As reported in The Lancet Oncology by Evan Y. Yu, MD, and colleagues, findings in a cohort of the phase II EV-201 study showed a high response rate with the nectin-4–directed antibody-drug conjugate enfortumab vedotin-ejfv in cisplatin-ineligible patients with advanced or metastatic urothelial carcinoma who had received prior treatment with a PD-1 or PD-L1 inhibitor.

Evan Y. Yu, MD

Findings in another cohort of EV-201 supported the December 2019 accelerated approval of enfortumab vedotin-ejfv for treatment of patients with locally advanced or metastatic urothelial cancer with previous PD-1 or PD-L1 inhibitor therapy and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.

Study Details

The cohort (cohort 2) included 89 patients enrolled between October 2017 and February 2020 from sites in North America, Europe, and Asia. Patients were considered ineligible for cisplatin therapy at enrollment and had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. All patients except one had metastatic disease.

Enfortumab vedotin was given intravenously at 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity.  The primary endpoint was confirmed objective response rate on blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1.

Responses

Median follow-up was 13.4 months (interquartile range [IQR] = 11.3–18.9 months). At data cutoff (September 2020), confirmed objective responses were observed in 46 patients (52%, 95% confidence interval [CI] = 41%–62%), with complete response in 18 (20%). An additional 27 patients (30%) had stable disease. The disease control rate at 16 weeks was 58% (95% CI = 48%–69%).

Among 77 patients evaluable for target lesion response, 68 (88%) had reductions in target lesions. Median time to objective response was 1.8 months (IQR = 1.7–1.9 months). Median duration of response was 10.9 months (95% CI = 5.78 months–not reached).

Median progression-free survival was 5.8 months (95% CI = 5.03–8.28 months), with an estimated rate of 50% at 6 months and 33% at 12 months. Median overall survival was 14.7 months (95% CI = 10.51–18.20 months).

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 55% of patients, with the most common being neutropenia (9%), maculopapular rash (8%), fatigue (7%), and anemia, diarrhea, hyperglycemia, increased lipase, and decreased appetite (6% each). Treatment-related serious adverse events occurred in 15 (17%) patients, with the most common being acute kidney injury (3%) and decreased appetite, diarrhea, hyperglycemia, hypotension, and neutropenia (2% each).

Treatment-related adverse events led to discontinuation of treatment in 16% of patients, with the most common cause being peripheral sensory neuropathy (4%). Adverse events considered related to treatment led to death in four patients, including acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome occurring within 30 days of first dose in one patient each and pneumonitis occurring at more than 30 days after the last dose in one patient.

The investigators concluded, “Treatment with enfortumab vedotin was tolerable, and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need.”

Dr. Yu, of the Clinical Research Division, Fred Hutchinson Cancer Research Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Astellas Pharma Global Development and Seagen. For full disclosures of the study authors, visit thelancet.com.