Perioperative therapies for metastatic renal cell carcinoma

Abstract

Systemic therapy for metastatic renal cell carcinoma (mRCC) has advanced considerably over the past decade. Studies of systemic therapies in the adjuvant, neoadjuvant, and now perioperative settings as solitary, dual, and triplet combinations are underway. The timing of systemic therapy relative to extirpative surgery has yielded varying results. With the rise of novel therapeutics, new methods for risk stratification and patient selection, including initial biomarker evaluation, have begun. This perspective aims to summarize investigations into perioperative mRCC therapies and discuss the foundations of these concepts based on recent adjuvant and neoadjuvant trials, and to discuss future directions in this space.

Keywords

Metastatic renal cell carcinoma / perioperative therapy / neoadjuvant / adjuvant / cytoreductive nephrectomy / immune checkpoint inhibitor / tyrosine kinase inhibitor / clinical trials / biomarkers

References

[1] Siegel RL,Giaquinto AN,Jemal A.Cancer statistics, 2025.CA Cancer J Clin2025;75:10-45 PMCID:PMC11745215

[2] Rathmell WK,Van Veldhuizen PJ.Management of metastatic clear cell renal cell carcinoma: ASCO guideline.J Clin Oncol2022;40:2957-95

[3] Ljungberg B,Abu-Ghanem Y.European association of urology guidelines on renal cell carcinoma: the 2022 update.Eur Urol2022;82:399-410

[4] Mori K,Mostafaei H.The predictive value of programmed death ligand 1 in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors: a systematic review and meta-analysis.Eur Urol2021;79:783-92

[5] Lasorsa F,Rutigliano M.Immune checkpoint inhibitors in renal cell carcinoma: molecular basis and rationale for their use in clinical practice.Biomedicines2023;11:1071 PMCID:PMC10136190

[6] Fiorentino V,Larocca LM,Martini M.First-line ICIs in renal cell carcinoma.Hum Vaccin Immunother2023;19:2225386 PMCID:PMC10332208

[7] Napolitano L,Cirillo L.Cytoreductive nephrectomy and metastatic renal cell carcinoma: state of the art and future perspectives.Medicina2023;59:767 PMCID:PMC10143323

[8] Bex A,Jewett M.Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial.JAMA Oncol2019;5:164-70 PMCID:PMC6439568

[9] Méjean A,Thezenas S.Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma.N Engl J Med2018;379:417-27

[10] Bhindi B,Mason RJ.Comparative survival following initial cytoreductive nephrectomy vs. initial targeted therapy for metastatic renal cell carcinoma.J Urol2018;200:528-34

[11] García-Perdomo HA,Castillo-Cobaleda DF.Role of cytoreductive nephrectomy in the targeted therapy era: a systematic review and meta-analysis.Investig Clin Urol2018;59:2-9 PMCID:PMC5754578

[12] Versluis JM,Blank CU.Learning from clinical trials of neoadjuvant checkpoint blockade.Nat Med2020;26:475-84

[13] Westerman ME,Wood CG.Neoadjuvant therapy for locally advanced renal cell carcinoma.Urol Clin North Am2020;47:329-43

[14] Bex A,Blank C.Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: initial experience with downsizing to reconsider cytoreductive surgery.World J Urol2009;27:533-9

[15] Cowey CL,Pruthi RS.Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma.J Clin Oncol2010;28:1502-7

[16] de Velasco G,Guerrero-Ramos F.A case series of advanced renal cell carcinoma patients treated with neoadjuvant cabozantinib prior to cytoreductive nephrectomy within the phase 2 CABOPRE trial.Oncotarget2020;11:4457-62 PMCID:PMC7720770

[17] Hatiboglu G,Arslan A.Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma.Langenbecks Arch Surg2017;402:637-44

[18] Hellenthal NJ,Penetrante R.Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma.J Urol2010;184:859-64 PMCID:PMC3105599

[19] Karam JA,Urbauer DL.Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.Eur Urol2014;66:874-80 PMCID:PMC4396847

[20] Kroon BK,Prevoo W,Powles T.Probability of downsizing primary tumors of renal cell carcinoma by targeted therapies is related to size at presentation.Urology2013;81:111-5

[21] Lane BR,Kim HL.Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma.Urol Oncol2015;33:112.e15-21

