This phase III trial compares the effect of stero-ablative radiotherapy (SAbR) followed by standard of care systemic therapy, to standard of care systemic therapy alone, in patients with kidney cancer that has spread from where it first started (primary site) to a limited (2-5) number of places in the body (metastatic). Study doctors want to find out if this approach is better or worse than the usual approach for metastatic kidney cancer. The usual approach is defined as the care most people get for metastatic kidney cancer which includes systemic therapy such as immunotherapy (given through the veins) and/or small molecular inhibitor (tablets taken by mouth). Radiotherapy uses high energy x-rays to kill cancer cells and shrink tumors. SAbR uses special equipment to position a patient and deliver radiation to tumors with high precision. Giving SAbR prior to systemic therapy may kill more tumor cells than the usual approach, which is systemic therapy alone.

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) between patients receiving SAbR + systemic therapy (SABR+ST) versus systemic therapy (ST) only.

II. To compare average adverse event (AE) score between SAbR+ST arm and ST only arm.

SECONDARY OBJECTIVES:

I. To compare global health status / quality of life (QOL) between patients receiving SAbR+ST versus ST only.

II. To compare progression-free survival (PFS) between the arms.

EXPLORATORY OBJECTIVES:

I. To estimate PFS on first line systemic therapy (PFS-SST) in the SAbR+ST arm and compare with first line systemic therapy PFS of the ST arm.

II. To explore local control from SAbR by looking at the amount of local failures after SAbR in the SAbR+ST arm.

III. To assess the cost-effectiveness between the arms in terms of cost per unit gain in quality-of-life years.

QOL OBJECTIVES:

I. To compare global health status / quality of life (QOL) between patients receiving SabR+ST versus ST only using the National Comprehensive Cancer Network (NCCN) / Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index -19 item (NFKSI-19).

II. To compare quality-adjusted survival between patients randomized to receive SabR+ST vs ST alone using European Quality of Life (EUROQOL) 5-dimension, 5-level (EQ-5D-5L) at 3, 6, 9, 12, 18, and 24 months.

III. To compare global health status / QOL of the NFKSI-19 at all of the 3, 6, 9, 12, 18, and 24 month time points between patients randomized to receive SabR+ST versus ST alone.

IV. To compare scale scores of the NFKSI-19 (disease-related symptoms - physical disease-related symptoms - emotional, treatment side effects, and function & well-being) at 3, 6, 9, 12, 18, 24 months between patients randomized to receive SabR+ST versus ST alone.

V. To compare time to global quality of life deterioration between patients randomized to receive SabR+ST versus ST alone using NFKSI-19.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard of care systemic therapy on study.

ARM II: Patients undergo repeated SAbR until progression and then receive standard of care systemic therapy on study.

Patients in both arms undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial.

Inclusion Criteria:

• Patient must be >= 18 years of age

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

• Patient may have any RCC histology except a histology that has a sarcomatoid component

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

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

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

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

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

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

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible 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 sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:

    • Has achieved menarche at some point
    • Has not undergone a hysterectomy or bilateral oophorectomy
    • Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available 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 recommended guidelines and the respective Food and Drug Administration [FDA] package insert required for the systemic therapy chosen by the treating oncologist. We recognize that patients may have varying levels of renal and liver function that will impact which systemic therapy is appropriate for the patient. We do not require all patients to have specific baseline laboratory thresholds but do ask the treating oncologist to attest that the patient has adequate organ and bone marrow function to safely receive one of the first line systemic therapies listed in the protocol as a standard of care treatment option

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for 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 HBV viral load must be undetectable on suppressive therapy, if indicated. If no previous history, testing for HBV is not required for entry onto the study

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible 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 speak one 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 adjuvant setting) for metastatic RCC
• Active autoimmune disease requiring ongoing therapy including systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications daily. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies
• Active tuberculosis (purified protein derivative [PPD] response without active TB is allowed)
• 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 to randomization
• 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 in respiratory 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 to randomization
• 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 an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
• Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after the last dose of protocol treatment