The antibody–drug conjugate (ADC) enfortumab vedotin (PADCEV®) has been shown to increase the survival of patients with urothelial carcinoma in a recent study. Results from the randomized open-label Phase 3 trial were published in the New England Journal of Medicine.
Urothelial carcinoma originates in urothelial cells and accounts for ~ 90% of all bladder cancers. This cell type lines several components of the urinary tract meaning, in addition to the bladder, tumors can also develop in the ureters, urethra and parts of the kidney.
The clinical trial involved 608 adult participants across 19 countries. The efficacy of enfortumab vedotin was investigated in participants with a confirmed diagnosis of either locally advanced or metastatic urothelial cancer, who had previously been treated with platinum-based chemotherapy and had had disease progression during or after treatment with a specific type of immunotherapy known as an immunomodulator (PD-1/L1 inhibitor).
“This new type of drug has led to a survival advantage in bladder cancer which has been difficult to achieve in this difficult disease. It reduced the death rate by 30% and beat chemotherapy in every setting, so this really is a big deal,”
– Tom Powles, professor of genitourinary oncology at Queen Mary University of London, and director of Barts Cancer Centre, Barts Health NHS Trust.
Study design and key findings
Trial participants were randomly assigned to receive enfortumab vedotin (n=301) at a dose of 1.25 mg per kg of body weight on days 1, 8 and 15 of a 28-day treatment cycle, or chemotherapy (n=307) administered on day 1 of a 21-day treatment cycle.
The risk of death was 30% lower in participants administered enfortumab vedotin compared with chemotherapy. The median survival of participants administered enfortumab vedotin was ~ 13 months versus ~ 9 months for the chemotherapy arm.
Median progression-free survival, was 5.6 months (95% CI, 5.32 to 5.82) for enfortumab vedotin versus 3.7 months (95% CI, 3.52 to 3.94) for chemotherapy alone.
While enfortumab vedotin was shown to be beneficial across multiple subgroups, it did not provide an advantage over chemotherapy in the female patient subgroup.
Overall response rate, defined as the proportion of participants in the trial who had a full or partial response to treatment, was 40.6% [95% CI, 34.9 to 46.5] for enfortumab vedotin versus 17.9% [95% CI, 13.7 to 22.8] for chemotherapy alone; P<0.001.
The study authors noted that “incidence of treatment-related adverse events was high overall but was similar in the two groups”. Treatment-related adverse effects are defined as those for which there is a reasonable chance that they were caused by the treatment. While most adverse events observed in the trial were mild to moderate, the authors highlighted that there is a chance that some patients may experience serious adverse events upon administration of enfortumab vedotin. They should therefore be monitored closely for signs of rash (likely related to the presence of nectin-4 in the skin), peripheral neuropathy and hyperglycemia. The incidence of treatment-related deaths in the enfortumab vedotin arm was comparable to previous trials involving patients with this type of cancer.
In summary, significantly longer overall survival and progression-free survival was observed in patients with urothelial carcinoma administered enfortumab vedotin and a higher overall response was achieved compared with those in the chemotherapy arm.
Reference: Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. New Eng. J. Med. 2021. doi:10.1056/NEJMoa2035807