Tailored ImmunoTherapy Approach With Nivolumab in Subjects With Metastatic or Advanced Renal Cell Carcinoma

Inclusion Criteria: * Signed Written Informed Consent * Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. * Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. * Target Population * Histological confirmation of RCC with a clear-cell component. * Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC * One (anti-angiogenic or temsirolimus) \[to be eligible for 2nd line tier\] or no prior systemic therapy for RCC \[to be eligible for 1st line tier\] with the following exception: * One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets VEGF or VEGF receptors as well as CTLA-4- or PD-1/PD-L1 immune checkpoint inhibitors, respectively, and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy. * KPS of at least 70% * Measurable disease as per RECIST v1.1 * Tumor tissue (FFPE archival or recent acquisition) must be received by the central vendor (block or unstained slides). (Note: Fine Needle Aspiration \[FNA\] and bone metastases samples are not acceptable for submission). * Patients with intermediate and poor risk categories will be eligible for the study. * To be eligible as intermediate or poor-risk, at least one of the following prognostic factors as per the International Metastatic RCC Database Consortium (IMDC) criteria must be present: * KPS equal to 70% * Less than 1 year from initial diagnosis of RCC (eg, nephrectomy or first diagnostic biopsy) to registration (1st line) or to start of first-line targeted therapy (2nd line), respectively * Hemoglobin less than the lower limit of normal (LLN) * Corrected calcium concentration greater than the upper limit of normal (ULN) * Absolute neutrophil count greater than the ULN * Platelet count greater than the ULN * If none of the above factors are present, subjects are not eligible (favorable-risk). * Age and Reproductive Status * Males and Females, ≥ 18 years of age * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. * Women must not be breastfeeding * Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. * Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Males who receive nivolumab combined with ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. * Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy testing as described in this section. Exclusion Criteria: * Target Disease Exceptions * Any history of or current CNS metastases. Baseline imaging of the brain by MRI (preferred) or CT scan is required within 28 days prior to registration. * Medical History and Concurrent Diseases * Prior systemic treatment with more than one of the following drugs: mTOR, VEGF or VEGF receptor targeted therapy (including, but not limited to, temsirolimus, everolimus, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab). * Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. * Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll. * Any condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. * Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. * Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS). * Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection. * Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results. * Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug. * Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug. * Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug. * Physical and Laboratory Test Findings * Any of the following laboratory test findings: * WBC \< 2,000/mm3 * Neutrophils \< 1,500/mm3 * Platelets \< 100,000/mm3 * AST or ALT \> 3 x ULN (\> 5 x ULN if liver metastases are present) * Total Bilirubin \> 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) * Serum creatinine \> 1.5 x upper limit of normal (ULN) or creatinine clearance \< 40 mL/min (measured or calculated by Cockroft-Gault formula) * Allergies and Adverse Drug Reaction * History of severe hypersensitivity reaction to any monoclonal antibody or any constituent of the product. * Other Exclusion Criteria * Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts. * Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.