• Objective response rate (ORR) [ Time Frame: up to 42 months ]
  Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator
• Time to response (TTR) [ Time Frame: Every 12 weeks up to 42 months ]
  Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
• Duration of response (DOR) [ Time Frame: Every 12 weeks up to 42 months ]
  Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
• Disease control rate (DCR) [ Time Frame: Every 12 weeks up to 42 months ]
  Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
• Progression-free survival (PFS) [ Time Frame: Every 12 weeks up to 42 months ]
  Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
• Change in disease-related symptoms [ Time Frame: Every 12 weeks up to 42 months ]
  Assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire.
• Overall survival (OS) [ Time Frame: Every 12 weeks starting after End of Study Treatment visit (30 days after the last dose) until the subject expires or the end of the study (18 months after the last subject received the first cabozantinib dose), whichever occurs first. ]

• Best overall response (BOR) [ Time Frame: Every 12 weeks up to 42 months ]
  Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by independent central review
• Time to response (TTR) [ Time Frame: Every 12 weeks up to 42 months ]
  Assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by independent central review
• Duration of response (DOR) [ Time Frame: Every 12 weeks up to 42 months ]
  Assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by independent central review
• Disease control rate (DCR) [ Time Frame: Every 12 weeks up to 42 months ]
  Assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by independent central review
• Progression-free survival (PFS) [ Time Frame: Every 12 weeks up to 42 months ]
  Assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by independent central review
• Change in disease-related symptoms [ Time Frame: Every 12 weeks up to 42 months ]
  Assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire.
• Overall survival (OS) [ Time Frame: Every 12 weeks starting after End of Study Treatment visit (30 days after the last dose) until the subject expires or the end of the study (18 months after the last subject received the first cabozantinib dose), whichever occurs first. ]

• Experimental: Cohort A
  Subjects who radiographically progressed after one prior line by CPI therapy with ipilimumab and nivolumab.
  Intervention: Drug: Cabozantinib
• Experimental: Cohort B
  Subjects who radiographically progressed after one prior line by CPI therapy combined with VEGF-targeted therapy.
  Intervention: Drug: Cabozantinib

Inclusion Criteria:

All subjects must fulfil all the following criteria to be included in the study:

1. Subjects must provide a signed informed consent prior to any study-related procedures;
2. Male or female subjects must be aged ≥18 years on the day the informed consent is signed;
3. Subjects must have histologically confirmed unresectable, locally advanced (defined as disease not eligible for curative surgery or radiation therapy) or metastatic RCC with a clear-cell carcinoma component;
4. Subjects must have radiographic disease progression, according to Investigator's judgement following 1st line treatment with CPI (ipilimumab plus nivolumab) (Cohort A) or CPI in combination with VEGF-targeted therapy (Cohort B);
5. Subjects present ≥1 target lesion according to RECIST 1.1 per Investigator;
6. Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1;
7. Subjects with treated brain metastases are eligible if metastases have been shown to be stable as per Investigator's judgement;

8. Subjects must have adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 15 days before baseline:

   1. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L).
   2. Platelets ≥ 100,000/mm3 (≥ 100 GI/L).
   3. Haemoglobin ≥ 9 g/dL (≥ 90 g/L).
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal (ULN).
   5. Total bilirubin ≤ 1.5 × ULN. For subjects with Gilbert's disease ≤ 3 mg/dL (≤ 51.3 μmol/L).
   6. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation
   7. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine or 24-hour urine protein < 1 g.
9. Subject must have recovered to baseline or ≤ Grade 1 per CTCAE v5 from toxicities related to any prior treatments, unless Adverse Events (AE(s)) are clinically nonsignificant and/or stable on supportive therapy as determined by the Investigator;
10. Subject must have completed a steroid taper if he/she had an immune-related adverse event associated with immune CPI;
11. Female subjects of childbearing potential (i.e. less than or equal to 2 years postmenopause and not surgically sterile) must provide a negative pregnancy test within 7 days prior to the start of study treatment. If a urine test cannot be confirmed as negative, a negative serum pregnancy test is required;
12. Female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and not surgically sterile) and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 4 months after the last dose of study treatment;
13. All male participants must agree to refrain from donating sperm and unprotected sexual intercourse with female partners during the study and for 120 days after the last dose of study treatment;
14. Subjects must be willing and able to comply with study requirements, remain at the investigational site for the required duration of each study visit and be willing to return to the investigational site for the follow up evaluation, as specified in the protocol
15. Subjects must be covered by social security or be the beneficiary of such a system (only applicable for French subjects).

