Enfortumab Vedotin Demonstrates Superior Efficacy versus Chemotherapy in Bladder Cancer

Web Exclusives — April 13, 2021

Patients with advanced urothelial carcinoma and disease progression after treatment with platinum-based chemotherapy and PD-1 or PD-L1 inhibitors have limited treatment options. Enfortumab vedotin (Padcev), a Nectin-4–directed antibody and microtubule inhibitor conjugate, demonstrated an objective response rate (ORR) in more than 40% of patients with advanced urothelial carcinoma who had progression after previous treatment.

In a new study, researchers reported the results from the confirmatory phase 3 EV-301 study for the benefit of enfortumab vedotin versus chemotherapy in this setting (Powles T, et al. N Engl J Med. 2021;384:1125-1135).

EV-301 was a global, open-label, phase 3 study that included 608 patients with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types. Eligible patients had radiographic progression or had relapsed during or after immune checkpoint inhibitor for the treatment of advanced urothelial cancer and had received previous platinum-containing chemotherapy. Patients also had an Eastern Cooperative Oncology Group performance status score of 0 or 1.

The patients were randomized in a 1:1 ratio to enfortumab vedotin 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle or to investigator-chosen chemotherapy on day 1 of every 21-day cycle. The primary end point was overall survival (OS). The secondary end points included progression-free survival (PFS), ORR, and safety.

As of the data cutoff, a total of 301 deaths occurred (134 deaths in the enfortumab vedotin cohort and 167 deaths in the chemotherapy cohort). At a median follow-up of 11.1 months, the median treatment exposure was 5 months in the enfortumab vedotin arm and 3.5 months in the chemotherapy arm.

Enfortumab vedotin demonstrated a 30% lower risk for death, indicating a significantly longer OS. The median OS with enfortumab vedotin was 12.88 months versus 8.97 months with chemotherapy (hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.56-0.89; P = .001). Treatment with enfortumab vedotin also resulted in a significantly longer PFS than chemotherapy and a 38% lower risk for disease progression or death (HR, 0.62; 95% CI, 0.51-0.75; P <.001).

The median PFS was 5.5 months in the enfortumab vedotin group and 3.7 months in the chemotherapy group. The confirmed ORR was also higher in the enfortumab vedotin arm than in the chemotherapy arm (40.6% vs 17.9%, respectively), with a complete response observed in 4.9% and 2.7% of the patients, respectively.

The incidence of treatment-related adverse events was high overall, but was similar in the 2 arms (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group). Treatment-related adverse events of special interest in the enfortumab vedotin arm included rash (43.9%), peripheral neuropathy (46.3%), and hyperglycemia (6.4%); these events were mild to moderate in severity.

“The efficacy data from this trial suggest that enfortumab vedotin may play a role in the treatment of advanced urothelial carcinoma. In light of recent data that support maintenance treatment with the PD-L1 inhibitor avelumab [Bavencio] after platinum-containing chemotherapy for advanced urothelial carcinoma, enfortumab vedotin may be considered at the time of the first relapse after maintenance immunotherapy,” noted the researchers.

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