N-803 in Combination With Pembrolizumab and Enfortumab Vedotin for Treatment of Urothelial Cancer

Inclusion Criteria: 1. Age ≥ 18 years old. 2. Histologically or cytologically confirmed locally advanced/ mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as \>50% urothelial component is present (mixed histology other than small cell/ neuroendocrine are allowed). 3. No prior systemic treatment for locally advanced/mUC. 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2. 5. Measurable disease according to RECIST v1.1. 6. Prior perioperative systemic therapy including neoadjuvant or adjuvant chemotherapy, immune checkpoint inhibitors, and EV is allowed if treatment was completed \>12 months before trial enrollment. 7. Participants enrolling in the trial must agree with discontinuing EV upon demonstrating confirmed CR/PR/SD at the second or third scan timepoint on treatment (after 5.5 to 8 months of intended EV treatment). 8. Adequate organ and marrow function as defined below: 1. Leukocytes ≥ institutional lower limit of normal (LLN) 2. Absolute neutrophil count (ANC) ≥ 1,500/μL 3. Platelets ≥ 100,000/μL 4. Total bilirubin \< 1.5 × institutional upper limit of normal (ULN) (if previously abnormal due to non-malignant causes such as Gilbert's disease bilirubin ≤ 2 × ULN will be permitted.) 5. Aspartate aminotransferase (AST) (SGOT)/ alanine aminotransferase (ALT) (SGPT) ≤ 2.5 × institutional upper limit of normal (ULN) 6. Creatinine clearance ≥ 30 mL/min/1.73 m2 calculated using the Cockcroft-Gault equation 9. Must have archival tumor tissue available or have disease amenable to a fresh biopsy for diagnosis confirmation and correlative studies. 10. Human immunodeficiency virus (HIV)-infected individuals with undetectable viral load within 6 months are eligible for this trial. Trial participants who are on antiretroviral therapy (ART) should be on established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrollment. 11. For participants with history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable, and the participant should be on suppressive antiviral therapy, if indicated. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured, with HCV viral load below the level of quantification. A participant who is HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution is eligible for this trial. For individuals with HCV infection who are currently on treatment, they are eligible if HCV viral load is below the level of quantification. 12. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. 13. Participants who are on beta blockers can enroll in the trial, but discontinuation of beta-blockers should be strongly considered at the time of initiating NAI. Beta blocker use can continue per physician discretion if necessary. 14. Agreement to practice effective contraception for female participants of childbearing potential and nonsterile males. Female participants of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Female participants of childbearing potential must have a negative pregnancy test and adhere to using a highly effective method of contraception (refer to Section 4.1.3) prior to screening and agree to continue its use during the study or be surgically sterilized (eg, hysterectomy) while on study and for 7 months post last dose of study drug. Male participants must agree to use barrier methods of birth control while on study and to advise their female partners to use a highly effective method of contraception for 7 months post last dose of study drug. 15. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines. Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: 1. Symptomatic or untreated central nervous system (CNS) metastases. Note: Participants with previously treated brain or CNS metastases are eligible if the participant have recovered from any acute effects of surgery or radiotherapy and do not require steroids (prednisone equivalent ≥ 10 mg daily), and any whole brain radiation therapy or any stereotactic radiosurgery was completed at least 2 weeks prior to initiation of therapy. 2. History of active autoimmune disease and on active management with immunosuppressive agents within the past 2 years. 3. History of interstitial lung disease. 4. Congestive heart failure (New York Heart Association class III or IV) 5. Participants on systemic intravenous (IV) or oral corticosteroid therapy (prednisone equivalent ≥ 10 mg daily) or other immunosuppressive agents such as azathioprine or cyclosporin A. For these participants, these excluded treatments must be discontinued at least 1 week prior to enrollment for recent short course use (≤ 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (\> 14 days). Note: The use of corticosteroids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study. Participants requiring hormone replacement with corticosteroids if the steroids are administered only for the purpose of hormonal replacement or participants treated at doses ≤ 10 mg of prednisone or equivalent per day are allowed. 6. History of uncontrolled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 8%. 7. Grade ≥ 2 peripheral neuropathy at baseline. 8. Radiotherapy or major surgery within 2 weeks prior to treatment start. 9. History of another significant life-limiting malignancy within 2 years prior to the first dose of study drug. Participants with nonmelanoma skin cancer, curatively treated localized prostate cancer, or carcinoma in situ of any type (if complete resection was done) are allowed. 10. History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to EV and/or pembrolizumab and/or NAI. 11. Received hematopoietic stem cell transplantation or solid organ transplantation. 12. Known active keratitis or corneal ulcerations. 13. Received or will receive a live vaccine within 30 days prior to the first administration of study intervention. Note: Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved COVID-19 vaccines are permitted. 14. Pregnant and nursing women. 15. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. 16. Severe uncontrolled intercurrent illness that would limit compliance with study requirements in the judgement of the Investigator.