Efficacy of PErioperative PEmbrolizumab Treatment in Patients With Resectable Metastases From Kidney Cancer

Inclusion Criteria:

1. Male/female participants who are at least 18 years of age on the day of signinginformed consent with histologically confirmed diagnosis of clear cell renal cellcarcinoma will be enrolled in this study.
2. Have undergone a partial nephrectomy or radical complete nephrectomy with negativesurgical margins.
3. Evidence of oligo-metastatic disease eligible for local treatment with radiotherapy orsurgery, defined as:
4. Appearance of new metastases within 5 years from previous eradication of primarytumors or previous metastasectomy.
5. Presence of maximum 3 metastases in the same site or in different sites with theexception of bone metastases that cannot exceed the number of 2 if they are thesole disease site or one in case of multiple sites.
6. Each metastasis should be less than 3 cm in the maximum diameter and less than 5cm in the sum of the longest tumor diameters (this evaluation should apply alsofor lymph nodes).
7. Has received no prior systemic therapy for Renal Cell Carcinoma (RCC).
8. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 7days of before the start of study intervention.
9. The participant (or legally acceptable representative) has provided documentedinformed consent/assent for the study.
10. Have provided archival tumor tissue sample or newly obtained core or excisional biopsyof a primary tumor or tumor lesion not previously irradiated. Formalin-fixed, paraffinembedded (FFPE) tissue blocks are preferred to slide. Newly obtained biopsies arepreferred to archived tissue. Female participants:
11. A female participant is eligible to participate if she is not pregnant, notbreastfeeding, and at least one of the following conditions applies:
12. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 of theStudy protocol OR
13. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during thetreatment period and for at least 120 days (corresponding to time needed toeliminate any study treatment(s)) plus 30 days (a menstruation cycle) for studytreatments with risk of genotoxicity after the last dose of study treatment.
14. Adequate organ function defined as: System - Laboratory Value Hematological

• Absolute neutrophil count (ANC): ≥ 1500/μl
• Platelets: ≥ 100 000/μl
• Hemoglobin: ≥ 9.0 g/dL or ≥ 5.6 mmol/L Renal
• Creatinine: ≤1.5 x Upper Limit of Normal (ULN) OR
• Measured or calculated creatinine clearance: ≥ 30 mL/min for participant withcreatinine levels > 1.5 x institutional ULN (GFR can also be used in place ofcreatinine or CrCl) Hepatic
• Total bilirubin: ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for participants with totalbilirubin levels > 1.5 x ULN
• Aspartate transaminase (AST or SGOT) and alanine transaminase (ALT or SGPT): ≤ 2.5 xULN (≤ 5 ULN for participants with liver metastases) Coagulation
• International normalized ratio (INR) OR prothrombin time (PT)
• Activated partial thromboplastin time (aPTT): ≤ 1.5 x ULN unless participant isreceiving anticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants

Exclusion Criteria:

1. Has had major surgery, other than nephrectomy, within 4 weeks prior to randomization. Note: If participants received major surgery, they must have recovered adequately fromthe toxicity and/or complications from the intervention prior to starting studytreatment.
2. Has residual thrombus post nephrectomy in the vena renalis or vena cava.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or withan agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,OX-40, CD137).
4. Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks prior to randomization. Note: Participants must have recovered from all Adverse Events (AEs) due to previoustherapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may beeligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment orhormone replacement may be eligible
5. Has clinically significant cardiovascular disease within 12 months from first dose ofstudy intervention, including NYHA Class III or IV congestive heart failure, unstableangina, myocardial infarction, cerebral vascular accident, undergone CABG or PTCA, orcardiac arrhythmia. Note: Medically controlled arrhythmia stable on medication is permitted.
6. Has moderate to severe hepatic impairment (Child-Pugh B or C).
7. Has received prior radiotherapy within 2 weeks of start of study intervention.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout is permittedfor palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
8. Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of study drug. Administration of killed vaccines is allowed.
9. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first dose ofstudy intervention. Note: Participants who have entered the follow-up phase of an investigational studymay participate as long as it has been 4 weeks after the last dose of the previousinvestigational agent.
10. 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 ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.
11. Has a known additional malignancy that is progressing or has required active treatmentwithin the past 3 years. Participants with basal cell carcinoma of the skin, squamouscell carcinoma of the skin, non-muscle invasive bladder cancer, prostate cancer pT2 orless, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that haveundergone potentially curative therapy are not excluded.
12. Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously surgically treated brain metastases may participate provided they are notradiological evidence of disease at the time of screening and without evidence ofprogression for at least 12 months by repeat imaging (note that the repeat imagingshould be performed during study screening).
13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considered aform of systemic treatment and is allowed.
15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that requiredsteroids or has current pneumonitis/interstitial lung disease.
16. Has an active infection requiring systemic therapy.
17. Has a known history of Human Immunodeficiency Virus (HIV) infection.
18. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]reactive) or known active Hepatitis C virus (HCV, defined as HCV RNA is detected)infection. Note: no testing for Hepatitis B and Hepatitis C is required unlessmandated by local health authority.
19. Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the participant'sparticipation for the full duration of the study, or is not in the best interest ofthe participant to participate, in the opinion of the treating investigator.
20. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.
21. Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.
22. Has had an allogenic tissue/solid organ transplant.
23. A WOCBP who has a positive urine pregnancy test within 72 hours prior torandomization. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and thefirst dose of study treatment, another pregnancy test (urine or serum) must be performedand must be negative in order for subject to start receiving study medication.