Molecular Residual Disease (MRD) Guided Adjuvant ThErapy in Renal Cell Carcinoma (RCC)

Inclusion Criteria:

• Participants are eligible to be included in the study only if all the followingcriteria apply.

Type of Participant and Disease Characteristics

1. Must have histologically confirmed diagnosis of RCC with clear cell component withor without sarcomatoid features. Diagnosis of RCC with clear cell component is to bemade by the investigator and does not require central histology review. Molecular Residual Disease

2. Patients must have at least ONE available assessment of molecular residual diseaseby the Signatera® (Natera Inc.) assay performed within the last 90 days prior toenrollment in study. Demographics

3. Be ≥18 years of age on the day of signing informed consent. Female Participants:

4. Female participants of childbearing potential must have a negative urine or serumpregnancy test within 72 hours prior to randomization. If the urine test is positiveor cannot be confirmed as negative, a serum pregnancy test will be required.

5. Female participants of childbearing potential must be willing to use an adequatemethod of contraception, for the course of the study through 120 days after the lastdose of study drug. Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the participant. Male Participants:

6. Male participants of childbearing potential must agree to use an adequate method ofcontraception, starting with the first dose of trial therapy through 120 days afterthe last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the participant. Informed Consent

7. The participant provides written informed consent for the trial. The participant mayalso provide consent for Future Biomedical Research; however, the participant mayparticipate in the main trial without participating in Future Biomedical Research. Other Inclusion Criteria

8. Have intermediate-high risk, high risk RCC as defined by the following pathologicaltumor-node-metastasis and Fuhrman grading status {Oza, 2022 #4431}

9. Intermediate-high risk RCC

• pT2, Gr. 4 or sarcomatoid, N0, M0
• pT3, Any Gr., N0, M0

2. High risk RCC

• pT4, Any Gr. N0, M0
• pT Any stage, Any Gr., N+, M0

9. Have received no prior systemic therapy for advanced RCC unless having recentlyinitiated immunotherapy with pembrolizumab for no more than 6 weeks or 1 dose priorto enrollment.

10. Have undergone a partial nephroprotective or radical complete nephrectomy)

11. Must have undergone a nephrectomy ≥28 days prior to signing informed consent and ≤12weeks prior to enrollment.

12. Must be tumor free as assessed by the investigator and validated by either CT or MRIscan of the brain and CAP ≤28 days from randomization.

13. Have an ECOG PS ≤2.

14. Have adequate organ function

Exclusion Criteria:

• Medical Conditions

1. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroidtherapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any otherform of immunosuppressive therapy within 7 days prior the first dose of studytreatment.

2. Has an active autoimmune disease that has required systemic treatment in past 2years (ie, with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment and is allowed.

3. Has a known additional malignancy that is progressing or required activetreatment ≤3 years ago. Exceptions include early-stage cancers (carcinoma insitu or Stage 1) treated with curative intent, basal cell carcinoma of theskin, squamous cell carcinoma of the skin, in situ cervical cancer, in situprostate cancer, or in situ breast cancer that has undergone potentiallycurative therapy.

4. Has an active infection requiring systemic therapy.

5. Has a history of, or is currently on, dialysis.

6. Has a known history of human immunodeficiency virus infection. No humanimmunodeficiency virus testing is required unless mandated by local healthauthority.

7. Has a known active hepatitis B (hepatitis B surface antigen reactive) or HCV (eg, HCV RNA [qualitative] is detected).

8. Has a known history of active tuberculosis (Bacillus tuberculosis).

9. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with theparticipant's participation for the full duration of the trial, or is not inthe best interest of the participant to participate, in the opinion of thetreating investigator.

10. Has a known psychiatric or substance abuse disorder that would interfere withthe cooperation with the requirements of the trial in the opinion of theinvestigator.

11. Has had a prior solid organ transplant.

12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients (refer to Investigator's Brochure for further details onexcipients).

13. A Woman of Childbearing Potential (WOCBP) who has a positive urine pregnancytest within 72 hours before randomization. If the urine test is positive orcannot be confirmed as negative, a serum pregnancy test will be required.Participants must be excluded/discontinued from the trial in the event of apositive or borderline positive test result.

14. Is pregnant or breastfeeding or expecting to conceive or father children withinthe projected duration of the trial, starting with the Screening visit through 120 days after the last dose of study treatment.Prior/Concomitant Therapy

15. Has received prior anticancer therapy and not recovered from AEs due topreviously administered agents. Note: denosumab may be allowed for boneprotective purposes if dosing has been stable for ≥2 weeks before screening.

16. Has received a live vaccine within 30 days prior to the first dose of studytreatment. Examples of live vaccines include, but are not limited to, thefollowing: measles, mumps, rubella, varicella/zoster (chicken pox), yellowfever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonalinfluenza vaccines for injection are generally killed virus vaccines and areallowed; however, intranasal influenza vaccines (eg, FluMist®) are liveattenuated vaccines and are not allowed.Prior/Concurrent Clinical Study Experience

17. Is currently participating in or has participated in a trial of aninvestigational agent or has used an investigational device within 4 weeksprior to the first dose of study treatment.