A Phase 3, Randomized, Double-blind, Placebo-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) versus CRT Alone in Participants with Muscle-invasive Bladder Cancer (MIBC) (KEYNOTE-992)

1. Has a histologically confirmed initial diagnosis of MIBC with predominant
urothelial histology (histology and presence of muscle invasion to be confirmed
by BICR) obtained via a diagnostic or maximal TURBT performed within 90 days
before enrollment (signing of ICF).
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 and
verified by BICR.
3. Has provided tumor specimen to the central vendor to determine PDL1 status
before randomization.
4. Has planned and is eligible to receive CRT and one of the protocolspecified
radiosensitizing chemotherapy regimens.
5. Has an ECOG performance status of 0, 1, or 2 assessed within 14 days before
randomization.
6. Demonstrates adequate organ function. All screening laboratory tests should
be performed within 14 days before randomization.
7. Is male or female, at least 18 years of age, at the time of signing the
informed consent.
8. Male participants are eligible to participate if they agree to the following
during the intervention period and for at least 90 days after
the last dose of CRT treatment.
- Refrain from donating sperm
PLUS either:
- Be abstinent from heterosexual intercourse as their preferred and usual
lifestyle (abstinent on a long term and persistent basis) and agree to remain
abstinent
OR
- Must agree to use contraception unless confirmed to be azoospermic
(vasectomized or secondary to medical cause) as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive
method when having penile-vaginal intercourse with a WOCBP who is not currently
pregnant.
9. A female participant is eligible to participate if she is not pregnant or
breastfeeding, and at least one of the following conditions applies:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a
failure rate of <1% per year), with low user dependency, or be abstinent from
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a
long term and persistent basis), during the intervention period and for at
least the time needed to eliminate each study intervention after the last dose
of study intervention and agrees not to donate eggs (ova, oocytes) to others or
freeze/store for her own use for the purpose of reproduction during this
period. The length of time required to continue contraception for each study
intervention is as follows: MK-3475 [120 days], CRT [180 days].
The investigator should evaluate the potential for contraceptive method failure
(ie, noncompliance, recently initiated) in relationship to the first dose of
study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum,
as required by local regulations) within 24 hours before the first dose of
study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a
serum pregnancy test is required. In such cases, the participant must be
excluded from participation if the serum pregnancy result is positive.
- Abstains from breastfeeding during the study intervention period and for at
least 120 days (5 half-lives) after study intervention.
- The investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk for inclusion of a
woman with an early undetected pregnancy.
- Contraceptive use by women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies. If the contraception requirements in the local label for any of the
study interventions is more stringent than the requirements above, the local
label requirements are to be followed.
10. The participant (or legally acceptable representative if applicable) has
provided documented informed consent/assent for the study. The participant may
also provide consent/assent for FBR. However, the participant may participate
in the main study without participating in future biomedical research.

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.
5. Has the presence of bilateral hydronephrosis during the Screening period.
6. Has limited bladder function with frequency of small amounts of urine (< 30
mL), urinary incontinence, or requires self-catheterization or a permanent
indwelling catheter.
7. Has received prior pelvic/local radiation therapy or any antineoplastic
treatment for MIBC.
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent
or with an agent directed to another stimulatory or coinhibitory T-cell
receptor (eg, CTLA-4, OX- 40, CD137).
9. Has received a live vaccine within 30 days before the first dose of study
drug. Examples of live vaccines include, but are not limited to, the following:
measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,
BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
10. Is currently participating in or has participated in a study of an
investigational agent or has used an investigational device within 4 weeks
before the first dose of study intervention.
11. Has known severe hypersensitivity (>=Grade 3) to the selected chemotherapy
regimen, and/or any of their excipients and excipients of pembrolizumab.
12. 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 before the first dose
of study drug.
13. Has an active autoimmune disease that has required systemic treatment in
the past 2 years (ie, 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) is not considered a form of systemic treatment and is allowed.
14. Has a history of (non-infectious) pneumonitis that required steroids or has
current pneumonitis.
15. Has an active infection requiring systemic therapy.
16. Has a known history of HIV infection. No HIV testing is required unless
mandated by local health authority.
17. Has a known history of Hepatitis B (defined as HBsAg reactive) or known
active Hepatitis C virus (defined as HCV RNA [qualitative] is detected)
infection.
18. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). No
TB testing is required unless mandated by local health authority.
19. Has a history or current evidence of any condition, therapy, 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 is not in the best interest of the participant to
participate, in the opinion of the treating investigator.
20. Has a known psychiatric or substance abuse disorder that would interfere
with the participant's ability to cooperate with the requirements of the study.
21. Has had an allogenic tissue/solid organ transplant.