Positive findings have been seen with a novel antibody–drug conjugate in a pivotal trial for patients with advanced or metastatic urothelial cancer who have previously been treated with immunotherapy and chemotherapy, according to an announcement from the co-manufacturers Seattle Genetics and Astellas Pharma.
Roger Dansey, MD
Roger Dansey, MD
Positive findings have been seen with the novel antibodydrug conjugate (ADC) enfortumab vedotin in a pivotal trial for patients with advanced or metastatic urothelial cancer who have previously been treated with immunotherapy and chemotherapy, according to an announcement from the co-manufacturers Seattle Genetics and Astellas Pharma.1
In the single-arm phase II EV-201 study, enfortumab vedotin demonstrated an objective response rate (ORR) of 44% by blinded independent central review in patients who had previously received platinum-containing chemotherapy and a PD-1/L1 inhibitor.
“Despite recent approvals of multiple checkpoint inhibitors for previously treated locally advanced or metastatic urothelial cancer, there remains a high unmet need for effective treatments upon progression after initial chemotherapy and immunotherapy,” said Roger Dansey, MD, chief medical officer, Seattle Genetics, in a statement. “These results for enfortumab vedotin indicate it may be able to help patients whose urothelial cancer progresses following treatment with standard chemotherapy and a PD-1 or PD-L1 inhibitor.”
Common treatment-related adverse events with enfortumab vedotin included fatigue, alopecia, decreased appetite, rash, and peripheral neuropathy. The companies noted that further findings would be presented at an upcoming medical meeting.
“After progression on platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor, patients with locally advanced or metastatic urothelial cancer are left with no approved standard of care treatment options,” Steven Benner, MD, senior vice president and Global Therapeutic Area Head, Oncology Development, Astellas, said in a statement. “These data are very encouraging, and we look forward to discussing the data with relevant health authorities.”
The ADC targets Nectin-4, a cell adhesion molecule that is highly expressed in urothelial cancers and other solid tumors; the monoclonal antibody is attached to vedotin, a microtubule-disrupting agent. The FDA’s breakthrough designation for enfortumab vedotin, granted in March 2018, was based on preliminary findings of the phase I trial that were presented at the 2018 ASCO Annual Meeting.2
The duration of response in the phase II trial was consistent with findings from the phase I EV-101 trial that led to abreakthrough therapy designation from the FDA for the ADCas a treatment for patients with locally advanced or metastatic urothelial cancer who had progressed following immune checkpoint inhibition therapy.
The ORR in the phase I dose-escalation/dose-expansion trial was 41% (95% CI, 29.3%-53.2%) among 71 evaluable patients. Three of these patients achieved a complete response and an additional 26 patients achieved a partial response. The ORR at the recommended phase II dose was 53%.
Investigators planned to enroll 200 patients with locally advanced or metastatic urothelial cancer who received prior checkpoint blockade in EV-201, 100 of whom who have received prior treatment with a platinum-containing chemotherapy regimen (cohort 1) and the other 100 patients would be platinum-naïve and cisplatin-ineligible (cohort 2). Patients were administered enfortumab vedotin intravenously on days 1, 8, and 15 of every 28-day cycle.
The primary endpoint of the trial is ORR by independent review and secondary endpoints include duration of response, disease control rate at 16 weeks, progression-free survival, overall survival, safety, and pharmacokinetics.
A biologics license application (BLA) is expected to be submitted to the FDA later this year based on the results of the first cohort of EV-201.
In addition, the global, open-label, randomized EV-301 trial (NCT03474107) has recently begun enrolling patients and will serve as confirmation of the results of the phase II trial. The phase III trial is exploring overall survival in previously treated patients with locally advanced or metastatic urothelial cancer when treated with enfortumab vedotin versus chemotherapy.
Trials exploring enfortumab vedotin in patients with urothelial cancer in other settings are also underway, including a study of the ADC in combination with pembrolizumab (Keytruda) and/or platinum chemotherapy in newly diagnosed patients.