Pembrolizumab and EV With Radiation Therapy for MIBC Patients (PEVRAD)

Inclusion Criteria: * Participants are eligible to be included in the study only if all of the following criteria apply: 1. Male/female participants who are at least 18 years of age on the day of signing informed consent and who have a first confirmed diagnosis of MIBC with predominant urothelial histology obtained via a diagnostic or maximal TURBT within 90 days prior to enrollment. Note: Participants with mixed histology are eligible provided the urothelial component is ≥50%. 2. Has clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT of the chest and CTU/MRU of abdomen and pelvis), assessed by the site. 3. Male participants: A male participant must agree to use a contraception and not to donate sperm during the administration of MK-3475 and ASG-22CE and for at least 90 days after the last dose of MK-3475 and for 6 months after ASG-22CE. 4. Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) OR 2. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of MK3475 and for 6 months after ASG-22CE and RT. 5. The participant provides written informed consent for the trial. 6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. 7. Demonstrates adequate organ function. All screening laboratory tests should be performed within 10 days prior to the first dose of study intervention. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1. Has the presence of diffuse CIS (multiple foci \[4 or greater\] of CIS) throughout the bladder. 2. Has the presence of UC at any site outside of the urinary bladder in the previous 2 years except for Ta/T1/CIS of the upper tract if the patient has undergone a complete nephroureterectomy. 3. Has the presence of any small cell or neuroendocrine component in the tumor tissue sample. 4. Has a known additional malignancy that is progressing or has required active therapy within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) who have undergone potentially curative therapy are not excluded. Participants with low-risk prostate cancer (T1-T2a, Gleason score ≤6, and PSA \<10 ng/mL) either treated with definitive intent any time before screening or untreated in active surveillance are not excluded. 5. Has limited bladder function with frequency of small amounts of urine (\< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter. 6. Has a history of radiation therapy to the pelvic region for any reason. Prior/Concomitant Therapy 7. Has received prior pelvic/local radiation therapy or any antineoplastic treatment for MIBC. Note: Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted, but must be completed ≥28 days before the first dose of the trial drug. Prior systemic treatment received for treatment of NMIBC is not permitted. 8. 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). 9. Has received prior therapy with an ASG-22CE or other MMAE-containing ADCs. 10. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. Note: please refer to Section 5.5 for information on COVID-19 vaccines Prior/Concurrent Clinical Study Experience 11. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 months before the first dose of study intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Diagnostic Assessments 12. A WOCBP who has a positive urine pregnancy test within 72 hours prior to the first dose of study intervention (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 13. Has uncontrolled diabetes. Uncontrol diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to \<8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. 14. Has ongoing sensory or motor neuropathy Grade 2 or higher. 15. Has active keratitis or corneal ulceration. Subjects with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator. 16. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted. 17. 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 trial drug. 18. Has severe hypersensitivity (≥Grade 3) to MK-3475, ASG-22CE and/or any of their excipients. 19. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid). 20. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 21. Has an active infection requiring systemic therapy. 22. Has a known history of Human Immunodeficiency Virus (HIV) infection. The test should be performed within 28 days prior to the first dose of the trial drug. 23. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. The test should be performed within 28 days prior to the first dose of the trial drug. 24. Has not adequately recovered from major surgery or has ongoing surgical complications. 25. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 26. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 27. Pregnant or lactating, or female patients or male patients who wish to become pregnant from the time of screening to 120 days after the last dose of MK-3475 and 6 months after radiotherapy and the last dose of ASG-22CE, or their partners. 28. Has had an allogenic tissue/solid organ transplant. 29. Has a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV within 6 months prior to the first dose of the trial drug. 30. Or, if participation in this clinical trial is considered inappropriate according to the judgment of the investigator.