[22] Lebacle C,Bernhard JC.Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study.BJU Int2019;123:804-10

[23] Rini BI,Elson P.The effect of sunitinib on primary renal cell carcinoma and facilitation of subsequent surgery.J Urol2012;187:1548-54

[24] Rini BI,Takagi T.A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma.J Urol2015;194:297-303

[25] Silberstein JL,Mehrazin R.Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery.BJU Int2010;106:1270-6

[26] Thomas AA,Lane BR.Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma.J Urol2009;181:518-23; discussion 523

[27] van der Veldt AA,van den Eertwegh AJ.Sunitinib for treatment of advanced renal cell cancer: primary tumor response.Clin Cancer Res2008;14:2431-6

[28] Zhang Y,Deng J,Yu H.Sorafenib neoadjuvant therapy in the treatment of high risk renal cell carcinoma.PLoS One2015;10:e0115896 PMCID:PMC4315594

[29] Bickley LJ,Jackson-Spence F.Systemic therapies and primary tumour downsizing in renal cell carcinoma: a real-world comparison of anti-angiogenic and immune checkpoint inhibition regimens.World J Urol2024;42:442

[30] Meerveld-Eggink A,Wilgenhof S.Primary renal tumour response in patients treated with nivolumab and ipilimumab for metastatic renal cell carcinoma: real-world data assessment.Eur Urol Open Sci2022;35:54-8 PMCID:PMC8738899

[31] Pignot G,Albigès L.Oncological outcomes of delayed nephrectomy after optimal response to immune checkpoint inhibitors for metastatic renal cell carcinoma.Eur Urol Oncol2022;5:577-84

[32] Shirotake S,Baba Y.Impact of cytoreductive nephrectomy following nivolumab plus ipilimumab therapy for patients with advanced renal cell carcinoma.Anticancer Res2022;42:2727-35

[33] Motzer RJ,McDermott DF.Nivolumab plus ipilimumab vs. sunitinib in advanced renal-cell carcinoma.N Engl J Med2018;378:1277-90

[34] Albiges L,Burotto M.First-line nivolumab plus ipilimumab vs. sunitinib in patients without nephrectomy and with an evaluable primary renal tumor in the CheckMate 214 trial.Eur Urol2022;81:266-71 PMCID:PMC10202028

[35] Shapiro DD,Zemp L.Cytoreductive nephrectomy following immune checkpoint inhibitor therapy is safe and facilitates treatment-free intervals.Eur Urol Open Sci2023;50:43-6

[36] Graafland NM,Tanabalan C.Surgical safety of deferred cytoreductive nephrectomy following pretreatment with immune checkpoint inhibitor-based dual combination therapy.Eur Urol Oncol2022;5:373-4

[37] Gerlinger M,Horswell S.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N Engl J Med2012;366:883-92

[38] Marandino L,Amparore D.Neoadjuvant and adjuvant immune-based approach for renal cell carcinoma: pros, cons, and future directions.Eur Urol Oncol2025;8:494-509

[39] Bex A,Van Thienen JV.Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).J Clin Oncol2022;40:289

[40] Au L,Robert de Massy M.Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.Cancer Cell2021;39:1497-518.e11

[41] Ghoreifi A,Yin M,Djaladat H.Immune checkpoint inhibitor therapy before nephrectomy for locally advanced and metastatic renal cell carcinoma: a review.JAMA Oncol2024;10:240-8

[42] Allaf ME,Master V.Perioperative nivolumab vs. observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.Lancet Oncol2024;25:1038-52

[43] Runcie K,Ornstein MC.Cyto-KIK: A phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib).J Clin Oncol2021;39:TPS4598

[44] Vaishampayan UN,Tripathi A.SWOG S1931 (PROBE): Phase III randomized trial of immune checkpoint inhibitor (ICI) combination regimen with or without cytoreductive nephrectomy (CN) in advanced renal cancer.J Clin Oncol2022;40:TPS402

[45] Iisager L,Donskov F.Multicenter randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma receiving checkpoint inhibitors: the NORDIC-SUN-Trial.BMC Cancer2024;24:260

[46] Choueiri TK,Park SH.Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma.N Engl J Med2021;385:683-94

[47] Choueiri TK,Park SH.Overall survival with adjuvant pembrolizumab in renal-cell carcinoma.N Engl J Med2024;390:1359-71

