Dr. Wallis. You can see here that there was 745 patients that were screened, and ultimately 608 underwent randomization, including 301 to the enfortumab vedotin arm and 307 to the chemotherapy arm. At the bottom of this figure, you can see that 245 patients in the enfortumab vedotin arm discontinued treatment, compared to 285 patients in the chemotherapy arm.

This is the table of characteristics of patients at baseline. On the left of this table, you can see enfortumab vedotin, and on the right, the chemotherapy arm. The median age for these patients was 68 years, majority of these patients, almost 80%, were males, and you can see that the majority of these patients were either former or current tobacco users. As Chris mentioned, this was limited to ECOG 0 and 1, with the majority of patients being an econ one at about 60%. You can see, interestingly, that the almost one-third of these patients had upper urinary tract primary disease, and the majority of these patients had urothelial or transitional carcinoma without any other subtypes.

Looking at the sites of metastasis, you can see that nearly 80% of these patients had visceral metastasis, including 31% with liver metastasis. Majority of these patients did have one to two lines of treatment, with 13% having more than three lines of treatment. And you can see that when looking at the best response among patients who previously received checkpoint inhibitor treatment, majority of these patients, over two-thirds, had no response to immune checkpoint inhibitor therapy.

This is the Kaplan-Meier curve for overall survival. You can see the enfortumab vedotin arm is in blue and the chemotherapy arm is in orange. The median overall survival for enfortumab vedotin and was 12.9 months, compared to nearly 9 months for chemotherapy, which led to a hazard ratio of favoring in format dose of 0.70, and a 95% confidence interval of 0.56 to 0.89.

This is the subgroup analysis for overall survival, enfortumab vedotin on the left and chemotherapy on the right. Several important notes here in terms of subgroups that did not favor statistically enfortumab vedotin, including patients that were older, female patients, however, this may be secondary to a lower sample size in the female subgroup, patients that had an ECOG performance status of 0, those that had previous vinflunine chemotherapy, and interestingly, patients who had upper tract disease did not have a statistically significant benefit from enfortumab vedotin, And finally, you can see patients who had three or more therapies did not have a benefit, as well as patients that had a previous response to immune checkpoint inhibitor therapy.

This is the progression-free survival Kaplan-Meier curve in the intention-to-treat population. Once again, early and durable splitting of the Kaplan-Meier curve, favoring enfortumab vedotin, with a median progression-free survival of 5.5 months, compared to chemotherapy of 3.7 months. So this has a ratio also favored the enfortumab vedotin arm with a hazard ratio of 0.62, and 95% confidence interval of 0.51 to 0.75.

This is the subgroup analysis for progression-free survival. Very similar to the overall survival subgroup analyses in terms of there was no benefit for patients over or equal to 75-years-of-age, as well as female patients, those previously receiving vinflunine chemotherapy, and those with three or more prior lines of chemotherapy or treatment.

This is the adverse events, separated between the two groups. You can see here, we'll focus on the greater than or equal to three adverse events. And so, it was about 50% for both of these arms in terms of grade 3 or greater adverse events. Common adverse events in the enfortumab vedotin arm included peripheral sensory neuropathy at 3%, you can also see here that maculopapular rash was 7.4% in the enfortumab group. In the chemotherapy group, it was standard adverse events related to chemotherapy, including neutropenia, decreased neutrophil count, as well as anemia. They did make note in one of the appendix tables of hyperglycemia in the enfortumab vedotin group of 3.7%, compared to chemotherapy of 0%.

Several discussion points from the EV-301 trial. There are limited and largely ineffective, treatment options for patients who receive a treatment for bladder cancer and after disease progression with platinum-chemotherapy and PD-1 or PD-L1 inhibitors. So these are heavily pretreated patients who have often progressed quickly, and in this highly pretreated group, enfortumab vedotin offered a 30% lower risk of death versus chemotherapy in this disease space. Nectin-4 expression was not required for entry into the EV-301 trial, so I think this has important implications for utilization across the board in this third-line treatment. A high expression has been observed in the majority of patients with advanced urothelial carcinoma, so I think moving forward into the real world, there probably will not need to be sequencing of these tumors to confirm nectin-4 expression. The skin reaction adverse events, which we talked about, likely related to nectin-4 expression in the skin.

Subsequently, because of superior overall survival benefit in the planned interim analysis, the EV-301 trial was stopped early. However, they will continue future analyses for quality of life data, and further, contextualize efficacy and safety. As we heard last year from Dr. Powles' group as well, there was a recent approval for avelumab in platinum-chemotherapy as a maintenance treatment, and enfortumab vedotin may be considered at the time of relapse after this maintenance therapy. So we're starting to see some clarity in terms of how patients are going to be treated with upfront first-line chemotherapy, followed by avelumab maintenance therapy, and then after progression with avelumab, they will receive enfortumab vedotin.

There's lots of trials ongoing with this drug. I think we're going to see a lot of data coming out in the near future. In terms of the first-line treatment, there's the EV-302 study, a phase 3 trial of enfortumab vedotin and pembrolizumab versus chemotherapy, as well as the EV-103 trial. There's also a perioperative trial looking at a phase 3 pembrolizumab plus cystectomy versus pembrolizumab plus enfortumab vedotin plus cystectomy, versus cystectomy alone in cisplatin-ineligible patients with muscle-invasive bladder cancer. So we're going to continue to see this treatment move further up in the disease process for bladder cancer.

In conclusion, enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. And although the skin reactions, neuropathy, and hyperglycemia were common with enfortumab vedotin, these events were commonly mild to moderate severity. So, I think we have a new third-line treatment for metastatic urothelial carcinoma, and we'll look forward to seeing these other trials present data as the treatment moves further up in the disease process. Thank you for your attention. We hope you enjoyed this discussion of the EV-301 trial, first presented at GU ASCO 2021.