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

NCT ID: NCT03977571

Last Updated: 2025-06-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 400 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-06
• Study Completion Date: 2029-09-01

Brief Summary

BACKGROUND: For synchronous metastatic renal cell carcinoma (RCC), surgical resection of the primary tumor in the presence of distant metastases has been the standard of therapy for select patients followed by systemic therapy. In the era of TKIs two randomized trials, CARMENA and SURTIME, have questioned the role and timing of surgery in these patients, results point towards no surgery or a deferred approach.

RATIONALE: The antitumor activity of immune checkpoint blockage (ICB) is more potent than other therapy in mRCC. The deferred cytoreductive nephrectomy approach ensures systemic therapy for all patients, avoid systemic treatment delay, and spare surgery in patients with progressive tumors. Current data only point towards a survival benefit for cytoreductive nephrectomy in intermediate risk patients, but not in poor risk patients

HYPOTHESIS: Deferred cytoreductive nephrectomy after initial nivolumab combined with ipilimumab or a TKI/IO-combination will improve OS in patients with synchronous metastatic RCC and ≤3 IMDC risk features

This is an open, randomized, multicenter comparison trial, designed to evaluate the effect of deferred cytoreductive nephrectomy compared with no surgery following initial nivolumab combined with ipilimumab or a TKI-combination, in mRCC patients with IMDC intermediate and poor risk.

Detailed Description

OUTLINE: This is a multicenter trial, patients are stratified according to institution, treatment choice, number of IMDC risk factors, and combined elevated neutrophil-lymphocyte ratio and hyponatremia.

All patients will receive induction checkpoint immunotherapy immediately after inclusion. After 3 months or a total of 4 series of nivolumab combined with ipilimumab or a TKI/IO-combination, the patient will be discussed for resectability at the multidisciplinary meeting (MDT). Whether the patient is eligible for cytoreductive nephrectomy is at the discretion of the urologist at the local MDT. Patients with ≤ 3 IMDC risk factors and deemed suitable for cytoreductive nephrectomy will then undergo randomization. Patients deemed not suitable for surgery or have > 3 IMDC risk features at the 3 month evaluation continue systemic therapy for 3 months, followed by a 2nd evaluation. Patients with ≤ 3 IMDC risk factors and deemed suitable for cytoreductive nephrectomy at 2nd evaluation will then undergo randomization. Patients deemed not suitable for surgery or have > 3 IMDC risk features at the 6 month evaluation continue systemic therapy. Nivolumab may continue until unacceptable toxicity or total treatment length of 2 years from inclusion.

ARM A: Deferred cytoreductive nephrectomy, followed by maintenance nivolumab or a TKI/IO-combination.

ARM B: No surgery, receive maintenance nivolumab or a TKI/IO-combination.

Patients undergo tumor tissue, blood, and stool collection at baseline, 3 and 6 months, for planned translational research.

Conditions

Kidney Cancer; Renal Cell Carcinoma Metastatic; Synchronous Neoplasm

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Deferred nephrectomy

Surgery after induction therapy with IO/IO or a TKI/IO-combination, followed by maintenance therapy with nivolumab or a TKI/IO-combination.

Group Type: EXPERIMENTAL

Cytoreductive nephrectomy

Intervention Type: PROCEDURE

Partial or complete nephrectomy by open, laparoscopic, or robotic approach.

Tissue sampling

Intervention Type: OTHER

Tumor biopsies, blood, and stool specimens for translational biomarker research will be sampled at baseline and after 3 or 6 months.

No surgery

Induction therapy wih IO/IO or a TKI/IO-combination, followed by maintenance therapy with nivolumab or a TKI/IO-combination.

Group Type: ACTIVE_COMPARATOR

Tissue sampling

Intervention Type: OTHER

Tumor biopsies, blood, and stool specimens for translational biomarker research will be sampled at baseline and after 3 or 6 months.

Interventions

Cytoreductive nephrectomy

Partial or complete nephrectomy by open, laparoscopic, or robotic approach.

Intervention Type: PROCEDURE

Tissue sampling

Tumor biopsies, blood, and stool specimens for translational biomarker research will be sampled at baseline and after 3 or 6 months.

Intervention Type: OTHER

Eligibility Criteria

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 subtypes acceptable.

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

6. Measurable disease as per RECIST v 1.1

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

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

9. Fertile women of childbearing potential (<2 years after last menstruation) and men must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal 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 ULN if 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 localised prostate cancer with undetectable PSA).

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

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

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

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

7. Any active or recent history of a known or suspected autoimmune disease or recent history of a condition that require systemic corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications, excluding inhaled steroids and topical steroids. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, 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 known acquired 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 systemic therapy.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aarhus University Hospital

OTHER

Sponsor Role: collaborator

Niels Fristrup

OTHER

Sponsor Role: lead

Responsible Party

Niels Fristrup

MD PhD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Niels Fristrup, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Department of Oncology, Aarhus University Hospital.

Locations

Department of Oncology, Aarhus University Hospital

Aarhus, Central Region of Denmark, Denmark

Site Status: RECRUITING

Department of Oncology, Herlev Hospital

Herlev, Herlev, Denmark

Site Status: RECRUITING

Department of Oncology, Odense University Hospital

Odense, , Denmark

Site Status: RECRUITING

Department of Urology, Haukeland University Hospital

Bergen, , Norway

Site Status: RECRUITING

Countries

Denmark; Norway

Central Contacts

Niels Fristrup, MD PhD

Role: CONTACT

niels.fristrup@rm.dk

004520914161

Ane Iversen, MD PhD

Role: CONTACT

ANEIVE@rm.dk

Facility Contacts

Niels Fristrup, MD PhD

Role: primary

niels.fristrup@rm.dk

004520914161

Anne Kirstine Moeller, MD, PhD

Role: primary

anne.kirstine.moeller.darras@regionh.dk

Jesper Palshof, MD PhD

Role: backup

Jesper.Andreas.Palshof@regionh.dk

Jon R Henriksen, MD

Role: primary

Jon.Henriksen@rsyd.dk

Niels Viggo Jensen, MD

Role: backup

Niels.Viggo.Jensen@rsyd.dk

Christian Beisland, Professor, Head of Department

Role: primary

christian.beisland@helse-bergen.no

0047 47301005

Karin Hjelle, MD

Role: backup

karin.margrethe.hjelle@helse-bergen.no

0047 92899241

References

Iisager L, Ahrenfeldt J, Donskov F, Ljungberg B, Bex A, Lund L, Lyskjaer I, Fristrup N. Multicenter randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma receiving checkpoint inhibitors: the NORDIC-SUN-Trial. BMC Cancer. 2024 Feb 24;24(1):260. doi: 10.1186/s12885-024-11987-3.

Reference Type: DERIVED

PMID: 38402173 (View on PubMed)

Kuusk T, Abu-Ghanem Y, Mumtaz F, Powles T, Bex A. Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy. Curr Opin Urol. 2021 May 1;31(3):262-269. doi: 10.1097/MOU.0000000000000868.

Reference Type: DERIVED

PMID: 33742979 (View on PubMed)

Other Identifiers

NORDIC-SUN

Identifier Type: -

Identifier Source: org_study_id