In the EV-302 study, the risk of disease progression or death in the enfortumab vedotin and pembrolizumab arm was 55% lower than the risk in the standard platinum-based chemotherapy arm among patients who received the first-line treatment for locally advanced or metastatic urothelial cancer. Treatment with enfortumab vedotin and pembrolizumab also resulted in a 53% lower risk of death than chemotherapy.
The percentages of patients who had an overall response were also significantly higher with enfortumab vedotin and pembrolizumab than with chemotherapy. A majority of these responses were ongoing at 12 and 18 months in the enfortumab vedotin and pembrolizumab arm. The efficacy benefits were seen across all the prespecified subgroups. The study findings are published by Prof. Thomas Powles of the Barts Cancer Institute Biomedical Research Centre, Queen Mary University of London in London, UK and colleagues in the 7th March 2024 issue of The New England Journal of Medicine.
The authors wrote in the background that the treatment outcomes with standard platinum-based chemotherapy are poor with a low 5-year survival rate. Maintenance treatment with avelumab has been shown to result in longer overall survival (OS) than best supportive care alone, but a notable proportion of patients do not receive maintenance treatment due to disease progression or death.
A modest improvement in OS has recently been shown for nivolumab when added to gemcitabine-cisplatin, other studies with a combination of chemotherapy and immune checkpoint inhibition have not shown an improvement in OS in patients with locally advanced or metastatic urothelial cancer.
Enfortumab vedotin, an antibody–drug conjugate directed against nectin-4, and pembrolizumab, a PD1 inhibitor, have individually been associated with a survival benefit in patients with previously treated locally advanced or metastatic urothelial cancer. In preclinical studies, the combination of enfortumab vedotin and a PD1 inhibitor showed enhanced antitumour activity with lasting antitumour immunity.
Based on the results of a phase Ib/II study in which the combination resulted in high incidences of response and durable responses, enfortumab vedotin in combination with pembrolizumab received accelerated approval in the United States for the use in patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy.
EV-302 is a phase III, global, open-label, randomised study comparing the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin and pembrolizumab or gemcitabine and either cisplatin or carboplatin. The primary endpoints were progression-free survival (PFS) as assessed by blinded independent central review and OS.
A total of 886 patients underwent randomisation, 442 to the enfortumab vedotin and pembrolizumab arm and 444 to the chemotherapy arm. As of 8th August 2023, the median duration of follow-up for survival was 17.2 months. PFS was longer in the enfortumab vedotin and pembrolizumab arm than in the chemotherapy arm with a median of 12.5 months versus 6.3 months (hazard ratio [HR] for disease progression or death 0.45, 95% confidence interval [CI] 0.38 to 0.54; p < 0.001), as was OS with a median of 31.5 months versus 16.1 months (HR for death 0.47, 95% CI 0.38 to 0.58; p < 0.001).
The percentage of patients who had a complete response with enfortumab vedotin and pembrolizumab was higher than the percentage observed with chemotherapy and is higher than results reported previously. The efficacy benefits were seen across all the prespecified subgroups, such as those defined according to the presence or absence of liver metastases, cisplatin eligibility status, and PD-L1 expression status.
The delay in the patient-reported outcome, time to pain progression, did not differ significantly between the two arms. More detailed patient-reported analysis will be needed to contextualise the effect of these findings in patients. At the time of data cut-off, 31.7% of the patients in the enfortumab vedotin and pembrolizumab arm had received subsequent anticancer treatments, with a majority of patients having received platinum-based chemotherapy as second-line therapy, and 32.6% of the patients continued to receive the study treatment.
The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin and pembrolizumab arm and 6 (range, 1 to 6) in the chemotherapy arm. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin and pembrolizumab arm and in 69.5% of those in the chemotherapy arm.
The most common adverse events of special interest of grade 3 or higher that have previously been associated with enfortumab vedotin were skin reactions, peripheral neuropathy, and hyperglycaemia. The most common adverse events of special interest of grade 3 or higher that have previously been associated with pembrolizumab included severe skin reactions, pneumonitis, and hepatitis. Early recognition of adverse reactions through proactive monitoring and management of symptoms remains a cornerstone of patient care with enfortumab vedotin and pembrolizumab.
In an accompanied editorial, Dr. Günter Niegisch of the Department of Urology, University Hospital and Medical Faculty of the Heinrich Heine University Düsseldorf, Germany wrote that given the significant and clinically relevant improvement in oncologic outcomes with the combination of enfortumab vedotin and pembrolizumab, this study should be considered a landmark trial that has set a new standard-of-care regimen against which future trials must be compared.
However, the economic aspects of treatment with enfortumab vedotin and pembrolizumab should not be ignored. The general use of enfortumab vedotin and pembrolizumab in place of platinum-based chemotherapy with or without avelumab maintenance will depend largely on the respective healthcare system and the local economic conditions. In this context, a question about the actual duration of treatment needed for tumour control is relevant as well.
This work was supported by Astellas Pharma US; Merck Sharp and Dohme, a subsidiary of Merck; and Seagen, which was acquired by Pfizer in December 2023.
References
- Powles T, Valderrama BP, Gupta S, et al. for the EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024;390:875-888.
- Niegisch G. Enfortumab Vedotin and Pembrolizumab — A New Perspective on Urothelial Cancer. N Engl J Med 2024; 390:944-946.