CARE1 Pragmatic Clinical Trial

Inclusion Criteria: 1. Histologically confirmed metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component. 2. Intermediate- or poor-risk mRCC as defined by IMDC classification. 3. Adult male or female patients (≥ 18 years of age at inclusion). 4. Karnofsky Performance Status (KPS) ≥70%. 5. Adequate organ and marrow function, according to investigator assessment and 1. Absolute neutrophil count (ANC) ≥ 1000/μL (≥ 1.5 GI/L) 2. Platelets ≥ 100,000/μL (≥ 100 GI/L) 3. Hemoglobin ≥ 8 g/dL (≥ 80 g/L) 4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN. 5. Calculated creatinine clearance ≥ 30 mL/min (≥ 0.67 mL/sec) using the CKD- EPI equation 6. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. 7. Patient should be able and willing to comply with study visits and procedures as per protocol 8. Patients must be affiliated to a social security system or beneficiary of the same 9. Female patients must either be of non-reproductive potential or must have a negative serum pregnancy test within 14 days prior to the administration of study drug. Childbearing potential women must have agreed to use one barrier method of contraception, such as condom, plus an additional highly effective method of contraception during treatment on this trial and for up to 5 months after the last dose of study treatment. 10. Fertile men with a female partner of childbearing potential must agree to use one barrier method of contraception, such as condom, during treatment on this trial and for up to 4 months after the last dose of treatment. Their women of childbearing potential partner must agree to use a highly effective method of contraception during the same period. 11. Female subjects of childbearing potential must not be pregnant at screening. Exclusion Criteria: 1. Prior systemic anticancer therapy for mRCC including investigational agents. Note: One prior systemic adjuvant therapy is allowed for completely resected RCC and if recurrence occurred at least 6 months after the last dose of adjuvant therapy. 2. Uncontrolled brain metastases (adequately treated with radiotherapy and/or radiosurgery prior to randomization are eligible). Subjects who are neurologically symptomatic as a result of their CNS metastasis or are receiving systemic corticosteroid treatment (prednisone equivalent \> 10 mg/day) at the planned time of randomization are not eligible. 3. Concomitant oral anti-vitamin K anticoagulation. An exception is the use of LMWH or direct oral anticoagulants (DOAC), if considered safe by investigator assessment. 4. The subject has uncontrolled, significant intercurrent or recent illness such as the following conditions: a. Cardiovascular disorders: i. Congestive heart failure (CHF) class III or IV as defined by the New York Heart Association, unstable angina pectoris, myocardial infarction, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes). ii. Uncontrolled hypertension despite optimal antihypertensive treatment. iii. Stroke, or other symptomatic ischemic event or severe thromboembolic event (e.g., symptomatic pulmonary embolism \[PE\], incidental PE is acceptable if deemed safe by the investigator) within 3 months before randomization. b. Active GI bleeding or symptomatic Gastrointestinal (GI) tract obstruction c. Clinically significant bleeding including uncontrolled hematuria, hematemesis, or hemoptysis d. Autoimmune disease that has been symptomatic or required immunosuppressive systemic treatment within the past two years from the date of randomization. Note: Patients with a history of Crohn's disease or ulcerative colitis are always excluded e. Any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted. Adrenal replacement steroid doses \> 10 mg daily prednisone equivalent are permitted. Transient short-term use of systemic corticosteroids for allergic conditions (e.g., contrast allergy) is also allowed. f. Active infection requiring systemic treatment. g. Major surgery (e.g., nephrectomy, GI surgery, removal of brain metastasis) within 4 weeks prior to randomization or serious non-healing wound/ulcer/bone fracture. 5. Pregnant or breastfeeding females. 6. Any other active malignancy at time of randomization or diagnosis of another malignancy within 3 years prior to randomization that requires active treatment, except for locally curable cancers that have been apparently cured. 7. Hypersensitivity to any of the active substances or to any of the excipients administered during the study 8. Use of live vaccines within 28 days before randomization 9. Persons deprived of their freedom or under guardianship, or for whom it would be impossible to undergo the medical follow-up required by the trial, for geographic, social or psychological reasons.