2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Renal Cancer

Perioperative Systemic Therapy in High-Risk Renal Cell Carcinoma Following Nephrectomy: A Narrative Review - Beyond the Abstract

In our published review article, “Perioperative systemic therapy in high-risk renal cell carcinoma following nephrectomy,” we summarized the current evidence for the use of perioperative systemic therapies in patients with localized clear-cell RCC (ccRCC) at high risk for disease recurrence following surgery.1 Despite curative intent, a significant proportion of patients with localized disease experience recurrence, which has prompted immense interest in developing more effective treatment strategies.2

An adjuvant systemic treatment approach has been investigated given its potential to eliminate micrometastatic disease and improve survival outcomes.3 Most of the adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI) trials have yielded negative results with the exception of S-TRAC. Although the S-TRAC trial did show a disease-free survival (DFS) benefit, there was no overall survival (OS) benefit, and the high rate of toxicity precluded its use in clinical practice.3,4 More recently, there has been increased interest in the use of adjuvant immune checkpoint inhibitors (ICIs), given their efficacy in metastatic RCC. Currently, pembrolizumab is the only adjuvant ICI approved for use in patients with localized high-risk ccRCC based on results of the KEYNOTE-564 trial, which showed significantly improved DFS [HR 0.72, 95% CI 0.59−0.87] and OS [HR 0.62, 95% CI 0.44−0.87; P = 0.002].5 In KEYNOTE-564, high-risk ccRCC was defined as pT2 (grade 4 or sarcomatoid histology), ≥pT3, pTxN+, or M1 with no evidence of disease after resection; this represents the standard patient selection criteria to guide appropriateness for adjuvant treatment.6 By contrast, other major adjuvant or perioperative ICI trials (Checkmate-914, IMmotion010, PROSPER RCC) failed to show a survival benefit, likely due to differences in study design and inclusion criteria for high-risk disease.7–9

A neoadjuvant systemic treatment approach has also been evaluated in localized high-risk ccRCC. The rationale for this is based upon preclinical evidence of a more robust antitumor immune response due to enhanced T-cell priming on a tumor in situ.10 To date, several phase 2 TKI/ICI studies have illustrated potential benefits such as promoting tumor downstaging and improving surgical outcomes.11 However, its impact on survival outcomes remains less clear, and therefore, the use of neoadjuvant TKI/ICI remains limited to clinical trials.

Nevertheless, there continues to be significant interest in devising more effective treatment strategies. Several perioperative trials are currently underway, and these include: 1) RAMPART (NCT03288532) – adjuvant durvalumab +/- tremelimumab (anti-CTLA-4) versus observation; 2) LITESPARK-022 (NCT05239728) – adjuvant pembrolizumab +/- belzutifan (HIF-2α inhibitor); 3) INTERPATH-004 (NCT06307431) – adjuvant pembrolizumab +/- V940 (mRNA vaccine); and 4) NESCIO (NCT05148546) – neoadjuvant nivolumab +/- ipilimumab or relatlimab (anti-LAG-3).

Additionally, significant efforts are being made to identify novel biomarkers that can more accurately identify patients at the highest risk of recurrence following surgery and overcome limitations associated with contemporary risk models. About 50% of patients are overtreated based on current selection criteria. Circulating tumor DNA (ctDNA), defined as genetic material shed by tumor cells into the bloodstream, is emerging as a potential prognostic biomarker. One study utilized a tissue-informed ctDNA assay (SignateraTM) in 45 patients with localized RCC (≥cT1b) who underwent nephrectomy. Those with detectable ctDNA levels either before or after surgery had significantly worse recurrence-free survival than those with undetectable levels [HR 2.70, 95% CI: 1.02-7.15; P = 0.046; HR 3.23, 95% CI: 1.5-6.9; P = 0.003, respectively].12 Kidney injury molecule-1 (KIM-1), which is frequently overexpressed in RCC, is another promising prognostic biomarker. Higher KIM-1 levels post-nephrectomy have been shown to be associated with a higher risk of recurrence.13 Moreover, patients with higher baseline KIM-1 levels were enriched for improved response to adjuvant atezolizumab compared to placebo.14 However, these biomarkers need to be prospectively validated before becoming standard of care.

Written by: Adam Khorasanchi1 and Yuanquan Yang2

  1. Division of Hospital Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
  2. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
References:

  1. Khorasanchi A, Goodstein T, Dason S, Singer EA, Zimmerman D, Yang Y. Perioperative systemic therapy in high-risk renal cell carcinoma following nephrectomy: a narrative review. Transl Cancer Res. 2023 Jan;0(0):0–0.
  2. Labaki C, Choueiri TK. Perioperative immunotherapy for renal cell carcinoma: looking beyond the data. Nat Rev Clin Oncol. 2023 Feb 23;20(2):65–6.
  3. Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. New England Journal of Medicine. 2016 Dec 8;375(23):2246–54.
  4. Lenis AT, Donin NM, Johnson DC, Faiena I, Salmasi A, Drakaki A, et al. Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials. Journal of Urology. 2018 Jan;199(1):43–52.
  5. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. New England Journal of Medicine. 2024 Apr 18;390(15):1359–71.
  6. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. New England Journal of Medicine. 2021 Aug 19;385(8):683–94.
  7. Motzer RJ, Russo P, Grünwald V, Tomita Y, Zurawski B, Parikh O, et al. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. The Lancet. 2023 Mar;401(10379):821–32.
  8. Pal SK, Uzzo R, Karam JA, Master VA, Donskov F, Suarez C, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. The Lancet. 2022 Oct;400(10358):1103–16.
  9. Allaf ME, Kim SE, Master V, McDermott DF, Harshman LC, Cole SM, et al. Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study. Lancet Oncol. 2024 Aug;25(8):1038–52.
  10. Sinicrope FA, Turk MJ. Immune checkpoint blockade: timing is everything. J Immunother Cancer. 2024 Aug 28;12(8):e009722.
  11. Westerman ME, Shapiro DD, Wood CG, Karam JA. Neoadjuvant Therapy for Locally Advanced Renal Cell Carcinoma. Urologic Clinics of North America. 2020 Aug;47(3):329–43.
  12. Correa AF, Kalashnikova E, Wu HT, Winters RM, Balcioglu M, Sudhaman S, et al. Association of circulating tumor DNA with patient prognosis in surgically resected renal cell carcinoma. Oncologist. 2024 Oct 3;29(10):887–93.
  13. Xu W, Puligandla M, Halbert B, Haas NB, Flaherty KT, Uzzo RG, et al. Plasma KIM-1 Is Associated with Recurrence Risk after Nephrectomy for Localized Renal Cell Carcinoma: A Trial of the ECOG-ACRIN Research Group (E2805). Clinical Cancer Research. 2021 Jun 15;27(12):3397–403.
  14. Albiges L, Bex A, Suárez C, Uzzo R, Tang X, Assaf ZJ, et al. Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection. Journal of Clinical Oncology. 2024 Jun 1;42(16_suppl):4506–4506.
Read the Abstract