Globally, approximately 580,000 people will be diagnosed with bladder cancer in 2020.
Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (the tube that connects the kidneys to the bladder), and urethra. Approximately 80% of people do not respond to programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors after a platinum-containing therapy has failed as an initial treatment for advanced disease.
A different approach
In December 2019 enfortumab vedotin was approved by the U.S. Food and Drug Administration (FDA) under the Accelerated Approval Program based on the tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
The drug is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and neoadjuvant or adjuvant platinum-containing chemotherapy before or after surgery or in a locally advanced or metastatic setting.
Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. Nonclinical data suggest the anticancer activity of Enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).
The EV-301 trial (NCT03474107) is a global, multicenter, open-label, randomized phase III trial designed to evaluate enfortumab vedotin versus physician’s choice of chemotherapy (docetaxel, paclitaxel, or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1 or PD-L1 inhibitor and platinum-based therapies.
The primary endpoint is overall survival (OS) of participants treated with enfortumab vedotin compared to those treated with chemotherapy. Secondary endpoints include progression-free survival (PFS) duration of response (DOR), and overall response rate (ORR), as well as the assessment of safety/tolerability and health-related Quality-of-Life (hrQoL) parameters.
The results were reviewed by an independent Data Monitoring Committee following a planned interim analysis. The global EV-301 clinical trial compared enfortumab vedotin to chemotherapy in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor.
In the trial, enfortumab vedotin significantly improved overall survival (OS), with a 30% reduction in risk of death (Hazard Ratio [HR]=0.70; [95% Confidence Interval (CI): 0.56, 0.89]; p=0.001). Enfortumab vedotin also significantly improved progression-free survival (PFS), a secondary endpoint, with a 39% reduction in risk of disease progression or death (HR=0.61 [95% CI: 0.50, 0.75]; p<0.00001).
For patients in the enfortumab vedotin arm of the trial, treatment-related adverse events (TRAEs) were consistent with those listed in the U.S. Prescribing Information, with rash, hyperglycemia, decreased neutrophil count, fatigue, anemia, and decreased appetite as the most frequent Grade 3 or greater adverse event(s) occurring in more than 5% of patients.
Data from EV-301 will be submitted for presentation at an upcoming scientific congress. Patients in the chemotherapy arm of the trial will be offered the opportunity to receive enfortumab vedotin.
The results will be submitted to the U.S. Food and Drug Administration (FDA) as the confirmatory trial following the drug’s accelerated approval in 2019. EV-301 is also intended to support global registrations.
“These survival results from the confirmatory trial for PADCEV are welcome news for patients whose cancer has progressed after platinum-based chemotherapy and immunotherapy,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.
“We continue to explore enfortumab vedotin’s activity across the spectrum of urothelial cancer including its potential for use in earlier lines of therapy,” Dansey added.
“EV-301 is the first randomized trial to show overall survival results compared to chemotherapy in patients with locally advanced or metastatic urothelial cancer who previously have received platinum-based treatment and a PD-1 or PD-L1 inhibitor, and we are encouraged by the potential this may have in helping patients who have otherwise limited alternatives,” said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas.
“We look forward to discussing these results with global health authorities,” Krivoshik noted.
A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) – NCT03474107
 International Agency for Research on Cancer. Cancer Tomorrow: Bladder. Online. Last accessed on September 17, 2020
 American Society of Clinical Oncology. Bladder cancer: Introduction. Online. Last accessed on September 17, 2020.
 Shah, Manasee V., et al. Targeted Literature Review of the Burden of Illness in UC. (PCN108), Nov 2018.
 Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.
Featured image: Seattle Genetics. Exhibition booth during the 2019 annual meeting of the American Society of Medical Oncology (ASCO). In the back of the booth the enfortumab vedotin/PADCEV® presentation. Photo courtesy: © 2019 Sunvalley Communication. Used with permission.
An edited version of this article was published in ADC Review | Journal of Antibody-drug Conjugates.