BACKGROUND: Patients with advanced urothelial carcinoma whose disease progressed after platinum-based chemotherapy and PD-1/PD-L1 inhibitor have limited treatment options. Enfortumab vedotin, 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 whose disease progressed after previous treatment. Researchers reported new results from the confirmatory phase 3 EV-301 study, showing the superiority of enfortumab vedotin compared with chemotherapy in this setting.
METHODS: EV-301 was a global, open-label, phase 3 study of 608 patients with histologically or cytologically confirmed advanced urothelial cancer, including patients with squamous differentiation or mixed cell types. Eligible patients had radiographic progression or relapsed disease during or after receiving an immune checkpoint inhibitor and have previously received platinum-containing chemotherapy. The patients’ Eastern Cooperative Oncology Group performance status score was 0 or 1. All 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 (docetaxel, paclitaxel, or vinflunine, where this drug was approved) 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.
RESULTS: 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 mortality risk, 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 with enfortumab vedotin versus 3.7 months with chemotherapy. The confirmed ORR was 40.6% with enfortumab vedotin versus 17.9% with chemotherapy, including complete response rate of 4.9% and 2.7%, 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). Mild to moderate treatment-related adverse events of special interest with enfortumab vedotin included rash (43.9%), peripheral neuropathy (46.3%), and hyperglycemia (6.4%).
“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 after platinum-containing chemotherapy for advanced urothelial carcinoma, enfortumab vedotin may be considered at the time of the first relapse after maintenance immunotherapy,” the researchers wrote.
Source: Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384:1125-1135.
Commentary by Robert J. Ignoffo
This was an international, randomized trial in patients with advanced urothelial cancer whose disease was refractory to treatment with platinum or PD-1/PD-L1 inhibitor. A modest benefit was seen in median OS (12.88 months vs 8.97 months, respectively) and in PFS (5.55 months vs 3.71 months) in men receiving enfortumab vedotin versus chemotherapy. Only 23% of the study population were women. Further study is needed in women to determine if enfortumab vedotin offers any benefit over chemotherapy for those with refractory or relapsed disease.
As expected, more nonhematologic toxicities occurred in the enfortumab vedotin group than the PD-1/PD-L1 group, particularly sensory neuropathy, maculopapular rash, diarrhea, and hyperglycemia. Peripheral sensory neuropathy was the most common treatment-related adverse event, which resulted in dose reduction (7.1%), treatment interruption (15.5%), or withdrawal of treatment (2.4%) in the enfortumab vedotin group. Hyperglycemia occurred more frequently in patients with a baseline or with a body mass index of ≥30 kg/m2.
The National Comprehensive Cancer Network guidelines should be updated to indicate that enfortumab vedotin is an effective treatment for refractory urothelial cancer after platinum and/or PD-1/PD-L1 inhibitor therapy.