A Randomized Trial of Maintenance Systemic Therapy After Radiation for Oligometastatic Renal Cell Carcinoma (ASTROs)

Inclusion Criteria:

In order to be eligible for trial participation, patients must have:

1. The participant provides written informed consent for the trial.

2. Pathologically confirmed diagnosis of RCC with a clear cell component.

3. Be willing and able to undergo biopsy of a lesion planned for definitive RT. If alesion amenable to SBRT was biopsied prior to enrollment, this material can be usedin lieu of a planned biopsy if the tissue is available for review at MD Anderson.

4. Patients may be allowed on this trial without a biopsy if they are deemedmedically unfit for biopsy or if the biopsy poses undue risk in the opinion ofthe treating physician(s).

5. Be ≥18 years of age on the day of signing informed consent.

6. ECOG performance status 0-1.

NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is ambulatory for the purpose of assessing their performance status.

1. Have measurable disease based on RECIST 1.1. Lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated insuch lesions.

2. Oligometastatic RCC patients (≤5 metastatic lesions at the time of study entry). Perthe discretion of the treating clinicians, we will not count lung lesions <1 cmshort axis and LNs <1.5 cm short axis as these lesions are often equivocal.

3. CNS disease will be allowed and the number of CNS lesions counted towards thenumber of metastatic lesions for the purposes of study entry.

4. Demonstrate adequate organ function as defined in the table below, all screeninglabs should be performed within 10 days prior to enrollment.

5. At least one site, which in the opinion of the treating radiation oncologist, istreatable with definitive RT and can be biopsied.

6. Criteria for known Hepatitis B and C positive subjects. Hepatitis B and C screeningtests are not required unless:

•Known history of HBV or HCV infection

• As mandated by local health authority

6. Hepatitis B positive subjects • Participants who are HBsAg positive are eligible ifthey have received HBV antiviral therapy for at least 4 weeks and have undetectableHBV viral load prior to randomization.

• Participants should remain on anti-viral therapy throughout study intervention andfollow local guidelines for HBV anti-viral therapy post completion of studyintervention.

7. Participants with history of HCV infection are eligible if HCV viral load isundetectable at screening.

• Participants must have completed curative anti-viral therapy at least 4 weeksprior to randomization. Table Adequate Organ Function Laboratory Values System Laboratory Value --Hematological --Absolute neutrophil count (ANC) ≥1500/µL --Platelets ≥100 000/µL --Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La --Renal --Creatinine OR Measured orcalculatedb creatinine clearance (GFR can also be used in place of creatinine orCrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 ×institutional ULN Hepatic --Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN forparticipants with total bilirubin levels >1.5 × ULN --AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)

--Coagulation International normalized ratio (INR) OR prothrombin time (PT)

--Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant isreceiving anticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants

--ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);

-- AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); ----GFR=glomerular filtration rate; ULN=upper limit of normal. a Criteria must be met without erythropoietin dependency and without packed redblood cell (pRBC) transfusion within last 2 weeks. b Creatinine clearance (CrCl) should be calculated per institutional standard. Note:This table includes eligibility-defining laboratory value requirements fortreatment; laboratory value requirements should be adapted according to localregulations and guidelines for the administration of specific chemotherapies.

Exclusion Criteria: The patient must be excluded from participating in the trial based on the followingconditions:

1. The patient must have received their last dose of systemic therapy ≥24 weeks prior to initiation of their first dose of RT if this therapy included immunotherapy (e.g. pembrolizumab, nivolumab, ipilimumab, etc.) or ≥4 weeks prior to initiation of the first dose of radiation if this systemic therapy did not include immunotherapy.

2. Immunocompromising conditions, as follows:

• Known acute or chronic human immunodeficiency virus (HIV) infection

• History of primary immunodeficiency

• History of allogeneic tissue/solid organ transplant

• Current or prior use of immunosuppressive medication within 7 days before the firstdose of study treatment, except for topical, ocular, intranasal, and inhaledcorticosteroids, or systemic corticosteroids at an equivalent dose ≤10 mg ofprednisone daily.

3. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial as determined by the treatingphysician and/or member of the study team.

4. Patients with a prior history of grade 3 or worse immune-related adverse eventsattributed to checkpoint inhibitors (PD-1, PD-L1, or CTLA-4), except endocrineadverse events with appropriate hormone replacement.

5. Has received a live vaccine or live-attenuated vaccine within 30 days before thefirst dose of study intervention. Administration of killed vaccines is allowed.

6. Per the opinion of the treating physician of study team has cognitive impairmentssuch that appropriate informed consent cannot be obtained or that he/she cannotparticipate in required study activities.

7. Diffuse metastatic processes including leptomeningeal disease, diffuse bonemarrow involvement, and peritoneal carcinomatous, which by the discretion ofthe treating physician cannot be treated definitively.

8. Is pregnant, breast feeding, or expecting to conceive within the projectedduration of the trial at the screening visit and at least one of the followingconditions apply.

• Not a woman of childbearing potential (WOCBP) as defined in Appendix OR

• A WOCBP who agrees to follow the contraceptive guidance in Appendix during thetreatment period and for at least 120 days (corresponding to time needed toeliminate any study treatment(s) (pembrolizumab and/or any activecomparator/combination) plus 30 days (a menstruation cycle) after the last dose ofstudy treatment.

3. A WOCBP who has a positive urine pregnancy test within 72 hours prior toenrollment. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.