Immediate Versus Deferred Cytoreductive Nephrectomy With Ipilimumab/Nivolumab in mRCC (IVE in mRCC)

November 25, 2025 updated by: Chang Wook Jeong, Seoul National University Hospital

Immediate Versus Deferred Cytoreductive Nephrectomy With Ipilimumab/Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: A Multicenter, Randomized, Open-Label, Phase III Trial

The goal of this clinical trial is to learn whether the timing of surgery (cytoreductive nephrectomy) improves outcomes when combined with immunotherapy (ipilimumab and nivolumab) in adults with metastatic clear cell renal cell carcinoma.

The main questions this study aims to answer are:

  • Does upfront (immediate) surgery before immunotherapy improve survival compared to delayed surgery after immunotherapy?
  • What medical problems (side effects or complications) occur with each treatment sequence?
  • How do the two strategies affect quality of life?

Researchers will compare two groups:

  • Upfront surgery group: Participants will have surgery first, then receive 4 cycles of ipilimumab/nivolumab, followed by nivolumab maintenance.
  • Deferred surgery group: Participants will receive 4 cycles of ipilimumab/nivolumab first, then surgery, followed by nivolumab maintenance.

Participants will:

  • Be randomly assigned to one of the two groups
  • Undergo regular clinic visits, imaging tests, and blood collections for safety and biomarker studies
  • Be followed for 15 months to check disease progression, complications, survival, and quality of life

This trial will help determine the best timing for surgery in the era of immunotherapy and provide evidence for improved treatment strategies for patients with metastatic kidney cancer

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a multicenter, randomized, open-label phase III trial designed to evaluate the optimal timing of cytoreductive nephrectomy (CN) in patients with synchronous metastatic clear cell renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors.

Although CN has historically been considered standard in mRCC, the timing of surgery (immediate vs deferred) remains controversial, particularly after the introduction of immune checkpoint blockade. Recent retrospective studies and meta-analyses suggest potential survival benefits of deferred CN following systemic therapy, but high-level prospective evidence is lacking.

In this study, participants with intermediate or poor IMDC risk mRCC will be randomized into two groups:

  • Upfront CN arm: Patients undergo immediate CN followed by 4 cycles of ipilimumab plus nivolumab (Ipi/Nivo) and then nivolumab maintenance.
  • Deferred CN arm: Patients receive 4 cycles of Ipi/Nivo induction first, followed by CN, and then nivolumab maintenance.

The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), perioperative morbidity, radiologic response, rate of unresectable tumors in the deferred group, impact of CN on early progression, surgical outcomes, and quality of life. Exploratory endpoints include biomarker studies using peripheral blood mononuclear cells (PBMCs) to characterize responders vs non-responders to Ipi/Nivo.

Patients will be followed for 15 months after treatment initiation, with regular imaging, clinical assessments, and laboratory monitoring. Approximately 172 patients across 12 institutions in Korea will be enrolled.

The results of this trial are expected to establish high-level evidence regarding the role and optimal timing of CN in mRCC, improve clinical decision-making, and provide guidance for treatment strategies in the immuno-oncology era

Study Type

Interventional

Enrollment (Estimated)

172

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Chang Wook Jeong, MD, PhD
  • Phone Number: +82-2-2072-3899
  • Email: drboss@snu.ac.kr

Study Contact Backup

  • Name: Jang Hee Han, MD, PhD
  • Phone Number: +82-2-2072-1486
  • Email: urohan@snu.ac.kr

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Participants must meet all of the following:
  • Age ≥ 19 years (male or female).
  • Histologically confirmed synchronous metastatic clear cell renal cell carcinoma.
  • ECOG performance status 0-1.
  • At least one measurable metastatic lesion (per RECIST v1.1).
  • Primary renal tumor considered surgically resectable.
  • IMDC intermediate- or poor-risk classification.
  • Estimated life expectancy > 3 months.
  • Ability to understand and voluntarily sign informed consent.

Exclusion Criteria:

  • Prior systemic therapy for metastatic RCC.
  • History of another malignancy diagnosed or treated within 2 years (except for cured non-melanoma skin cancer or in-situ cancers).
  • Significant comorbid conditions making participation inappropriate, such as:

Moderate to severe cardiovascular, cerebrovascular, pulmonary, or hepatic disease.

