Immediate Versus Deferred Cytoreductive Nephrectomy With Ipilimumab/Nivolumab in mRCC

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

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.