Focused Radiation Versus Systemic Therapy for Kidney Cancer Patients With Limited Metastasis, SOAR Study

Inclusion Criteria:

• Patient must be >= 18 years of age

• Patient must have a pathologically (histologically or cytologically) provendiagnosis of renal cell carcinoma (RCC) prior to randomization

• Patient may have any RCC histology except a histology that has a sarcomatoidcomponent

• Patient must have primary site addressed by local therapy. If the primary RCC isintact, the patient must undergo local treatment to the primary before randomization

• Patient must have favorable or intermediate International Metastatic RCC DatabaseConsortium (IMDC) risk (0-2) at the time of randomization

• Patient must have a total of between 2 and 5 metastatic lesions, as defined byResponse Evaluation Criteria in Solid Tumors (RECIST) criteria with imaging obtainedwithin 45 days prior to randomization

• Patient must have a documentation from a radiation oncologist confirming that allsites are amenable to SAbR

• Patient may have received prior therapy in the adjuvant setting as long as potentialtrial participants have recovered from clinically significant adverse events oftheir most recent therapy/intervention prior to enrollment

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy

• A patient of childbearing potential is defined as anyone, regardless of sexualorientation or whether they have undergone tubal ligation, who meets thefollowing criteria:

• Has achieved menarche at some point

• Has not undergone a hysterectomy or bilateral oophorectomy

• Has not been naturally postmenopausal (amenorrhea following cancer therapydoes not rule out childbearing potential) for at least 24 consecutivemonths (i.e., has had menses at any time in the preceding 24 consecutivemonths)

• Patient must have the ability to understand and the willingness to sign a writteninformed consent document. Patients with impaired decision-making capacity (IDMC)who have a legally authorized representative (LAR) or caregiver and/or family memberavailable will also be considered eligible

• Patient must have a Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

• Patients must have adequate organ and bone marrow function as per the recommendedguidelines and the respective Food and Drug Administration [FDA] package insertrequired for the systemic therapy chosen by the treating oncologist. We recognizethat patients may have varying levels of renal and liver function that will impactwhich systemic therapy is appropriate for the patient. We do not require allpatients to have specific baseline laboratory thresholds but do ask the treatingoncologist to attest that the patient has adequate organ and bone marrow function tosafely receive one of the first line systemic therapies listed in the protocol as astandard of care treatment option

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months of randomization are eligiblefor this trial. Testing for HIV is not required for entry onto the study

• For patients with history of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated. If no previoushistory, testing for HBV is not required for entry onto the study

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load. If no previous history,testing for HCV is not required for entry onto the study

• In order to participate in the QOL portion of the protocol, the patient must speakone of the languages in which the NFKSI-19 and EQ-5D-5L is available

• NOTE: Sites cannot translate the associated QOL forms

Exclusion Criteria:

• Patient must not have brain metastases

• Patient must not have metastasis involving the following locations: ultra-central (within 2cm of carina) lung, invading gastrointestinal tract (such as esophagus,stomach, intestines, colon, rectum), skin, and scalp

• Patient must not have received any prior systemic therapy (except for adjuvantsetting) for metastatic RCC

• Active autoimmune disease requiring ongoing therapy including systemic treatmentwith corticosteroids (> 10 mg daily prednisone equivalents) or otherimmunosuppressive medications daily. Inhaled steroids and adrenal replacementsteroid doses > 10 mg daily prednisone equivalents are permitted in the absence ofactive autoimmune disease

• History of severe allergic, anaphylactic or other hypersensitivity reactions tochimeric or humanized antibodies

• Active tuberculosis (purified protein derivative [PPD] response without active TB isallowed)

• Uncontrolled hypertension (systolic blood pressure [BP] > 190mmHg or diastolic BP > 110mmHg)

• Major surgery within 30 days prior to randomization

• Any serious (requiring hospital stay or long term rehab) non-healing wound, ulcer,or bone fracture within 30 days prior to randomization

• Any arterial thrombotic (ST elevation myocardial infarction [STEMI], non-STEMI [NSTEMI], cerebrovascular accident [CVA], etc.) events within 180 days prior torandomization

• Moderate or severe hepatic impairment (child-Pugh B or C)

• Untreated pulmonary embolism (PE) or deep-vein thrombosis (DVT) is not allowed.Treated PE or DVT is allowed > 30 days from diagnosis and when not resulting inrespiratory impairment

• Unstable cardiac arrhythmia within 180 days prior to randomization

• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess,bowel obstruction, or gastric outlet obstruction within 180 days prior torandomization

• History of or active inflammatory bowel disease

• Malabsorption syndrome within 30 days prior to randomization

• Patient must not be pregnant or breast-feeding due to the potential harm to anunborn fetus and possible risk for adverse events in nursing infants with thetreatment regimens being used

• Patient must not expect to conceive or father children by using accepted andeffective method(s) of contraception or by abstaining from sexual intercourse forthe duration of their participation in the study and for 6 months after the lastdose of protocol treatment