Xin Gao, MD, on Advanced or Metastatic Urothelial Carcinoma: LY4101174

This is a clinical trial that was performed as a dose-escalation study in patients with advanced metastatic urothelial carcinoma as well as other solid tumors known to express Nectin-4. The background for this study is that we know that enfortumab vedotin and pembrolizumab have really revolutionized the treatment for patients with advanced and metastatic urothelial cancers. But unfortunately, treatment resistance and treatment intolerability become an issue. Patients do need additional treatments beyond EV plus pembrolizumab, and unfortunately, at this time, the standard of care remains unclear and prognosis remains poor for patients who need another therapy beyond EV and pembrolizumab. We conducted this phase 1 clinical trial with a dose-escalation design. Eighty-six patients in total had metastatic urothelial cancers, and we looked at various dose levels, starting with low doses, Q2-week dosing as well as Q3-week dosing, which was explored after patients developed DLTs at the third dose level of Q2-week dosing. The vast majority of patients were heavily pretreated patients. Median lines of prior therapy was 3; 88% of patients had received prior platinum-based chemotherapy, 92% had received prior enfortumab vedotin, and all patients had received prior immune checkpoint inhibitors. So I think this was a study that really captured, you know, what's going on in the real world when patients need to think about another therapy beyond EV plus pembrolizumab and platinum-based chemotherapy. What we saw was that there was antitumor activity, particularly at the highest dose level of 4 mg/kg Q3-week dosing. We saw an objective response rate of 36% with the dose, with a disease control rate of 76%. However, we also ran into dose-limiting and significant hematologic toxicities, including grade 3 or higher anemia, neutropenia, thrombocytopenia, as well as febrile neutropenia at the highest dose level despite use of G-CSF prophylaxis. So the EXCEED study was a proof of concept that further targeting of Nectin-4 remains a viable and important clinical strategy for patients with treatment-refractory metastatic urothelial cancers after enfortumab vedotin. I think future work will be needed to continue to develop and study newer, other kinds of Nectin-4-targeting drugs with different payloads, different linkers, that hopefully will be able to find a dose that's both efficacious and tolerable for patients.