  • History or suspicion of autoimmune disease incompatible with immune checkpoint inhibitor therapy.
  • Requirement for systemic corticosteroid therapy >10 mg/day prednisone equivalent, or other immunosuppressive drugs.
  • Any other condition judged by the investigator to make the patient unsuitable for trial participation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Upfront Cytoreductive Nephrectomy (CN)
Participants will undergo immediate cytoreductive nephrectomy. About 4 weeks after surgery, they will receive induction therapy with ipilimumab plus nivolumab for 4 cycles, followed by maintenance nivolumab. Regular assessments of progression, perioperative complications, safety, and quality of life will be performed for 15 months.
Drug: Ipilimumab plus Nivolumab
Participants will receive 4 cycles of ipilimumab combined with nivolumab as induction therapy, followed by nivolumab maintenance depending on randomization schedule (before or after surgery).
Procedure: Cytoreductive Nephrectomy
Surgical removal of the primary kidney tumor (cytoreductive nephrectomy), performed either upfront (before systemic therapy) or deferred (after 4 cycles of ipilimumab/nivolumab induction), depending on randomization arm.
Experimental: Deferred Cytoreductive Nephrectomy (CN)
Participants will first receive 4 cycles of ipilimumab plus nivolumab induction therapy. After reassessment, they will undergo deferred cytoreductive nephrectomy, followed by maintenance nivolumab. Safety, perioperative complications, progression, and quality of life will be evaluated regularly for 15 months
Drug: Ipilimumab plus Nivolumab
Participants will receive 4 cycles of ipilimumab combined with nivolumab as induction therapy, followed by nivolumab maintenance depending on randomization schedule (before or after surgery).
Procedure: Cytoreductive Nephrectomy
Surgical removal of the primary kidney tumor (cytoreductive nephrectomy), performed either upfront (before systemic therapy) or deferred (after 4 cycles of ipilimumab/nivolumab induction), depending on randomization arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-Free Survival (PFS) assessed by RECIST version 1.1
Time Frame: Up to 15 months after treatment initiation
Time from randomization to first documented disease progression or death from any cause, whichever occurs first. Disease progression will be assessed according to RECIST version 1.1 criteria and clinical evaluation.
Up to 15 months after treatment initiation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: Up to 15 months after treatment initiation
Time from randomization to death from any cause.
Up to 15 months after treatment initiation
Rate of Unresectable Tumors in the Deferred Arm
Time Frame: At the time of planned deferred cytoreductive nephrectomy
Proportion of participants in the deferred arm with tumors deemed unresectable at surgery.
At the time of planned deferred cytoreductive nephrectomy
Rate and Severity of Perioperative Complications Assessed by Clavien-Dindo Classification
Time Frame: Within 90 days after cytoreductive nephrectomy
Proportion of patients experiencing perioperative complications graded using the Clavien-Dindo classification (Grades I-V).
Within 90 days after cytoreductive nephrectomy
Rate and Severity of Perioperative Adverse Events Assessed by CTCAE v4.0
Time Frame: Within 90 days after cytoreductive nephrectomy
Severity of postoperative adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Grade 1-5).
Within 90 days after cytoreductive nephrectomy
Radiologic Tumor Response Rate Assessed by RECIST v1.1
Time Frame: At baseline, at 12 weeks (after 4 cycles of ipilimumab/nivolumab induction therapy), and every 12 weeks thereafter up to 15 months
Rate of complete response (CR) and partial response (PR) to ipilimumab/nivolumab, assessed using RECIST version 1.1.
At baseline, at 12 weeks (after 4 cycles of ipilimumab/nivolumab induction therapy), and every 12 weeks thereafter up to 15 months
Early Disease Progression Rate Within 4 Weeks Post-Nephrectomy
Time Frame: Within 4 weeks of cytoreductive nephrectomy
Proportion of patients showing disease progression (PD) within 4 weeks after surgery in both arms.
Within 4 weeks of cytoreductive nephrectomy
Rate of Open vs Minimally Invasive Surgical Approach
Time Frame: At time of cytoreductive nephrectomy
Proportion of surgeries performed using open or minimally invasive techniques.
At time of cytoreductive nephrectomy
Extent of Surgery (e.g., Radical vs Partial Nephrectomy; Lymphadenectomy Yes/No)
Time Frame: At time of cytoreductive nephrectomy
Surgical extent categories documented at time of surgery.
At time of cytoreductive nephrectomy
Quality of Life Assessed by FACT-Kidney Symptom Index 15-item (FKSI-15)
Time Frame: Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months

Quality of life measured using the Functional Assessment of Cancer Therapy - Kidney Symptom Index 15-item (FKSI-15) questionnaire.

The total score ranges from 0 to 60, with higher scores indicating better quality of life and fewer kidney cancer-related symptoms.
Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months
Quality of Life Assessed by EORTC QLQ-C30
Time Frame: Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months
Patient-reported outcomes evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Scores for each domain range from 0 to 100.
Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months
Health Utility Score Assessed by EQ-5D-5L
Time Frame: Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months

Health status measured using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire.

The EQ-5D-5L utility index score typically ranges from <0 (health states worse than death) to 1 (full health), with higher scores representing better overall health status.

The EQ-VAS records self-rated health on a 0-100 scale, where higher scores indicate better perceived health.
Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Seoul National University Hospital

Investigators

  • Principal Investigator: Chang Wook Jeong, MD, PhD, Seoul National Universtiy Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 1, 2025

Primary Completion (Estimated)

October 1, 2028

Study Completion (Estimated)

February 1, 2029

Study Registration Dates

First Submitted

September 3, 2025

First Submitted That Met QC Criteria

November 14, 2025

First Posted (Estimated)

November 18, 2025

Study Record Updates

Last Update Posted (Estimated)

December 3, 2025

Last Update Submitted That Met QC Criteria

November 25, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2502-014-1611

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant-level data will not be shared due to privacy concerns and local regulations. Only aggregate study results will be published in peer-reviewed journals and scientific meetings.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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