E-VIRTUE: a study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors—design and rationale

Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 with a monomethyl auristatin E payload, a potent microtubule inhibitor. It is a standard of care in metastatic or locally advanced urothelial carcinoma in combination with pembrolizumab in the first line, and as monotherapy post-chemotherapy and post-anti-PD-1/PD-L1 therapy. This article describes the design and rationale behind E-VIRTUE, an open-label phase 2 trial of EV with or without pembrolizumab in locally advanced or metastatic urinary tract pure adenocarcinoma or urachal adenocarcinoma, pure squamous cell carcinoma and treatment-refractory germ cell tumors. As these rare genitourinary tumors lack an established standard of care and published literature suggests nectin-4 expression, we hypothesize that EV with or without pembrolizumab will be effective in them. NCT06041503 (ClinicalTrials.gov). There is currently a lack of effective treatments for rare cancers arising in the urinary tract, such as adenocarcinomas and squamous cell carcinomas, and testicular cancers that have become resistant to multiple lines of chemotherapy (known as refractory testicular cancer). Published literature demonstrates that these cancers express the protein, nectin-4. Nectin-4 serves as an important target for the anticancer medication enfortumab vedotin (EV), which has been shown to be effective in treating bladder cancer that has spread beyond the bladder (known as metastatic bladder cancer); this cancer almost universally expresses nectin-4. The immunotherapy drug, pembrolizumab, has been shown to lengthen life in multiple cancer types including melanoma skin cancer, lung cancer, bladder cancer and kidney cancer. More recently, the combination of EV with pembrolizumab was proven to lengthen life in patients with metastatic bladder cancer. Given reports of nectin-4 expression in urinary tract adenocarcinomas and squamous cell carcinomas, and in refractory testicular cancer, we believe that EV with or without pembrolizumab will be effective in treating these tumors. The E-VIRTUE trial aims to evaluate EV with pembrolizumab in patients with these cancers who have never received immunotherapy and EV alone in patients who have previously received immunotherapy. The primary objective is to determine the percentage of patients with cancers that shrink by at least 30% in response to treatment. We will also report the percentage of tumors that express nectin-4 and evaluate new methods of assessing cancer, such as a blood test that identifies circulating tumor DNA.