Axitinib +/- Pembrolizumab in First Line Treatment of mPRCC

Inclusion Criteria:

1. Age ≥ 18 years on the day of signing informed consent.
2. Metastatic or locally advanced (inoperable) type 2 or mixed PRCC, histologicallyconfirmed by central review: FFPE blocks (or all HES and IHC slides) with the initialhistology report must be sent for central reading before confirmation of inclusion inthe study.
3. No prior systemic treatment for renal cancer (chemotherapy, immunotherapy,anti-angiogenic drugs, or treatment under evaluation) even in adjuvant setting.
4. At least one measurable site of disease according to RECIST v1.1.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1 evaluated within 7 days prior to the date of inclusion.
6. In case of prior radiation therapy, discontinuation of irradiation for at least 3weeks before first dose of study treatment, with at least 1 site kept/preserved forevaluation. Participants must have recovered from all radiation-related toxicities,not require corticosteroids, and not have had radiation pneumonitis. A 1-week washoutis permitted for palliative radiation (≤ 2 weeks - limited field (<10% of the wholebody)) to non-CNS disease.
7. Adequate bone-marrow, hepatic, and renal functions within 14 days prior to theinclusion, with:

• Hemoglobin ≥ 9.0 g/dl ou ≥ 5.6 mmol/l, neutrophils ≥ 1 000/mm3 (1.0 G/l),Platelets ≥ 100 000/mm3 (100 G/l),
• Serum creatinine ≤ 2 x ULN OR creatinine clearance ≥ 50 ml/min/1.73m2 (calculatedusing either MDRD or CKD-EPI formula),
• AST and ALT ≤ 2.5 x ULN (or ≤ 5 x ULN in case of liver metastasis),
• Total serum bilirubin ≤ 1.5 x ULN (or direct bilirubin ≤ ULN for participantswith total bilirubin levels >1.5 × ULN),

8. Absence of significant proteinuria (<0.5 g/24h) confirmed by urinary dipstick test. Ifthe dipstick test is ≥ 2+, proteinuria will be quantitated on a complete 24h urinesample (< 1 g/l of protein/24h sample)
9. Covered by a medical/health insurance.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratorytests, and other study procedures.
11. Patients of childbearing potential accepting to use effective contraception or abstainfrom heterosexual activity during study treatment and within 4 months after final doseof study therapy or being surgically sterile. Refer to Appendix 1 for approved methodsof contraception.
12. Signed and dated approved informed consent form before any study specific proceduresor assessments.

Exclusion Criteria:

1. Presence of brain metastases on Magnetic Resonance Imaging (MRI) or ComputedTomography-scan (CT-scan) performed within 28 days prior to inclusion. Patients with ahistory of brain metastases treated by surgery or stereotactic surgery, with normalbrain MRI or CT-scan are allowed to participate.
2. Metastases with high risk of nervous compression or bone lesion with high risk offracture.
3. Prior history of other malignancies other than PRCC (except for curatively treatedbasal cell or squamous cell carcinoma of the skin or in situ uterine cervix carcinoma)unless the subjects has been free of the disease for at least 5 years.
4. Major surgical procedure, open biopsy, or serious none healing wound within 28 daysprior to inclusion.
5. Significant cardiovascular disease, including:

• Disorder of left ventricular function with a left ventricular ejection fraction (LVEF) < 50%,
• Uncontrolled arterial hypertension under adapted medication: systolic bloodpressure ≥ 150 mmHg or diastolic blood pressure ≥ 90 mmHg or both despiteappropriate therapy, blood pressure must be monitored and controlled beforeinclusion, or patients under 3 antihypertensive therapies at screening,
• Myocardial infarction, severe angina, or unstable angina within 6 months prior toinclusion,
• History of serious ventricular arrhythmia (ie ventricular tachycardia orventricular fibrillation),
• Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrialfibrillation that is well controlled with anti-arrhythmic medication),
• Coronary or peripheral artery bypass graft or active coronary stent within 6months prior to inclusion,
• Veinous thrombosis or pulmonary embolism within 6 months prior to inclusion.

6. Any anti-coagulation therapy except prophylactic low dose.
7. History of auto-immune disease except thyroiditis more than 6 months ago.
8. History of any allograft.
9. HIV, HBV, HCV active infections.
10. Any active acute or chronic or uncontrolled infection/disorder that would impair theability to evaluate the patient or the ability for the patient to complete the study.
11. Known history of active TB (Bacillus Tuberculosis).
12. Interstitial lung disease, respiratory insuffisancy whatever the cause.
13. Prior (non-infectious) pneumonitis requiring systemic corticosteroid therapy orcurrent pneumonitis.
14. Inability to swallow oral medications, or presence of active inflammatory boweldisease, partial or complete bowel obstruction or chronic diarrhea.
15. History of severe hypersensitivity to another monoclonal antibody.
16. Known hypersensitivity to the active substances or to any of the excipients.
17. Receiving or having received immunosuppressive therapy or corticosteroids within 1month prior to inclusion (except for hydrocortisone for substitution purposes).
18. Live vaccine within 30 days prior to the first dose of study drug. Examples of livevaccines include, but are not limited to, the following: measles, mumps, rubella,varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG),and typhoid vaccine. Seasonal influenza vaccines for injection are generally killedvirus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®)are live attenuated vaccines and are not allowed. COVID-19 vaccine is allowed ifnon-living/inactivated.
19. Psychological, familial, sociological, or geographical conditions that would limitcompliance with study protocol requirements or known psychiatric or substance abusedisorders that would interfere with cooperation with the requirements of the study.
20. Inclusion in another clinical trial, except for supportive care trials.
21. Pregnant or breastfeeding woman or patient expecting to conceive or father childrenwithin the projected duration of the study, starting with the screening visit through 4 months after the last dose of study treatment (mandatory negative serum or urinarypregnancy test at study entry for all women of childbearing potential).
22. Under or requiring tutorship or curatorship.