Immediate Versus Deferred Cytoreductive Nephrectomy With Ipilimumab/Nivolumab in mRCC

Официальное название

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

Обзор

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

Подробное описание

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

Вмешательства

• Препарат 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).
• Процедура 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.

Первичные конечные точки

• Progression-Free Survival (PFS) assessed by RECIST version 1.1 [Срок оценки: Up to 15 months after treatment initiation]

Вторичные конечные точки (11)

• Overall Survival (OS) [Срок оценки: Up to 15 months after treatment initiation]
• Rate and Severity of Perioperative Complications Assessed by Clavien-Dindo Classification [Срок оценки: Within 90 days after cytoreductive nephrectomy]
• Rate and Severity of Perioperative Adverse Events Assessed by CTCAE v4.0 [Срок оценки: Within 90 days after cytoreductive nephrectomy]
• Radiologic Tumor Response Rate Assessed by RECIST v1.1 [Срок оценки: At baseline, at 12 weeks (after 4 cycles of ipilimumab/nivolumab induction therapy), and every 12 weeks thereafter up to 15 months]
• Rate of Unresectable Tumors in the Deferred Arm [Срок оценки: At the time of planned deferred cytoreductive nephrectomy]
• Early Disease Progression Rate Within 4 Weeks Post-Nephrectomy [Срок оценки: Within 4 weeks of cytoreductive nephrectomy]
• Rate of Open vs Minimally Invasive Surgical Approach [Срок оценки: At time of cytoreductive nephrectomy]
• Extent of Surgery (e.g., Radical vs Partial Nephrectomy; Lymphadenectomy Yes/No) [Срок оценки: At time of cytoreductive nephrectomy]
• Quality of Life Assessed by FACT-Kidney Symptom Index 15-item (FKSI-15) [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Esagian SM, Karam JA, Msaouel P, Makrakis D. Upfront Versus Deferred Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma: A Systematic Review and Individual Patient Data Meta-analysis. Eur Urol Focus. 2025 Jan;11(1):100-108. doi: 10.1016/j.euf.2024.08.002. Epub 2024 Sep 16. PMID 39289076
• Yoshino M, Ishihara H, Nemoto Y, Nakamura K, Nishimura K, Tachibana H, Fukuda H, Toki D, Yoshida K, Kobayashi H, Iizuka J, Shimmura H, Hashimoto Y, Tanabe K, Kondo T, Takagi T. Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Jpn J Clin Oncol. 2022 Oct 6;52(10):1208-1214. doi: 10.1093/jjco/hyac099. PMID 35780441
• Gross EE, Li M, Yin M, Orcutt D, Hussey D, Trott E, Holt SK, Dwyer ER, Kramer J, Oliva K, Gore JL, Schade GR, Lin DW, Tykodi SS, Hall ET, Thompson JA, Parikh A, Yang Y, Collier KA, Miah A, Mori-Vogt S, Hinkley M, Mortazavi A, Monk P, Folefac E, Clinton SK, Psutka SP. A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therap PMID 36441070
• Powles T, Blank C, Chowdhury S, Horenblas S, Peters J, Shamash J, Sarwar N, Boleti E, Sahdev A, O'Brien T, Berney D, Beltran L, Nathan P, Haanen J, Bex A. The outcome of patients treated with sunitinib prior to planned nephrectomy in metastatic clear cell renal cancer. Eur Urol. 2011 Sep;60(3):448-54. doi: 10.1016/j.eururo.2011.05.028. Epub 2011 May 17. PMID 21612860
• Bex A, Mulders P, Jewett M, Wagstaff J, van Thienen JV, Blank CU, van Velthoven R, Del Pilar Laguna M, Wood L, van Melick HHE, Aarts MJ, Lattouf JB, Powles T, de Jong Md PhD IJ, Rottey S, Tombal B, Marreaud S, Collette S, Collette L, Haanen J. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME PMID 30543350
• Mejean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell PMID 29860937
• Singla N, Hutchinson RC, Ghandour RA, Freifeld Y, Fang D, Sagalowsky AI, Lotan Y, Bagrodia A, Margulis V, Hammers HJ, Woldu SL. Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: An analysis of the National Cancer Database. Urol Oncol. 2020 Jun;38(6):604.e9-604.e17. doi: 10.1016/j.urolonc.2020.02.029. Epub 2020 Apr 3. PMID 32253116
• Mazzaschi G, Quaini F, Bersanelli M, Buti S. Cytoreductive nephrectomy in the era of targeted- And immuno- therapy for metastatic renal cell carcinoma: An elusive issue? A systematic review of the literature. Crit Rev Oncol Hematol. 2021 Apr;160:103293. doi: 10.1016/j.critrevonc.2021.103293. Epub 2021 Mar 2. PMID 33667661

Идентификаторы

NCT: NCT07233668 · 2502-014-1611

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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