Cisplatin-based combination chemotherapy is the standard first-line therapy for patients with metastatic urothelial cancer (UC). Patients with high PD-L1 expression who are not eligible for platinum chemotherapy may receive first-line treatment with immune checkpoint inhibitors, pembrolizumab or atezolizumab. Following progression on platinum-based chemotherapy, most patients are treated with one of the five PD-(L)1 inhibitors currently available. However, only 15% to 20% of patients benefit from immunotherapy, and there is a high unmet need for new treatments for patients with metastatic urothelial carcinoma. Enfortumab vedotin (EV) is a nectin-4 targeting antibody-drug conjugate (ADC) that delivers the microtubule disrupting agent monomethyl auristatin E (MMAE) to tumor cells, inducing cell death. Nectin-4 is upregulated in 97% of UC, making it an attractive target for UC therapy.
At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Daniel Petrylak, MD (Yale Cancer Center, New Haven, Connecticut, United States), presented updated results from Cohort 1 of the single-arm phase II trial EV-201 trial (Abstract LBA4505), which evaluated EV monotherapy (1.25 mg/kg on days 1, 8, and 25 of a 28-day cycle) in 125 patients with advanced UC who had previously been treated with both platinum chemotherapy and a PD-(L)1 antibody. Cohort 2, which is evaluating EV in patients who have received prior PD-(L)1 inhibitor but are cisplatin ineligible, is currently ongoing.
Nectin-4 expression was detected in all patients of Cohort 1 with median H-score 290. The objective response rate (ORR) was 44%, including complete response in 12% of patients. A total of of patients experienced tumor shrinkage from baseline on EV treatment. Among patients who had not previously responded to anti-PD-(L)1 therapy, the ORR was 41%. Patients with liver metastases had a 38% ORR. The median duration of response (DoR) to EV was months, median progression-free survival (PFS) was months, and median overall survival (OS) was 11.7 months.
EV was well tolerated with a manageable adverse event (AE) profile. The AEs of interest with EV (any grade) included peripheral neuropathy (50%), rash (48%), and Only 12% of patients experienced AEs leading to treatment discontinuation. There was one treatment-related death due to interstitial lung disease.
Dr Petrylak concluded that EV is the first novel agent to demonstrate a substantial clinical benefit in patients who have progressed on both prior platinum-based chemotherapy and prior PD-(L)1 inhibitor, and that these data support EV as a potential new standard of care in this setting. The ongoing randomized phase III EV-301 is further evaluating EV in this setting.