Patients with MIBC will receive 3 cycles (C1-C3) of induction enfortumab vedotin plus pembrolizumab followed by restaging including MRI of the bladder, urine cytology, and cystoscopy with TURBT of any visible tumor and/or resection site plus random biopsies using a recommended template. Patients achieving a stringently defined cCR (clinical complete response) will receive 14 cycles of "maintenance" treatment. Enfortumab vedotin will be administered during the first 6 cycles (C4-C9) of "maintenance" treatment and pembrolizumab will be given all 14 cycles (C4-C14). Patients with any residual disease at clinical restaging (i.e., >cTa disease) will undergo cystectomy.

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of 0-1 within 28 days prior to registration.

4. Histological evidence of clinically localized muscle-invasive urothelial cancer of the bladder clinical stage T2-3N0M0. Participants with mixed histology are eligible provided the urothelial component is ≥50% with the following exceptions: (a) tumors with any degree of squamous differentiation are eligible provided there is a urothelial cancer component, (b) tumors that contain any component of neuroendocrine histology are not eligible. N0 will be considered as the absence of radiographically enlarged lymph nodes on baseline imaging (i.e., Patients with lymph nodes ≥1 cm in short axis on imaging are not eligible).

5. Have undergone a standard of care maximal transurethral resection of bladder tumor ≤ 90 days prior C1D1. A maximal TURBT should be performed when feasible and is defined as a macroscopically complete resection of bladder tumor.

6. All subjects must have adequate transurethral resection of bladder tumor tissue available for submission identified during screening. The specimen must include tumor tissue (i.e., if a restaging maximal TURBT was performed and there was no cancer in the specimen, tissue from the most recent prior TURBT that established the diagnosis of muscle-invasive urothelial cancer of the bladder should be submitted). Tissue from both the restaging TURBT and the prior diagnostic TURBT may be requested. Subjects without available archival tissue must be discussed with the sponsor-investigator.

7. Be deemed eligible to undergo radical cystectomy and pelvic lymph node dissection

8. Demonstrate adequate organ function as defined below. All screening labs to be obtained within 28 days prior to registration.

   • Absolute neutrophil count (ANC): ≥ 1.5 x 10^9/L
   • Hemoglobin (Hgb): ≥ 9 g/dL
   • Platelets: ≥ 100 x 10^9/L
   • Creatinine clearance: ≥ 30 mL/min
   • Bilirubin: ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN
   • Aspartate aminotransferase (AST): ≤ 2.5 × ULN
   • Alanine aminotransferase (ALT): ≤ 2.5 × ULN
   • International normalized ratio (INR) or Prothrombin time (PT) or Partial thromboplastin time (PTT): ≤ 1.5 ×ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range for intended use of anticoagulants

10. Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. WOCBP must agree to use contraception.

11. Male participants able to father a child who are sexually active with female of childbearing potential must be willing to use an effective method(s) of contraception.

Exclusion Criteria:

1. Pre-existing sensory or motor neuropathy Grade ≥ 2
2. Ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery).
3. Prior systemic chemotherapy for muscle-invasive urothelial cancer of the bladder.
4. Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured. Patients with intermediate or lower risk prostate cancer as defined by the National Comprehensive Cancer Network (NCCN) risk stratification guidelines may be eligible for enrollment.
5. Prior radiation therapy for bladder cancer.
6. Hemoglobin A1c ≥ 8% or hemoglobin A1c 7%-<8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained
7. Active infection requiring systemic therapy.
8. Known active Hepatitis B or C infection. NOTE: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
9. HIV-infected patients on effective anti-retroviral therapy with an undetectable viral load are eligible.
10. Has a known history of active TB (Bacillus Tuberculosis).
11. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
12. 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).
13. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
15. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or enfortumab vedotin and/or any of their excipients.
16. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
17. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
19. Has had an allogenic tissue/solid organ transplant.
20. Is currently receiving an investigational agent or has received an investigational agent or used an investigational device within 28 days of study registration.