[48] Pal SK,Karam JA.Adjuvant atezolizumab vs. placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial.Lancet2022;400:1103-16

[49] Ryan CW,Heath EI.Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial.Lancet2023;402:1043-51

[50] Procopio G,Cognetti F.Sorafenib vs. observation following radical metastasectomy for clear-cell renal cell carcinoma: results from the phase 2 randomized open-label RESORT study.Eur Urol Oncol2019;2:699-707

[51] Choueiri TK,Karam JA.LITESPARK-022: a phase 3 study of pembrolizumab plus belzutifan as adjuvant treatment of clear cell renal cell carcinoma (ccRCC).J Clin Oncol2022;40:TPS4602

[52] Bedke J,Albiges L.Updated European association of urology guidelines on the use of adjuvant immune checkpoint inhibitors and subsequent therapy for renal cell carcinoma.Eur Urol2025;87:491-6

[53] Singla N,Ghandour RA.Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: an analysis of the National Cancer Database.Urol Oncol2020;38:604.e9-17 PMCID:PMC7269798

[54] Dason S,Heh V.Impact of preoperative systemic therapy on cytoreductive nephrectomy outcomes in the national surgical quality improvement program (NSQIP).Clin Genitourin Cancer2025;23:102258 PMCID:PMC11757078

[55] Reese SW,White C.Surgical outcomes of cytoreductive nephrectomy in patients receiving systemic immunotherapy for advanced renal cell carcinoma.Urol Oncol2024;42:32.e9-16 PMCID:PMC10922785

[56] A phase III study of neoadjuvant/adjuvant durvalumab for the treatment of patients with resectable stage II/III non-small cell lung cancer (AEGEAN): contribution of treatment phase in perioperative trials. FDA Oncologic Drugs Advisory Committee Meeting; 2024, p. 1-6. Available from: https://www.fda.gov/media/180308/download [Last accessed on 9 Jul 2025]

[57] Heymach JV,Mitsudomi T.Perioperative durvalumab for resectable non-small-cell lung cancer.N Engl J Med2023;389:1672-84

[58] Berry DA.Of adaptive and factorial designs: a biostatistician's interpretation of last week's ODAC.Cancer Lett2024;50:32-6Available from: https://cancerletter.com/trials-and-tribulations/20240802_4/ [Last accessed on 9 Jul 2025]

[59] Rossi SH,Jewett M.What is required to deliver practice-changing neoadjuvant trials in kidney cancer? An international neoadjuvant kidney cancer consortium delphi study.Ann Oncol2025;S0923-7534(25)00769

[60] Liu Q,Li S.Programmed death receptor (PD-)1/PD-ligand (L)1 in urological cancers: the "all-around warrior" in immunotherapy.Mol Cancer2024;23:183 PMCID:PMC11367915

[61] Germanà E,Pizzimenti C.Programmed cell death ligand 1 (PD-L1) immunohistochemical expression in advanced urothelial bladder carcinoma: an updated review with clinical and pathological implications.Int J Mol Sci2024;25:6750 PMCID:PMC11203574

[62] Elhanani O,Keren L.Spatial profiling technologies illuminate the tumor microenvironment.Cancer Cell2023;41:404-20

[63] Meylan M,Becht E.Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer.Immunity2022;55:527-41.e5

[64] Haas NB,Uzzo RG.Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.Lancet2016;387:2008-16 PMCID:PMC4878938

[65] Ravaud A,Pandha HS.Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy.N Engl J Med2016;375:2246-54

[66] Motzer RJ,Haas N.Adjuvant pazopanib vs. placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma: final overall survival analysis of the phase 3 PROTECT trial.Eur Urol2021;79:334-8

[67] Gross-Goupil M,Eto M.Axitinib vs. placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial.Ann Oncol2018;29:2371-8 PMCID:PMC6311952

[68] Eisen T,Oza B.Adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: results from the SORCE randomized phase III intergroup trial.J Clin Oncol2020;38:4064-75

[69] Motzer RJ,Grünwald V.Adjuvant nivolumab plus ipilimumab vs. placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial.Lancet2023;401:821-32

[70] Oza B,Smith B.RAMPART: a phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse.Contemp Clin Trials2021;108:106482 PMCID:PMC8520913