This phase II clinical trial tests how well pembrolizumab plus enfortumab vedotin prior to and after radical nephroureterectomy works in treating patients with high-risk upper tract urothelial cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Enfortumab vedotin (EV) is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Radical nephroureterectomy (RNU) is the surgical removal of a kidney and its ureter. Giving pembrolizumab plus enfortumab vedotin before surgery may make the tumor smaller and may reduce the amount of normal tissue that needs to be removed and giving pembrolizumab after surgery may kill any remaining cancer cells.
Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of high-risk upper tract urothelial carcinoma will be enrolled in this study
Male participants: A male participant must agree to use a contraception during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period
Not a woman of childbearing potential (WOCBP) OR
A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 6 months after the last dose of study treatment
A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to allocation
Single group
Biopsy
Procedure/SurgeryUndergo tissue biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood and urine collection
Enfortumab Vedotin
DrugGiven IV
MR Urography
Procedure/SurgeryUndergo MRU
Nephroureterectomy
Procedure/SurgeryUndergo nephroureterectomy
Pembrolizumab
Biological/VaccineGiven IV
Pathological objective response (ORR) rate
Will be assessed by the combination of partial response (PR) and complete response (CR). PR is defined as pathologic stage \<T2 disease. CR is defined as pT0 disease and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.
Radiographic recurrence-free survival
Incidence of adverse events
Will be assessed using the National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.
Rates of completion of neoadjuvant pembrolizumab and enfortumab vedotin
Will be assessed as completion of all infusions of both agents and successful completion of radical nephroureterectomy.
Perioperative complications
Will be assessed based on the Clavien-Dindo classification.
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Jonsson Comprehensive Cancer Center
Lead sponsor
Merck Sharp & Dohme LLC
Collaborator
Seagen Inc.
Collaborator
