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Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club. Today, we are discussing the recently published EV-201 study entitled, Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma: A multicenter, single-arm, phase 2 trial. I'm Chris Wallis, a Fellow in Urological Oncology at Vanderbilt. And with me today is Zach Klaassen, Assistant Professor in Urology at The Medical College of Georgia.

This is the citation for EV-201, recently published in Lancet Oncology and headed by Dr. Yu.

NCCN guidelines as highlighted here from 2021, offer a variety of treatment options in the first-line systemic therapy space for locally advanced or metastatic urothelial carcinoma. As we can see for patients who are cisplatin-eligible, the preferred approaches involve chemotherapy followed by IO maintenance. However, for those who are ineligible, which comprises 50% of all patients diagnosed with locally advanced or metastatic urothelial carcinoma, nearly every regimen includes immunotherapy. As a result, when we see patients for second-line therapy, nearly all have received a prior IO.

And so we are looking for new targets in addition to our cytotoxics and our checkpoint inhibitors, and nectin-4 is a cell adhesion molecule in bladder cancer that is targeted by enfortumab vedotin, which is a humanized monoclonal antibody to nectin-4.  And as you can see here, this is a little schematic here of binding to the antigen intracellular transport, leading to microtubule disruption, cell cycle arrest, and apoptosis.

Enfortumab vedotin has previously been examined in the EV-301 study, which was published in The New England Journal of Medicine and we have previously described it in the UroToday Journal Club. To briefly summarize, this included patients who had prior platinum-based chemotherapy, as well as prior PD-1 or PD-L1 treatment, and patients were then in the third-line setting, randomized to either enfortumab or preselected choice at physician discretion of mono-agent chemotherapy. And this study showed improved overall survival for patients who had enfortumab vedotin versus investigator choice of chemotherapy.

In the EV-201 study, we looked at patients a little earlier in their disease trajectory and those who were cisplatin-ineligible. And so to be included in this cohort, patients had to have histologically confirmed urothelial carcinoma, metastatic disease according to RECIST criteria, and pure urothelial or mixed histology with some urothelial component. They had to have good performance stats with ECOG 0 to 2 and adequate organ function, as well as a life expectancy of at least three months. Further, patients had to have prior treatment with a PD-1 or PD-L1 inhibitor, either in the locally advanced or metastatic setting or in the neoadjuvant or adjuvant setting, as long as recurrence occurred within three months of therapy. Patients could not have had prior platinum chemotherapy exposure and had to be ineligible for cisplatin as a result of their performance status, their renal function, or prior hearing loss. Patients were excluded if they had sensory or motor neuropathies, uncontrolled diabetes, active central nervous system metastases, uncontrolled tumor-related bone pain, active hepatitis B or C, active HIV infection, or impending spinal cord compression.

This was a single-arm, two-cohort, open-label, multicenter trial, which was conducted in 59 sites across North America, Europe, and Asia. Enfortumab vedotin was administered at 1.25 mg/kg by intravenous infusion on days one, eight, and 15 of a 28-day treatment cycle. Dose modifications within the trial were allowed to manage treatment-related adverse events and treatment was continued until there was evidence of unequivocal disease progression, unacceptable toxicity, or the withdrawal of patient consent.

Now disease response was assessed on the basis of axial imaging using contrast CT or MRI in those with renal insufficiency. This was performed every eight weeks for 56 weeks and then every 12 weeks thereafter. These scans were assessed according to RECIST criteria and patients who had a complete or partial response, imaging was repeated at least four weeks after to confirm this response.

Safety assessments were performed on all dosing days through physical examination and laboratory testing and any detected adverse events were graded according to the CTCAE criteria. And there were a number of adverse events of special interest, including peripheral neuropathy, skin reactions, and hyperglycemia.

We see here, the primary endpoint was objective response rate with a variety of secondary endpoints, including the duration of response, disease control rate at 16 weeks, progression-free survival, overall survival, and safety. They assessed a number of biomarkers, including tumor nectin-4 expression and PD-L1 expression. And in addition, considered the H-score, which is defined as you see here and scored between zero and 300. Notably, PD-L1 expression was dichotomized at 10%.

This cohort 2, which was reported in the present study was designed to enroll 100 patients, which would allow for the half-width of the 95% confidence interval for the objective response rate to be 10.2% or less. Efficacy and safety were assessed in the intention to treat population among all who received at least one dose. The objective response rate and 95% confidence intervals were calculated using the Clopper-Pearson method and time to event outcomes were assessed using the Kaplan-Meier approach. The authors further performed subgroup analyses according to both demographic and disease characteristics.

