In this interview, Amanda Nizam, MD, Cleveland Clinic Taussig Cancer Institute, discusses her presentation from the 2024 ASCO Genitourinary Cancers Symposium titled "Outcomes in patients (pts) with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV) after switch maintenance avelumab (MAv) in the UNITE study.”

Transcript:

Amanda Nizam, MD: My name is Amanda Nizam, and I'm a genitourinary oncologist at the Cleveland Clinic.

Can you give some background about your study and what prompted you to undertake it?

Dr Nizam: In 2019, EV was approved by the FDA for the treatment of patients with advanced urothelial carcinoma refractory to both platinum-based chemotherapy and checkpoint inhibitor therapy. Around the same time in 2020, avelumab was approved as switch maintenance therapy in patients with advanced urothelial carcinoma without disease progression on first-line platinum-based chemotherapy. However, those patients whose disease progressed on maintenance avelumab were not included in the investigational trials that led to EV's approval. So in UNITE, it's a retrospective cohort study across 16 US academic sites comprised of patients with advanced urothelial carcinoma treated with novel systemic therapies, including EV. Noting the differing disease biology between patients with platinum responsive and platinum refractory disease, we wanted to investigate outcomes in patients treated with EV after platinum-based chemotherapy and maintenance avelumab where it's frequently used in contemporary clinical practice.

Can you briefly describe how the study was conducted?

Dr Nizam: So in the multi-institutional UNITE retrospective cohort study, we identified 49 patients who met criteria for receiving EV monotherapy and after platinum-based chemotherapy and maintenance avelumab and then enfortumab vedotinin sequence. We looked at observed response rates, which were determined by investigators at each site for patients with imaging after at least one cycle of EV, and those were compared using the chi-squared test and logistic regression. Progression-free and overall survival were assessed and then compared using the log-rank test in Cox proportional hazards. So in the overall cohort, we examined observer response rate, progression-free and overall survival from EV start, and overall survival from platinum-based chemotherapy start as an exploratory endpoint. And then in subgroups of interest, which included type of platinum-based chemotherapy received, best response to platinum-based chemotherapy, median time on maintenance avelumab and Bellmunt risk score. We also compared observer response rates and progression-free and overall survival from the start of EV.

What were the main findings of your study?

Dr Nizam: Just in terms of baseline characteristics of the patients, we identified 49 patients who met the inclusion criteria of receiving platinum-based chemotherapy maintenance avelumab and enfortumab vedotinin in sequence. And most patients had visceral metastases in Bellmunt  risk score of zero or one at baseline. And then prior to maintenance avelumab, most patients received cisplatin-based chemotherapy and had partial response or stable disease as the best response to platinum-based chemo. The baseline characteristics in this population were pretty similar to those that we saw in the EV-301 trial, which is the investigational trial that led to the approval of EV and the platinum and checkpoint inhibitor refractory setting. In addition, when we looked at the observed response rate, so at a median follow-up of eight and a half months from start of EV, the observed response rate was 54% in the invaluable patient population and 45% in the intention to treat population.

Most patients had a partial response or stable disease as the best response to EV. And this was pretty similar to what we saw compared to the 41% observed response rate in the intention to treat population in the EV-301 trial. When we looked at survival outcomes, median progression-free and overall survival were 7 months and 13.3 months, respectively. These were, again, consistent with what we saw in the EV-301 trial, which demonstrated a median progression-free survival of 5.6 months and median overall survival of 12.9 months. As an exploratory endpoint, we examined median overall survival from platinum-based chemotherapy, which is about 22.5 months. And the JAVELIN Bladder 100 trial, which led to the approval of maintenance avelumab, that median overall survival from the platinum-based chemotherapy start was 29.7 months. Just for reference.

So in the subgroups of interests that we discussed, so type of platinum-based chemotherapy, best response to platinum-based chemotherapy, and median time on maintenance avelumab, we didn't see any differences. Outcomes were pretty similar among subgroups. However, when we looked at patients with Bellmunt risk score 0 or 1 compared to those with 2 or 3, we observed improved progression-free and overall survival in those patients with Bellmunt risk score 0 or 1, and that's likely owing to patients with Bellmunt risk score 2 or 3 are more likely to have liver metastases, anemia, and/or poor ECOG performance status, which are known for prognostic factors in advanced urothelial carcinoma. So that makes sense.

What were the main takeaways from these results?

Dr Nizam: In this limited sample size and retrospective analysis, acknowledging the limitations of that kind of analysis, we did find overall similar outcomes to what we saw in the EV-301 trial, noting that our studies selected for patients with platinum responsive disease. Our findings reinforce that the presence of anemia, liver metastases, and/or poor ECOG performance status confer worse overall prognosis in advanced urothelial carcinoma. Our findings actually are practical as they inform on outcomes with EV in a setting where it's often used in clinical practice. And the consistency of outcomes with EV across clinical trial and nonclinical trial settings is encouraging. And finally, to put this into context, while EV in combination with pembrolizumab was recently approved by the FDA for the treatment of patients with untreated advanced urothelial carcinoma, most patients in the globe are not going to be able to access that combination regimen.

So clinicians will continue to encounter scenarios in which platinum-based chemotherapy maintenance avelumab and EV are used in sequence owing to these regulatory and reimbursement limitations, as well as other patient-related factors. So while the data for EV-302 is very clear and very strong that that is the new gold standard of care for untreated advanced UC, looking at it practically in nations and communities where EV and pembrolizumab in combination are not approved or not available due to reimbursement or access regulatory limitations, this is important data to know because this is the reality of what most of the world is going to see, is that patients are still going to be getting platinum maintenance avelumab and EV in sequence, at least for the foreseeable next couple of years. Thus, what's the big takeaway from this is that because of this, we need to acknowledge reality and that patients are going to be getting either EV and pembro in combination or platinum-based chemotherapy, maintenance avelumab and EV in sequence. Thus, we need to identify biomarkers that are associated with response and resistance to platinum-based chemotherapy and EV.