Exclusion Criteria:

Subjects will not be included in the study if the subject:

1. Inability to swallow tablets;
2. Was treated with any other investigational medicinal product (IMP) within the last 30 days before baseline;
3. Was previously treated with cabozantinib;
4. Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast medium used for Contrast Tomography (CT)-scan;
5. Presents untreated brain or leptomeningeal metastases, or current clinical or radiographic progression of known brain metastases;

6. Has a diagnosis of a serious cardiovascular disorder:

   1. Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, or serious cardiac arrhythmias;
   2. Uncontrolled hypertension, defined as sustained blood pressure (BP) (>140 mm Hg systolic or >90 mm Hg diastolic pressure) despite optimal antihypertensive treatment;
   3. Stroke (including transient ischaemic attack (TIA)), myocardial infarction (MI) or other ischaemic event, or thromboembolic event (e.g. deep venous thrombosis, pulmonary embolism) within 6 months before screening;
   4. History of risk factors for torsades de pointes (e.g., long QT syndrome);
7. Is receiving concomitant anticoagulation with coumarin agents (e.g. warfarin), direct thrombin inhibitor dabigatran, Direct Factor Xa inhibitors betrixaban or platelet inhibitors (e.g. clopidogrel); Note: The following are allowed anticoagulants: prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparin (LMWH) are permitted. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in patients without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before baseline without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumour.

8. Has a gastrointestinal (GI) disorder including those associated with a high risk of perforation or fistula formation:

   (a) Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction; b) Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before screening; Note: Complete healing of an intra-abdominal abscess must have been confirmed before screening

9. Presents a corrected QT (QTc) interval calculated by the Fridericia formula (QTcF) > 500 msec within 1 month prior to baseline; Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility

10. Presents clinically significant haematuria, hematemesis, or haemoptysis of >0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g.

    pulmonary haemorrhage) within 3 months before screening;

11. Presents cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
12. Presents lesions invading major pulmonary blood vessels;

13. Has been diagnosed with other clinically significant disorders such as:

    1. Serious nonhealing wound/ulcer/bone fracture;
    2. Malabsorption syndrome;
    3. Free thyroxine 4 (FT4) outside the laboratory normal reference range;
    4. Uncompensated/symptomatic hypothyroidism;
    5. Moderate to severe hepatic impairment (Child-Pugh B or C);
    6. Requirement for haemodialysis or peritoneal dialysis;
    7. History of solid organ transplantation;
14. Has a predicted life expectancy of less than 3 months;
15. Has had prior surgery within 4 weeks prior to baseline. Note: If the subject has undergone major surgery, complete wound healing must have occurred 1 month prior to baseline
16. Has had palliative radiation therapy for bone within 2 weeks or for radiation fields including viscera within 4 weeks prior to baseline. Note: Resolution/healing of side effects must be complete prior to baseline;
17. Has a history of another active malignancy within 3 years from screening except for locally curable cancers that have been apparently cured, such as low-grade thyroid carcinoma, prostate cancer not requiring treatment (Gleason Grade ≤6), basal or squamous cell skin cancer, superficial bladder cancer, in situ melanoma, in situ prostate, cervix or breast carcinoma or other treated malignancies with <5% chance of relapse according to the Investigator;
18. Has a history of allergy to study treatment components or agents with a similar chemical structure or any excipient used in the formulation as listed in the Summary of Product Characteristics (SmPC) document;
19. Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded;
20. Has a serious medical or psychiatric condition that renders the subject unable to understand the nature, scope and possible consequences of the study, and/or presents an uncooperative attitude;
21. Is pregnant or breastfeeding. A β-human chorionic gonadotrophin (HCG) serum pregnancy test will be performed up to 7 days prior to baseline for all female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and not surgically sterile);
22. Is likely to require treatment during the study with drugs that are not permitted by the study protocol;
23. Has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the subject's safety