At this point in time, I am now going to hand it over to Dr. Klaassen who will walk us through the results of the study.

Zachary Klaassen: Thanks, Chris.

This is the demographic and disease characteristics table at baseline. You can see that there were 66 patients or 74% that were male, with a median age of 75 years. A majority of these patients were recruited in North America at 64%. The most common ECOG performance status was one at 46%. However, you can see here that ECOG 2 was also included in this trial at 12% of patients. The most common BMI was less than 25 at 48%. Based on the cohort, these patients all had kidney dysfunction at baseline with the most common being creatinine clearance of 30 to 60 at 67%. Looking at primary tumor location, there was 57% of patients that have bladder or other with actually a high number of upper tract patients at 43%.

The most common histology with urothelial carcinoma only was at 70% with some squamous differentiation at 13% and with other histological variants at 17%. The majority of these patients were metastatic at 99% with most of these patients having visceral disease at 79%, including 25% of the bone, 24% to the liver, and 46% to the lung. The median number of previous therapies was one. And when you look at the response to PD-1 or PD-L1 containing therapy, the majority actually were non-responders at 75%. You can see the median nectin-4 H score was 275.

This summarizes the confirmed best overall response. And the objective response rate for this population was 52% with a 95% confidence interval of 41% to 62%. Impressively, the complete response rate was 20% of this population with 31% having a partial response, 30% having stable disease, and 9% of patients having progressive disease.

This is the forest plot of the subgroup analysis of objective response rate. And generally looking at this figure globally, you can see here that amongst all of the subgroups, there was a signal comparable to the 52% overall objective response rate. A particular of interest were females at 61%, nonwhite participants at 63%, ECOG 0 at 65%, upper tract tumors at 61%, and best response to previous checkpoint inhibitor therapy being the responders at 64%.

This waterfall plot shows the change in target lesions from baseline. Impressively, 88% of patients had a reduction in their target lesion as displayed here on the left.

This is a swimmer plot looking at response in patients with confirmed objective responses. 43% of responders had progressed or died at the time of the analysis. The median duration of response was 10.9 months with a 95% confidence interval of 5.78 to not reached. And the 16-week disease control rate was 58%.

This is the Kaplan-Meier curve for progression-free survival by blinded independent central review with a median progression-free survival of 5.8 months and a 95% confidence interval of 5.03 to 8.28.

This is the Kaplan-Meier curve for overall survival with a median overall survival of 14.7 months and a 95% confidence interval of 10.51 to 18.20 months.

This summarizes the adverse events. In terms of any adverse event, 100% of the patients, the majority of these treatment-related adverse events at 97%. There was a 55% grade greater than or equal to three treatment-related adverse events, serious adverse events were 17%, treatment-related adverse events resulting in discontinuation of therapy was 16%, and 3% of patients had treatment-related adverse events leading to mortality.

This table summarizes specific adverse events looking at the grade three, four adverse events. You can see here, there was 8% maculopapular rash, 7% fatigue, 6% grade three neutropenia, and 3% grade four neutropenia. And the majority of these had only one or two patients listed for these specific adverse events.

So, several discussion points from the EV-201 trial. Enfortumab vedotin had a clinically meaningful objective response rate of 52% with 20% of patients achieving a complete response. The median duration of response was 10.9 months in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who had previously received PD-1 or PD-L1 inhibitors and had not received chemotherapy. This is the first study to report efficacy and safety data in this population and these findings are notable given that deep responses are rarely reported in cisplatin-ineligible patients treated with carboplatin-based regimens in the first-line setting. And based on these findings, this addresses a substantial unmet need amongst this population. Other notable findings were that nectin-4 was highly expressed, but was neither a predictive biomarker for a response nor was it required to select patients for treatment in this trial. And enfortumab vedotin was tolerated in the population with advanced age.

In conclusion, treatment with enfortumab vedotin resulted in notable and durable responses in cisplatin-ineligible patients following PD-1 or PD-L1 therapy. The findings of cohort 2, which we discussed today, including a 20% complete response rate and acceptable tolerability, suggest that enfortumab vedotin could be a potent monotherapy in cisplatin-ineligible patients which are a difficult to treat population by underserved conventional therapies. Finally, these clinically meaningful results support continued investigation of enfortumab vedotin across the spectrum of urothelial carcinoma.

Thank you very much and we hope you enjoyed this UroToday Journal Club discussing the recently published EV-201 study.