Stereotactic Body Radiotherapy Followed by Cemiplimab With or Without Fianlimab for the Treatment of Oligo-Metastatic Clear Cell Renal Cell Carcinoma, LAG-BOOST Trial

Inclusion Criteria

• Patient must be >= 18 years of age
• Patient must have a biopsy/pathologically (histologically or cytologically) proven diagnosis of clear cell renal cell carcinoma (ccRCC) prior to randomization
• Patient must have at least 1 and not more than 5 metastatic lesions measurable by RECIST v 1.1, with imaging obtained within 45 days prior to randomization
• Patients with untreated brain metastasis measuring < 2cm in diameter (intracranial Response Assessment in Neuro-Oncology Brain Metastases [RANO-BM] measurable disease required) and with minimal neurological symptoms. Patients with treated brain metastasis are eligible for the trial as long as they have had three or fewer brain metastasis without signs of progression of disease on post-treatment MRI of the brain as per RANO for Brain Metastases (RANO-BM) guidelines
• Patient must have documentation from a radiation oncologist confirming that all sites (metastases and primary tumor, if present) are amenable to SBRT
• 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 serum test within 14 days prior to randomization to rule out pregnancy
• Patient must have the ability to understand and the willingness to sign a written informed consent document
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
• White blood cell (WBC) counts ≥ 2500/μL and ≤ 15,000/μL without granulocyte colony stimulating factor (G-CSF)
• Lymphocyte count ≥ 500/μL
• Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
• Hemoglobin ≥ 9.0 g/dL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 X upper limit of normal (ULN). ALP ≤ 5 x ULN if patient has documented bone metastases
• Serum bilirubin ≤ 1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 2 x ULN may be enrolled
• Creatinine ≤ 3.0 x ULN or Estimated Glomerular Filtration Rate (eGFR) ≥ 30mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
• 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
• For patients with hepatitis C virus (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
• Patients with prior radiation to sites but without evidence of progression will be allowed, however these radiation treatment (RT)-treated sites will not be treated on study. Patients who have had a prior nephrectomy can be included in the study, patients with prior metastasectomy are also eligible for the study

Exclusion Criteria

• Patients with untreated brain metastasis > 2cm, significant neurological deficits and unamenable to surgical resection
• Patient with variant histology renal cell carcinoma
• Patient with metastasis invading gastrointestinal tract (such as esophagus, stomach, intestines, colon, rectum)
• Patients with more than 2 liver metastatic lesions, or liver lesions resulting in obstructive jaundice
• Patient who have received any prior combination systemic therapy for metastatic RCC (including immune checkpoint inhibitors, tyrosine kinase inhibitors or combinations)
• Patients who have received any check point inhibitor or immune therapies (i.e. Vaccine or other immune-oncology agent) within the last 12 months. Patients who have previously been treated for non-metastatic RCC with adjuvant pembrolizumab can be included if over 12 months since last dose and they have not had radiographic progression within 12 months from the last dose of pembrolizumab
• Patients with 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
• Patients with no more than 1 prior systemic therapy for metastatic disease
• Patients with active tuberculosis * purified protein derivative [PPD] response without active tuberculosis (TB) is allowed
• Patients with uncontrolled hypertension (systolic blood pressure [BP] > 190mmHg or diastolic BP > 110mmHg)
• Patients requiring major surgery within 30 days prior to randomization
• Patients with any serious (requiring hospital stay or long-term rehab) non-healing wound, ulcer, or bone fracture within 30 days prior to randomization
• Patients with any arterial thrombotic (ST elevation myocardial infarction [STEMI], non-STEMI [NSTEMI], cerebrovascular accident [CVA], etc.) events within 180 days prior to randomization
• Patients with moderate or severe hepatic impairment (child-Pugh B or C)
• Patients with untreated pulmonary embolism (PE) or deep-vein thrombosis (DVT) is not allowed
• Patients with unstable cardiac arrhythmia within 180 days prior to randomization
• Patients with history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to randomization
• Patients with history of or active inflammatory bowel disease
• Patients with history of connective tissue disease or other disease in which radiation therapy is contraindicated
• Patient pregnant or breastfeeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
• Patients must not expect to conceive or father children and should use 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
• Patients with a history of myocarditis
• Patients with troponin T (TnT) or troponin I (TnI) > 2 x institutional ULN at baseline. * Patients with TnT or TnI levels between > 1 to 2 x ULN are permitted if repeat levels within 24 hours are ≤ 1 x ULN. If TnT or Tn1 levels are > 1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on the medical judgment in the patient’s best interest
• Patients with history or current evidence of significant (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥ 2) local or systemic infection (e.g., cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication
• Patients with active infection requiring therapy
• Patients with ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment
• Patients with uncontrolled infection with HIV, HBV, or HCV infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Notes: * Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. * Patients with known hepatitis B surface antigen (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on antiviral therapy for at least 6 months beyond the last dose of investigational study drug. * Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV ribonucleic acid [RNA] by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. * Patients with HIV or hepatitis must be reviewed by a qualified specialist (e.g., infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial
• Patients with known hypersensitivity to the active substances or to any of the excipients
• Patients who received a live vaccine within 30 days of planned start of study medication. * Live or live attenuated vaccination with replicating potential. If a patient intends to receive a coronavirus disease 2019 (COVID-19) vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing
• Women who are fertile following menarche until becoming postmenopausal or women of childbearing potential (WOCBP*), unless permanently sterile must have a negative serum (beta-hCG) at screening. * Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. * A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the Clinical Trials Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy * Male study participants with WOCBP partners are required to use condoms during the study and until 6 months after the last dose of study treatment unless they are vasectomized or practice sexual abstinence. * Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success. * Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactation amenorrheal method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together. * WOCBP who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include: ** stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated two or more menstrual cycles prior to screening. ** intrauterine device; intrauterine hormone-releasing system. ** bilateral tubal occlusion/ligation. ** vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or ** sexual abstinence * Pregnancy testing and contraception are required for WOCBP*. * Pregnancy testing and contraception are not required for women who are postmenopausal or permanently sterile. * Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. * WOCBP* must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial and until 6 months after last treatment * All men must agree not to donate sperm during the trial and for 6 months after receiving the last therapy dose
• Pregnant or breastfeeding women. * WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. * A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the CTFG guidance. * Periodic abstinence (calendar, symptothermal, or post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Female condom and male condom should not be used together