Deferred Cytoreductive Nephrectomy in Synchronous Metastatic Renal Cell Carcinoma: The NORDIC-SUN-Trial

Inclusion Criteria:

1. Signed written informed consent obtained prior to any study specific procedures.

2. Patient must be willing and able to comply with the protocol.

3. Age ≥18.

4. Core needle biopsy proven metastatic renal cell carcinoma - all histologic subtypesacceptable.

5. Synchronous metastatic renal cell carcinoma with the primary tumor present in thekidney.

6. Measurable disease as per RECIST v 1.1

7. Patients for which Nivolumab/Ipilimumab or a TKI/IO-combination is consideredindicated according to the recommendations by the European Medicines Agency and thenational health authorities of participating countries. The prescription ofnivolumab/ipilimumab or a TKI/IO-combination in the circumstances of the study isconsidered as a standard treatment.

8. Females with a negative serum pregnancy test unless childbearing potential can beotherwise excluded (postmenopausal, hysterectomy or oophorectomy) and not lactating.

9. Fertile women of childbearing potential (<2 years after last menstruation) and menmust use effective means of contraception (oral contraceptives, intrauterinecontraceptive device, barrier method of contraception in conjunction withspermicidal jelly or surgical sterilization).

10. Karnofsky Performance status ≥70

11. Life expectancy of greater than 4 months.

12. The required laboratory values are as follows:

• Adequate bone marrow function (Leucocytes > 3.0 x 109/l, platelets > 100 x 109/l, hemoglobin > 6.0 mmol/l or > 10.0 g/dL.)

• International normalized ratio (INR) ≤ 1.2 x upper limit of normal (ULN)

• Adequate hepatic function (bilirubin ≤ 1.5 x ULN, ALAT ≤ 2.5 x ULN or ≤ 5 x ULNif liver lesions)

• Adequate kidney function (eGFR > 35 mL/min)

Exclusion Criteria:

1. Prior systemic treatment for mRCC

2. Other cancer within 3 years (except in situ basal cell carcinoma and localisedprostate cancer with undetectable PSA).

3. Major surgical procedure, open surgical biopsy, or significant traumatic injurywithin 28 days prior to enrollment

4. Clinically significant (i.e active) cardiovascular disease for examplecerebrovascular accidents (< 6 months before inclusion), myocardial infarction (< 6months before inclusion), unstable angina, New York Heart Association (NYHA) gradeII or greater congestive heart failure.

5. No symptomatic brain metastasis requiring systemic corticosteroids (> 10 mg dailyprednisone equivalent)

6. Recent (within the 30 days prior to inclusion) treatment with anotherinvestigational drug or participation in another investigational study.

7. Any active or recent history of a known or suspected autoimmune disease or recenthistory of a condition that require systemic corticosteroids (> 10 mg dailyprednisone equivalent) or other immunosuppressive medications, excluding inhaledsteroids and topical steroids. Subjects with vitiligo or type I diabetes mellitus orresidual hypothyroidism due to autoimmune thyroiditis only requiring hormonereplacement, psoriasis not requiring systemic treatment are permitted to enroll.

8. Known hypersensitivity to monoclonal antibodies.

9. Known history of testing positive for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS).

10. Any positive test for hepatitis B- or C-Virus indicating acute or chronic infection.

11. Oral or i.v. antibiotics administered 14 days prior to initiation of systemictherapy.