ASCO GU 2025: Biomarkers in Renal Cell Carcinoma: Dead End or Turning Point?

(UroToday.com) The 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Annual Symposium held in San Francisco, CA was host to a session on the current state and future directions of biomarkers and adjuvant therapy for renal cell carcinoma (RCC). Dr. Simpa Salami discussed the need for clinically actionable biomarkers to risk stratify patients, predict treatment responses for guiding decision making, and the incorporation of biomarkers and correlative studies into clinical trials.

There are currently 82,000 incident cases of RCC annually in the United States (account for 3–5% of cancers), with 15,000 deaths annually in the United States. The overall 5-year mortality risk is ~30%, and up to 10% for patients with clinically localized disease. This highlights the importance of biomarker to risk stratify patient.

We currently risk stratify patients using clinical and pathologic features using available nomograms, including the stage, size, grade, and necrosis [SSIGN] and Leibovich scores. However, such an approach does not account for the clinical, pathologic, and molecular heterogeneity that exists within and between these patients, and, thus, the potential variable responses to therapy.

To date, there have been five randomized controlled trials of adjuvant systemic therapy, of which one has shown an overall survival benefit (KEYNOTE-564: pembrolizumab)^1,2 and another a disease-free survival (DFS) benefit (S-TRAC: Sunitinib)³. Three trials in this space have failed to demonstrate any survival benefits:

• IMmotion 010: atezolizumab vs placebo   No benefit⁴
• Checkmate-914: nivolumab + ipilimumab vs placebo   No benefit^5,6
• PROSPER: nivolumab vs placebo   No benefit⁷

What were the selection criteria for the KEYNOTE-564 trial? Eligible patients were those with clear cell RCC and:

• pT2 disease + either grade 4 disease or sarcomatoid features present
• pT3-4 disease
• Positive regional lymph nodes
• Fully resected M1 disease (i.e, M1 NED)

The initial results of this trial demonstrated a DFS benefit for adjuvant pembrolizumab (HR: 0.72, 95%CI: 0.59–0.87). At 4 years, the DFS rates were 65% and 57%, respectively. While these improvements are encouraging, it does highlight the need for biomarkers to identify which patients may benefit from additional treatment intensification. The 4-year DFS of 65% indicates that 35% of patients did recur within 4 years, and, perhaps, they would have benefited from further systemic therapy intensification to reduce that 35% figure. Conversely, there are patients who do not require/benefit from adjuvant therapy and may experience treatment-related adverse events, with up to 21% of patients in the pembrolizumab group terminating treatment for toxicity, and 19% experiencing grade 3–4 toxicity.

What biomarkers are needed in this space? Prognostic biomarkers provide information on outcomes independent of the treatment received. Predictive biomarkers specifically identify response or resistance to a specific therapy – but not all treatments. Both are used to personalize therapy.

Dr. Salami noted that studies from the TCGA cohort have enhanced our understanding of kidney cancer biology and have identified several additional driving mutations, besides VHL, as well as highlighting the inter- and intra-patient tumoral heterogeneity.

What is the current landscape of genomic biomarkers in localized ccRCC, and have they shown any benefit?

• Modest or no improvement in risk stratification:
  • Mutations: VHL, PBRM1, SETD2, BAP1, and KDM5C .
  • CNV: 3p, 9p and 14q loss; 5q and 8q gain, amongst others.
  • PD-1/PDL-1 expression.
  • TMB/TNB.
• Some association with oncologic outcomes
  • Multigene signatures.
    • ClearCode34.
    • Cell Cycle Progression (CCP) Score.
    • 16-gene assay (Rini et al).
    • EMT pathway.
    • 15G Score.
  • Markers of tumor immune microenvironment (TIME)

Recently, Dr. Salami’s team developed and validated a novel 15-gene (15G) prognostic signature to improve risk stratification of patients with ccRCC. They retrospectively identified 110 patients who underwent radical nephrectomy for ccRCC (discovery cohort). Patients who recurred were matched on the basis of grade/stage to patients without recurrence. Capture whole-transcriptome sequencing was performed on RNA isolated from archival tissue. They developed a gene-expression signature to predict recurrence-free survival/disease-free survival using a 15-fold lasso and elastic-net regularized linear Cox model. A 31-gene cell cycle progression (mxCCP) score was generated using RNA-seq data for each patient.

The 15G signature was independently associated with worse disease-free (HR: 11.1) and disease-specific survivals (HR: 9.7) in multivariable models adjusted for clinicopathologic parameters (including SSIGN score and Memorial Sloan Kettering Cancer Center nomogram) and mxCCP score. These results were validated in two additional validation sets.⁸

Studies of biomarkers in this setting must account for tumor heterogeneity. 63–69% of all somatic mutations are not detectable across every tumor region. Gene expression signatures of both good and prognosis can be detected in different regions of the same tumor.

This is where he believes that liquid biomarkers may have an advantage over tissue biomarkers, due to their ability to capture this heterogeneity. One possible biomarker in this setting is ctDNA. In a study of 69 patients with ≥pT1b disease, pre-operative ctDNA was positive in 61% and positive post-operatively in 6%. Patients with a positive ctDNA status post-operatively had significantly worse recurrence-free survival posts (HR: 3.23, p=0.003).⁹

He noted that these liquid biomarkers may help in:

• Early detection of relapse
• Monitor disease progression
• Monitor treatment response
• Identify patients for neoadjuvant or adjuvant treatment

Another emerging biomarker is Kidney Injury Molecule-1 (KIM-1), as both a diagnostic and prognostic biomarker. KIM-1 is a transmembrane protein that is overexpressed in ccRCC. The KIM-1 ectodomain is detectable in plasma and serum and is an emerging circulating biomarker for ccRCC. Prior studies have shown that high circulating KIM-1 is a biomarker for:^10-13

• Early detection and risk stratification of RCC
• Higher risk of recurrence after nephrectomy (ASSURE, CM 914, IMmotion010)
• Potential benefit from adjuvant immunotherapy (CM 914 Part A, IMmotion010)

In a prior exploratory analysis of a metastatic RCC trial (CheckMate 009):¹⁴

• Higher baseline KIM-1 was associated with worse overall survival
• Early decrease in KIM-1 from baseline to 3 weeks was positively associated with improved PFS to Nivolumab

Dr. Salami acknowledged the emerging role of artificial intelligence in this setting, which may allow for the interpretation and collation of imaging findings (radiomics), pathologic information, and clinical features into multifaceted nomograms, similar to what has been already achieved in the prostate cancer space (e.g., ArteraAI).

How do we implement biomarkers into clinical practice? There are notable barriers to adoption, which include:

1. Access
2. Cost
3. Lack of standardization
4. Limited validation studies
5. Reproducibility
6. Unclear actionable information

How do we possibly overcome these limitations?

1. Insurance coverage
2. Robust validation framework
3. Academic/industry partnerships
4. Biomarker-informed clinical trials
5. Policy support for development (e.g., FDA)

Dr. Salami summarized the potential benefits of kidney cancer biomarkers at the provider, payer/insurer, and patient levels:

Potential clinical scenarios where biomarkers may be of benefit to kidney cancer patients include:

• Small renal masses: Decision for treatment versus surveillance
• Large renal masses:
  • Surveillance versus adjuvant therapy after nephrectomy
  • Neoadjuvant versus adjuvant treatment 

Presented by: Simpa Salami, MD, MPH, Associate Professor, Department of Urology, University of Michigan, Ann Arbor, MI

Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025. 

References:

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2. Choueiri TK, Tomczak P, Park SH, et al. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. N Engl J Med. 2023; 388(17):1665-1676.
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