The antibody-drug conjugate was previously granted an accelerated approval by the FDA in this setting based on results from the phase 2 EV-201 trial.
Results from the confirmatory phase 3 EV-301 trial shared during the 2021 Genitourinary (GU) Cancers Symposium showed that the antibody-drug conjugate enfortumab vedotin (Padcev) reduced the risk of death by 30% versus chemotherapy in patients with heavily pretreated locally advanced or metastatic urothelial carcinoma.1
Patients enrolled in the trial had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor. The findings, which were simultaneously published in the New England Journal of Medicine2, showed that enfortumab vedotin improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus chemotherapy in this patient population.
“Enfortumab vedotin is the first drug beyond chemotherapy and immunotherapy to show a significant survival advantage in previously treated advanced urothelial cancer,” said Thomas Powles, MBBS, MRCP, MD, in a presentation during the GU Cancers Symposium. “This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited.”
The Nectin-4–directed antibody-drug conjugate was granted an accelerated approval by the FDA in December 2019 for the treatment of adult patients with locally advanced or urothelial cancer who have previously received a PD-1/ L1 inhibitor and platinum-containing chemotherapy.3 Accelerated approval was granted because treatment options are limited once urothelial cancer has progressed on both chemotherapy and immunotherapy. Data from the phase 2 EV-201 trial supported the approval.
The open-label, randomized EV-301 trial (NCT03474107) served as a confirmatory trial for the benefit of enfortumab vedotin over chemotherapy in this setting following the FDA approval.
A total of 608 patients with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types, were enrolled in the study and randomized 1:1 with stratification to either the enfortumab vedotin (n = 301) arm or the chemotherapy arm (n = 307). Eligible patients had radiographic progression or relapsed during or after immune checkpoint inhibition for the treatment of advanced urothelial cancer and had received prior platinum-containing chemotherapy; patients also had an ECOG performance status of 0 or 1. Stratification variables included ECOG performance status (0 or 1), region of the world, and the presence or absence of liver metastasis.
In the investigational arm, enfortumab vedotin was administered at 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Chemotherapy in the control arm consisted of docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine 320 mg/m2 each given on day 1 of every 21-day cycle.
OS was the primary end point of the study and secondary end points included PFS, ORR, disease control rate (DCR)—all assessed by the investigator per RECIST v1.1 criteria—and safety.
With enrollment of approximately 600 patients, the study had 85% power to detect a statistically significant difference in efficacy at an overall 1-sided 0.025 type I error rate with a hazard ratio of 0.75.
The trial was planned to have 2 analyses, an interim one at 285 deaths (65%) and a final analysis at 439. For the interim analysis, OS was tested with a 1-sided difference of 0.00679.
Powles, a professor of genitourinary oncology, director of the Barts Cancer Center, and lead for Solid Tumor Research at the Barts Cancer Institute, in London, United Kingdom, explained that as interim analysis was positive for survival this became the primary analysis.
Baseline characteristics were balanced between the 2 arms. The median age was 68 years and more than three-fourths of patients were male. Only 14% of patients were from the United States, 60% had an ECOG performance status of 1, two-thirds had a Bellmunt risk score of 0 or 1, 31% had liver metastases, and 87% had 1 or 2 prior lines of therapy. In the enfortumab vedotin arm, 20% responded to prior immune checkpoint inhibition and 16% responded in the chemotherapy arm.
As of data cutoff, 81% of patients had discontinued treatment in the enfortumab vedotin arm versus 93% in the chemotherapy arm, which was due to progressive disease in 59% of patients in both arms. At a median follow-up of 11.1 months, the median treatment exposure was 5.0 months (range, 0.5-19.4) in the enfortumab vedotin and 3.5 months (range, 0.2-15.0) in the chemotherapy arm.
The median OS with enfortumab vedotin was 12.88 months (95% CI, 10.58-15.21) versus 8.97 months (95% CI, 8.05-10.74) with chemotherapy, which translated to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.56-0.89; P = .00142). Powles commented that the Kaplain-Meier curves for OS “go apart and stay apart, and the data look impressive in my opinion.”
Subgroup analyses for OS favored the enfortumab vedotin arm for all groups excepts female patients (HR, 1.17), although Powles noted that some of the subgroups were too small to draw conclusions.
Median PFS with enfortumab vedotin was 5.55 months (95% CI, 5.32-5.82) versus 3.71 months (95% CI, 3.52-3.94) with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P < .00001).
Confirmed ORR in the enfortumab vedotin arm was 40.6% (95% CI, 34.9%-46.5%), which included complete responses in 4.9%, and the DCR was 71.9% (95% CI, 66.3%-77.0%). In the chemotherapy arm, the ORR was 17.9% (95% CI, 13.7%-22.8%) with complete responses in 2.7%, and a DCR of 53.4% (95% CI, 47.5%-59.2%; P < .001).
Treatment-related adverse event (TRAE) rates were similar between the 2 arms, with any-TRAE rates of 94% in the investigational arm and 92% in the control arm, and grade ≥3 TRAE rates of 51% and 50%, respectively. Serious TRAEs were reported in 23% of patients in each arm and TRAEs led to treatment discontinuation in 14% of patients in the enfortumab vedotin arm and 11% in the chemotherapy arm.
Powles highlighted that the rate of grade ≥3 maculopapular rash was increased in the enfortumab vedotin arm (7% vs 0%), whereas rates of grade ≥3 neutrophil count decrease (6% vs 13%), white blood cell count decrease (1% vs 7%), and febrile neutropenia (1% vs 6%) were all higher in the chemotherapy arm.
TRAEs of special interest in the enfortumab vedotin arm included skin reactions of rash (all grade, 44%; grade ≥3, 15%) and severe cutaneous adverse reactions (all grade, 20%; grade ≥3, 5%), peripheral neuropathy in terms of sensory events (all grade, 44%; grade ≥3, 4%) and motor events (all grade, 7%; grade ≥3, 2%), and hyperglycemia (all grade, 6%; grade ≥3, 4%). The majority of TRAEs of special interest were mild to moderate in severity.
1. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2021;39(suppl 6):393. doi:10.1200/JCO.2021.39.6_suppl.393
2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. Published online February 12, 2021. N Engl J Med. doi:10.1056/NEJMoa2035807
3. FDA approves new type of therapy to treat advanced urothelial cancer. FDA website. December 18, 2019. Accessed February 12, 2021. https://bit.ly/3agPr77