ASCO GU 2024: Update on Biomarkers in Renal Cell Carcinoma

( The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between January 25th and 27th was host to a session addressing the incorporation of radiation therapy, theranostics, and biomarkers into the management of renal cell carcinoma (RCC). Dr. David Braun provided an update on biomarkers in RCC.

Why do we need biomarkers in RCC? Given the emergence of numerous approved immunotherapy combinations (i.e., IO-IO and IO-TKI) over the past decade, we need a predictive biomarker that will help answer the question of what therapy combination a patient should receive. Prognostic biomarkers that predict prognoses and what chance the chosen therapy will work are also key to informing decision making and counseling patients. Does a patient need adjuvant therapy? A biomarker is key to answering that question, particularly in light of the recently presented KEYNOTE-564 trial that demonstrated an overall survival benefit for pembrolizumab in the adjuvant setting for select RCC patients post-nephrectomy. Additionally, will patients get toxicity, and to what degree with certain regimens? Biomarkers to help answer all these questions are of utmost importance.
Dr. Braun remarked that we cannot always draw parallels from other immunotherapy-responsive tumors, such as breast cancer and melanoma. In contrast to these cancers, RCC demonstrates only a modest tumor mutational burden. Additionally, while CD8+ T-cell infiltration is typically associated with improved outcomes in various solid organ malignancies, CD8+ T cell infiltration is historically associated with worse prognoses in RCC.
What are the current biomarker approaches in RCC?current biomarker approaches in RCC
Currently, the most actionable approach is with histology. One clear example of this is sarcomatoid and rhabdoid histologies which predict improved response with immune checkpoint inhibitors. In the CheckMate 214 trial, patients with such features had an ~50% durable progression-free survival.1 This has since been corroborated in “real world” and non-clear cell RCC cohorts.sarcomatoid and rhabdoid histologies
Another biomarker approach is with spatial phenotyping (immunohistochemistry, immunofluorescence). Significant work in this space comes from Dr. Signorretti’s lab, which evaluated CD8+ T-cell PD-L1 status and demonstrated that those tumors with a high preponderance of “antigen-experienced, but not terminally exhausted” T-cells (i.e., the most active T-cells) were more likely to derive benefit with immune checkpoint inhibitors, particularly with nivolumab.2 Additional work in this space demonstrated that tumors enriched with PD-1+ T-regulatory cells (typically suppress immunogenicity) are more likely to be resistant to immunotherapy.3
tumors enriched with PD-1+ T-regulatory cells
Next, with regards to genomics, Dr. Braun and colleagues have demonstrated that, in contrast to other tumors, the tumor mutational burden does not impact immune checkpoint inhibitor response in RCC. However, clonal (i.e., truncal) neoantigens, a surrogate of ‘bulk’ alterations, is associated with exceptional response to immune checkpoint inhibitors.tumor mutational burden does not impact immune checkpoint inhibitor response in RCC
When trying to evaluate the individual somatic genomic alterations, there was no clear answer (i.e., not one gene out there that will predict response). Dr. Braun and colleagues did note however that there is an interplay of tumor somatic genomic alterations and immunophenotype that impact immune checkpoint inhibitor therapy. While one expects that the CD8+ T-cell enriched/infiltrated tumors would fare better with ICIs, these tumors are enriched with 9p21.3 deletions that portend worse outcomes. Conversely, the ‘cold’, non-infiltrated tumors harbor the more favorable PBRM1 mutations, which predict improved prognoses.4 As such, we appreciate the complexity of these factors in this setting.PBRM1 mutations
Germline genetics may impact ICI response and immune-related toxicity, with evidence that HLA-A*03 carrier status is associated with ICI resistance and germline IL-7 variant is associated with increased ICI toxicity.Germline genetics may impact ICI response and immune-related toxicity
Transcriptomics have demonstrated that the expression of specific endogenous retroviruses is associated with ICI response. These retroviruses have long been embedded in our genetics and are typically dormant. However, this data suggests that when activated, they are associated with improved ICI responses.expression of specific endogenous retroviruses is associated with ICI response
Recent seminal work by Motzer et al. from the phase 3 IMmotion151 trial of atezolizumab + bevacizumab versus sunitinib identified seven different RCC molecular clusters. Dr. Braun highlighted two cluster groups: the angiogenic clusters (1 and 2) and the immunogenic/cell proliferative T-effector and cell cycle clusters. Patients in the 1st cluster fared well with sunitinib, whereas those in the immunogenic/cell proliferative cluster had a much better response with atezolizumab + bevacizumab.5RNA seq can help define distinct molecular substypes of RCC with differential ici
This RNA-seq-based biomarker approach is being prospectively evaluated in the OPTIC RCC prospective trial:OPTIC RCC prospective trial
What are some emerging biomarker approaches? Circulating, blood-based biomarkers such as cell-free methylated DNA are being assessed. Kidney tumors are ‘low shedding’ tumors and thus making the routine use of cfDNA challenging. However, by evaluating DNA methylation, and not just DNA mutations, cell-free methylated DNA levels are correlated with prognosis. Similarly, increased circulating KIM-1 levels have been associated with worse outcomes.Circulating blood-based biomarkers
Single-cell RNA-seq has uncovered co-evolving immune populations with RCC progression. T-cell exhaustion increases with advancing disease stage. Additionally, myeloid cells become increasingly more ‘pro-tumorigenic’ whereby M2-like genes are enriched in metastatic macrophages. Furthermore, there are interactions between the exhausted CD8 cells and M2-like tumor-associated macrophages, which leads to worse prognoses.exhausted CD8 cells and M2-like tumor-associated macrophages, which leads to worse prognoses
High-dimensional spatial phenotyping is another emerging area in this field. Spatial transcriptomics have identified IgG-producing tertiary lymphoid structures in ICI responders.Spatial transcriptomics have identified IgG-producing tertiary lymphoid structures in ICI responders 
Future directions in this field include:

  • Functional modeling with “living biomarkers”
  • Molecular imaging that may be able to capture dynamics and intertumoral heterogeneity
  • Multi-modal integration that leverages artificial intelligence technologies 

Dr. Braun concluded that:

  • Patients with sarcomatoid/rhabdoid clear cell RCC should be treated with a regimen containing PD-1 blockade
  • The development of putative RCC biomarkers is accelerating rapidly with utilization of conventional and emerging technologies
  • However, no other RCC biomarker is ready for routine use in the clinic
  • Current and future trials should aim to validate current and emerging biomarker approaches (e.g., OPTIC RCC)

Presented by: David A. Braun, MD, PhD, Assistant Professor of Medicine (Medical Oncology), Department of Medicine, Yale University, New Haven, CT

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024

  1. Tannir NM, Signorretti S, Choueiri TK, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma. Clin Cancer Res. 2021;27(1):78-86.
  2. Ficial M, Jegede OA, Sant’Angelo M, et al. Expression of T-Cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma. Clin Cancer Res. 2021;27(5):1371-1380.
  3. Denize T, Jegede OA, Matar S, et al. PD-1 Expression on Intratumoral Regulatory T Cells is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear Cell Renal Cell Carcinoma Patients. Clin Cancer Res. 2023.
  4. Braun DA, Hou Y, Bakouny Z, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26(6):909-918.
  5. Motzer RJ, Banchereau R, Hamidi H, et al. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade. Cancer Cell. 2020;38(6):803-817.
  6. Braun DA, Street K, Burke KP, et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell. 2021;39(5):632-648.