Rashid Sayyid: Hello everyone and thank you for joining us today in this UroToday Journal Club recording. I'm Rashid Sayyid, robotic urologic oncology fellow at the University of Southern California in Los Angeles. I'm joined as always by Zach Klaassen, associate professor and program director at Wellstar MCG Health in Augusta, Georgia. Today we'll be discussing the recently published updated results of the Phase III EV-302 trial of enfortumab vedotin plus pembrolizumab in patients with untreated locally advanced or metastatic urothelial carcinoma. This updated report of EV-302 was published earlier this month in the Annals of Oncology with Dr. Tom Powles as the lead author similar to the original report.

By way of background, we know that platinum-based combination chemotherapy has been the standard of care first-line therapy for these patients with locally advanced or metastatic urothelial carcinoma for nearly four decades now. But there are major limitations for this combination chemotherapy in the real-world setting. We know that the median overall survival for these patients is only 15 to 16 months, so barely over a year. The use of these agents is limited by platinum eligibility, and even more significant, we know that cisplatin works better than carboplatin in this setting. There are further limitations with regard mainly to kidney function with regard to being able to use these agents. Not only do they not work that well, but also we can't use them for all patients.

If we take a step back and take a historic look at the timeline of platinum combination chemotherapy, we really see that it was described and reported almost four decades ago in 1985 at MSK, where in the first batch of patients the overall response rate was about 72% with a complete response of 36%. We see here that the median overall survival was almost 15 months, which is roughly what it is nowadays. Later on, in 2000, we saw a phase III trial of standard MVAC as opposed to dose-dense MVAC versus gemcitabine-cisplatin in patients who were systemic therapy-naive. Essentially, we saw no meaningful difference in overall survival between the two regimens. We saw that MVAC or standard MVAC in this setting was more toxic with higher rates of grade 3 to 4 neutropenia, neutropenic fever, as well as sepsis. And then soon thereafter, we saw a trial of dose-dense MVAC versus standard MVAC, and we saw the dose-dense MVAC outperform standard MVAC for the objective response rate, progression-free survival and overall survival, which was 15 months roughly.

Can we do better? We saw in recent years with the CheckMate-901 trial trying to add immunotherapy in the form of nivolumab to gemcitabine-cisplatin in patients with advanced urothelial carcinoma. As we can see in the Kaplan-Meier curves below, there was a modest improvement in median overall survival by about three months from 19 to 22 months. But, really, does this move the needle? Are these three months for these patients who are treated in the first-line setting really deriving a huge benefit from adding nivolumab? And so the take-home message is we haven't really seen progress over the last four decades.

This all changed with ESMO 2023 and then later on with the official publication in the New England Journal of Medicine in March 2024, where we saw the first results of the EV-302 trial published with Dr. Tom Powles again as the lead investigator in this trial. To refresh our listeners, if we look at the trial design of EV-302, this was a phase III trial of 886 patients who have previously untreated locally advanced or metastatic urothelial carcinoma. When we say locally advanced or metastatic urothelial carcinoma, this could be either upper or lower urinary tract disease. These patients could have pure urothelial carcinoma, they could have mixed histology, or even pure variant histology. Importantly, and this really improves adoption in clinical practice, these patients were unselected for Nectin-4 and PD-L1 expression.

Notably, all patients were eligible for platinum, EV, and pembrolizumab, and all were PD-1/PD-L1 inhibitor-naive with an acceptable GFR, so they were platinum-eligible and had a good performance status. These patients, as we see here, were randomized one-to-one to either EV plus pembrolizumab or chemotherapy. Chemotherapy could be cisplatin for those that were eligible or carboplatin for those that were cisplatin-ineligible. This was given for a total of six cycles.

Conversely, I want to note that with EV and pembrolizumab, there was no maximum number of treatment cycles for EV. You continue giving EV as long as you don't see disease progression, clinical progression, or unacceptable toxicity. You give pembrolizumab for up to 35 cycles, typically given every three weeks.

The primary endpoints were dual: progression-free survival and overall survival. The secondary endpoints were pretty standard, as we see in these trials.

This trial met the PFS endpoint, as we see here in the Kaplan-Meier curves. We saw almost double the median progression-free survival with EV and pembrolizumab, 12.5 months versus 6.3 months. And then also in overall survival, we saw an almost twofold increase in overall survival from 16 months all the way up to 32 months with a hazard ratio of 0.47, which is very impressive in this setting.

Importantly for our patients, this progression-free survival and OS benefit was seen in both cisplatin-eligible patients, as we see here on the left side. It was also similarly seen with a similar magnitude of effect in cisplatin-ineligible patients. Really we see a benefit in these patients irrespective of their cisplatin eligibility, which is crucial in this setting.

