By Jennifer Lubell
Enfortumab vedotin (EV) outperformed chemotherapy on key survival metrics in a phase 3 trial, extending the life of patients with previously treated advanced urothelial cancer by nearly four months, compared with standard care.
EV is the first drug to show a significant survival advantage beyond chemotherapy and immunotherapy in this group of patients, said Thomas Powles, MD, PhD, director of Barts Cancer Centre, Queen Mary University of London. Dr. Powles presented findings from the EV-301 study (Abstract 393) at the American Society of Clinical Oncology’s 2021 Genitourinary Cancers Symposium.
Platinum-containing chemotherapy sequenced with programmed cell death protein-1/programmed death ligand 1 (PD-1/L1) inhibitors is the standard of care for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). “Overall survival is disappointing,” noted Dr. Powles, pointing out the need for new therapeutic agents supported by randomized trials.
EV — a U.S. FDA-approved antibody-drug conjugate that targets Nectin-4 — is a cell adhesion molecule highly expressed in urothelial cancer. In phase 1 and 2 studies, the drug demonstrated a consistent clinical benefit with response rates of approximately 40%.
Investigators conducted an open-label, phase 3 study to confirm these initial findings. The study included 608 patients with histologically confirmed la/mUC who had previously received platinum-containing chemotherapy, and whose disease had progressed during or after PD-1/L1 inhibitor treatment. Patients were randomized 1:1 to receive EV (1.25 mg/kg) on days 1, 8, and 15 of each 28-day cycle, or investigator choice of standard docetaxel, paclitaxel, or vinflunine chemotherapy.
Overall survival was the primary endpoint. Secondary endpoints included investigator-assessed progression-free survival, overall response rate, disease control rate, and safety/tolerability.
Investigators planned two analyses: a final analysis after 439 deaths and an interim analysis at 285 deaths. Dr. Powles presented the interim analysis, “which was actually the primary analysis, because the trial was positive for survival at this time frame,” he said. They set a median overall survival of 8 months for chemotherapy for the statistical analyses.
Progression of disease was the most common reason for withdrawing from the study in both arms. Adverse events leading to discontinuation occurred in 14% of patients in the EV group and 15% of patients in the chemotherapy group.
Overall survival favored EV, with a median overall survival of 12.9 months, 3.9 months longer than what was seen in the chemotherapy group (Hazard Ratio [HR] 0.70; 95% CI: 0.56-0.89, P=0.001).
EV significantly improved progression-free survival (5.6 months) versus chemotherapy (3.7 months), as well as overall response rate (40.6% versus 17.9%) and disease control rate (71.9% versus 53.4%).
Subgroup analyses showed a benefit with EV, although some of these groups were too small to draw definitive conclusions.
EV demonstrated a tolerable and manageable safety profile, Dr. Powles said. “No new safety signals were identified, and this profile was consistent with prior studies with EV.”
Serious adverse events were reported for 23% of patients in both arms. “The majority of treatment-related adverse events of special interest were mild-to-moderate in severity,” Dr. Powles said.
Treatments leading to death, excluding progression of disease, occurred in 2.4% of patients in the EV arm and 1% in the chemotherapy arm.
“This is a big step in the right direction for patients with advanced urothelial cancer where treatment options remain quite limited,” Dr. Powles said.