These results led to regulatory approval and adoption of this regimen as a first-line therapy in this setting. And so we saw in December 2023 the FDA approved EV plus pembrolizumab for patients with locally advanced or metastatic urothelial cancer. This was followed approximately nine months later with the EMA approving pembrolizumab plus enfortumab vedotin as first-line treatment for these patients, which represents excellent results for these patients and really changes their disease trajectory. And so in this report, the objective was to present an updated analysis of both efficacy and safety outcomes in the overall population with now a median follow-up of 2.5 years. As compared to before, this is one year of additional follow-up, so almost twice as long follow-up, which is very important because not only do we want to see that it works early on, but we want to see that this is maintained. We also want to understand further who are the patients that benefit the most as well as understanding among those who do respond, what is the duration of response in these patients.

At this point, I'll turn it over to Zach, who'll go over the results and the discussion of the study and really contextualize these results for our patients and provide an excellent perspective on these results.

Zachary Klaassen: Rashid, excellent intro as always.

Here we have the updated progression-free survival by blinded independent central review. We see here a median progression-free survival of 12.5 months for EV plus pembrolizumab, compared to 6.3 months for chemotherapy. Again, a strong hazard ratio holding strong from the initial analysis, hazard ratio of 0.48.

Again, when we look at the forest plot for progression-free survival, a clean sweep for EV plus pembrolizumab. Every single one of these subgroups benefited from the combination, particularly, as Rashid pointed out, with regard to cisplatin eligibility. Both cisplatin-eligible and cisplatin-ineligible patients benefited from EV plus pembrolizumab. Again, this is important because 50% of our patients are likely cisplatin-ineligible at the time of needing therapy.

Also, the co-primary endpoint, as Rashid mentioned, was overall survival. We see again 33.8 months with additional follow-up, median overall survival for EV plus pembrolizumab compared to chemotherapy, 15.9 months. Hazard ratio now 0.51, so a 49% risk reduction in mortality with the combination of EV plus pembrolizumab versus chemotherapy.

Again, forest plots for overall survival showing complete benefit for all these subgroups. Also highlighting, again, cisplatin eligibility for both eligible and ineligible patients. There is an overall survival benefit for EV plus pembrolizumab compared to chemotherapy.

This is the duration of response per RECIST by blinded independent central review. We see a median duration of response of 23.3 months for EV plus pembrolizumab compared to only seven months for chemotherapy. The second figure looks at duration of complete response, again by RECIST, not reached in the EV plus pembrolizumab arm compared to 15.2 months in the chemotherapy arm.

This is the updated safety analysis. This is treatment-emergent and treatment-related adverse events in the safety population. Looking at TEAEs first, I want to highlight that serious TEAEs were 53.2% in the EV plus pembrolizumab arm compared to 39% in the chemotherapy arm. Treatment-related adverse events, looking at serious events, 29.3% in the EV plus pembrolizumab arm, compared to 19.6% in the chemotherapy arm.

For specific treatment-related adverse events, I want to highlight also the ones we've seen over the last year or so using this combination therapy: peripheral sensory neuropathy and maculopapular rash, both higher in the EV plus pembrolizumab arms. We see any-grade peripheral sensory neuropathy, 51.8% compared to 9.9% in chemotherapy. Maculopapular rash, 32.7% versus 3.2%, and slightly higher grade 3 plus adverse events for EV plus pembrolizumab compared to chemotherapy. When we look at the bottom here, these are the ones that are typically associated with chemotherapy: anemia, neutropenia, thrombocytopenia, decreased neutrophil and platelet count. These were higher for any grade and grade 3 plus adverse events for chemotherapy compared to EV plus pembrolizumab.

By way of discussion, after median follow-up of almost 2.5 years, first-line EV plus pembrolizumab continues to demonstrate superior efficacy over chemotherapy alone. This holds true, which is really important, as we've emphasized several times in this discussion, for both cisplatin-eligible and cisplatin-ineligible patients, nearly doubling the median progression-free survival and more than doubling the median overall survival.

The response to EV plus pembrolizumab was durable. The median duration of response was nearly two years in patients with a confirmed response. For patients achieving a clinical complete response, there was a 74.3% probability of remaining in clinical complete response at 24 months. If you have a great response, we can tell our patients there's almost a 75% chance that at two years you're going to continue to have a complete response, which we've never seen before in locally advanced or metastatic urothelial carcinoma.

Importantly, no new safety signals for the combination after the initial year of follow-up. When we look at the rate of grade 3 plus peripheral sensory neuropathy, primary analysis was 3.6%, with additional follow-up, 4.1%. The rate of grade 1 to 2 ocular disorders with no grade 3 plus ocular disorders was essentially the same between primary analysis and additional follow-up at just over 21%.

Important take-home messages: with updated efficacy and safety data, with an additional year of follow-up, these were consistent with the primary analysis in the EV-302 trial. This represents the longest follow-up duration for EV plus pembrolizumab patients treated in this phase III setting. These results are also corroborated by five-year follow-up from cohort A of the phase Ib/II EV-103 trial, which assessed EV plus pembrolizumab in cisplatin-ineligible patients.

Taking this all together, the continued survival benefit with EV plus pembrolizumab versus chemotherapy from EV-302 reinforces EV plus pembrolizumab as standard of care for all patients in the first-line setting for metastatic urothelial carcinoma.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the updated analysis from the EV-302 trial.